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Periodontitis is an oral chronic inflammatory disease. Inhibiting tissue destruction and promoting tissue regeneration are important means for the treatment of periodontitis. Metformin not only has hypoglycemic effect but also has anti-inflammatory effect. Metformin has been shown to inhibit oxidative stress and activate autophagy through AMPK/mTOR pathway. High mobility group box 1 (HMGB1) has been implicated in the pathogenesis of many inflammatory diseases including periodontitis, it can participate in the induction of oxidative stress. HMGB1 is an autophagy regulator under oxidative stress, which can activate mTOR pathway. However, it is not clear whether metformin is related to HMGB1 and its mechanism in the process of periodontitis. Cell viability and expression of inflammatory cytokines were clarified by Cell Counting Kit-8, real-time PCR and enzyme-linked immunosorbent assay. Western blot and immunofluorescence were conducted to determine HMGB1 intracellular localization and expression of autophagy-associated proteins in vitro. Experimental periodontitis mice model was induced by administering a ligature. Immunohistochemistry was performed to detect the expression and localization of HMGB1 in vivo. The results of CCK-8, real-time PCR, enzyme-linked immunosorbent assay, Western blot and immunofluorescence showed lipopolysaccharide (LPS) treatment inhibited cell viability, and increased HMGB1 expression at a dose-independent manner. Metformin can reduce the effect of LPS. It also improves autophagy pathway inhibited by LPS and down-regulates mTOR expression. In addition, metformin attenuated alveolar bone resorption induced by ligation. This study provides new evidence for that metformin is a potential drug for the treatment of periodontitis and HMGB1 may be a potential target for periodontal intervention.

Danon disease (DD) is an X-linked multisystem disorder with clinical features characterized by the triad of hypertrophic cardiomyopathy, skeletal muscle weakness, and mental retardation. Cardiac involvement can be fatal in the absence of an effective treatment option such as heart transplantation. Molecular studies have proved that LAMP-2 protein deficiency, mainly LAMP-2B isoform, resulting from LAMP2 gene mutation, is the culprit for DD. Autophagy impairment due to LAMP-2 deficiency mediated the accumulation of abnormal autophagic vacuoles in cells. While it is not ideal for mimicking DD phenotypes in humans, the emergence of LAMP-2-deficient animal models and induced pluripotent stem cells from DD patients provided powerful tools for exploring DD mechanism. In both in vitro and in vivo studies, much evidence has demonstrated that mitochondria dysfunction and fragmentation can result in DD pathology. Fundamental research contributes to the therapeutic transformation. By targeting the molecular core, several potential therapies have demonstrated promising results in partial phenotypes improvement. Among them, gene therapies anticipate inaugurate a class of symptom control and prevention drugs as their in vivo effects are promising, and one clinical trial is currently underway.

Background Growing evidence has revealed abnormalities in the retinal structure of patients with alopecia areata (AA). However, the relationship between AA and retinopathy remains unclear. Objective To investigate the association between AA and retinal diseases. Method The study participants were recruited from the National Health Insurance Research Database in Taiwan. We included 9,909 patients with AA and 99,090 matched controls to assess the risk of retinal diseases. A Cox regression model was used for all analyses. Results Compared with the controls, patients with AA had an adjusted hazard ratio (aHR) of 2.96 (95% confidence interval [CI], 2.20–3.98) for retinal diseases. With respect to individual retinal disease, AA patients had a significantly higher risk of developing retinal detachment (aHR, 3.80; 95% CI, 1.97–7.31), retinal vascular occlusion (aHR, 2.14; 95% CI, 1.09–4.19), and retinopathy (aHR 3.18; 95% CI 2.21–4.57) than controls. Limitations This is a retrospective cohort study. Meanwhile, almost all the participating individuals were residents of Taiwan; therefore, the validity of our findings in other demographics remains unclear. Conclusion Patients with AA had a significantly higher risk of retinal disease than the controls. Further studies are needed to clarify the pathophysiology of AA and retinal diseases.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the heterogeneity of early PD leads to inter-rater and intra-rater variability in observation-based clinical assessment. Thus, objective monitoring of PD-induced motor abnormalities has attracted significant attention to manage disease progression. Here, we proposed a hierarchical architecture to reliably detect abnormal characteristics and comprehensively quantify the multi-symptom severity in patients with PD. A novel wearable device was designed to measure motor features in fifteen PD patients and fifteen age-matched healthy subjects, while performing five types of motor tasks. The abnormality classes of multi-modal measurements were recognized by hidden Markov models (HMMs) in the first layer of the proposed architecture, aiming at motivating the evaluation of specific motor manifestations. Subsequently, in the second layer, three single-symptom models differentiated PD motor characteristics from normal motion patterns and quantified the severity of cardinal PD symptoms in parallel. In order to further analyze the disease status, the multi-level severity quantification was fused in the third layer, where machine learning algorithms were adopted to develop a multi-symptom severity score. Experimental results demonstrated that the quantification of three cardinal symptoms were highly accurate to distinguish PD patients from healthy controls. Furthermore, strong correlations were observed between the Unified Parkinson’s Disease Rating Scale (UPDRS) scores and the predicted sub-scores for tremor (R=0.75, P=1.40e-3), bradykinesia (R=0.71, P=2.80e-3) and coordination impairments (R=0.69, P=4.20e-3), and the correlation coefficient can be enhanced to 0.88 (P=1.26e-5) based on the fusion schemes. In conclusion, the proposed assessment architecture holds great promise to push forward the in-home monitoring of clinical manifestations, thus enabling the self-assessment of disease progression.

This study aims to find out the possible optimal therapy and assess the prognosis properly for patient with spontaneous rupture of hepatocellular carcinoma (HCC).Propensity score matching (PSM) analysis was used to study the data from 325 patients with ruptured HCC (RHCC) and 2,291 patients with non-RHCC.The incidence and hospital mortality of RHCC were 5.1% and 0.8% respectively, with a median overall survival (OS) time of 17 months. There was no difference between ruptured and non-RHCC patients undergoing conservation treatment in terms of OS. Trans-arterial embolization (TAE) was carried out in 69 (21.2%) cases with RHCC, with a median OS of 7 months, which was no difference from that of non-RHCC (pre- and post-PSM). One hundred and sixty-nine (52.0%) RHCC cases underwent one-stage hepatectomy, with a median OS and disease-free survival (DFS) of 30 and 6 months respectively, which were shorter than that of non-RHCC (post-PSM). TAE plus two-stage hepatectomy was performed in 30 RHCC cases, with a median OS and DFS of 28 and 10 months respectively; these outcomes were better than that from RHCC patients undergoing TAE alone or one-stage hepatectomy (post-PSM), which were no difference from that of non-RHCC patients undergoing hepatectomy. The risk of death for RHCC patient undergoing one-stage hepatectomy is 1.545 times higher than that of one undergoing TAE + two-stage hepatectomy.TAE plus two-stage hepatectomy might be the optimal treatment for RHCC patient. Under the premise of the same pathological properties, there is no difference in prognosis between ruptured and non-RHCC patients if the therapy is appropriate.

Background/aimsFuchs’ uveitis syndrome (FUS) is one of the frequently misdiagnosed uveitis entities, which is partly due to the absence of internationally recognised diagnostic criteria. This study was performed to develop and evaluate a set of revised diagnostic criteria for FUS.MethodsThe clinical data of Chinese patients with FUS and patients with non-FUS were collected and analysed from a tertiary referral centre between April 2008 and December 2020. A total of 593 patients with FUS and 625 patients with non-FUS from northern China were enrolled for the development of diagnostic criteria for FUS. Three hundred and seventy-seven patients with FUS and 503 patients with non-FUS from southern China were used to validate the criteria. Clinical symptoms and ocular signs were collected from all patients with FUS and patients with non-FUS. Multivariate two-step cluster analysis, logistic regression and decision tree algorithms in combination with the clinical judgement of uveitis experts were used to revise diagnostic criteria for FUS.ResultsThree essential findings including diffuse iris depigmentation, absence of posterior synechiae, mild inflammation in the anterior chamber at presentation and five associated findings including mostly unilateral involvement, cataract, vitreous opacities, absence of acute symptoms and characteristic iris nodules were used in the development of FUS diagnostic criteria. All essential findings were required for the diagnosis of FUS, and the diagnosis was further strengthened by the presence of associated findings.ConclusionRevised diagnostic criteria for FUS were developed and validated by analysing data from Chinese patients and showed a high sensitivity (96.55%) and specificity (97.42%).

Purpose This study examined the efficacy of prescribing antibiotics, specifically a single dose of vancomycin, in reducing the incidence of culture-positive and culture-negative sepsis prior to the removal of peripherally inserted central catheters (PICCs). Materials and methods We retrospectively reviewed charts of infants who had PICCs in a tertiary level hospital during the period from 2010 to 2019. The incidence of post-catheter removal clinical sepsis between the groups with or without antibiotics was compared. The antibiotic group was defined by receiving a single dose of vancomycin or any other antibiotic prior to line removal. Results We enrolled 585 PICC removal episodes in 546 infants for analysis. Antibiotics were given prior to removal in 257 cases (43.9%) and not given prior to removal in 328 cases (56.1%). There were 13 episodes of post-catheter removal clinical sepsis detected within 72 h (2.2%), 2 of which were culture-positive (0.3%). A 9.3-fold decrease in the odds for clinical sepsis was observed in the antibiotic group (p = 0.01). The incidence of post-catheter removal sepsis was decreased by a single prophylactic dose of vancomycin (p = 0.02), whereas the use of other antibiotics showed no effect (p = 0.35). Logistic regression analysis demonstrated that comorbidities with gastrointestinal diseases (p = 0.01), PICC insertion sites in the scalp and neck (p = 0.04), and no vancomycin administration prior to line removal (p = 0.02) were independent risk factors for subsequent clinical sepsis. Conclusion A single prophylactic dose of vancomycin prior to PICC line removal might reduce clinical sepsis events in infants.

Background: Since the increasing use of asbestos occurred in China and the long latency period after asbestos exposure, predicting the incidence of malignant mesothelioma played an important role in attracting the attention of clinicians. The Bayesian age-period-cohort prediction model was fitted to predict the development trend from 2016 to 2030 based on the publicly available data of the national cancer registration network. Methods: Malignant mesothelioma incidence data were retrieved from the national cancer registration annual reports from 2005 to 2015. The Bayesian Age-Period-Cohort (APC) Modeling and Prediction package (Institute of Biomedical Engineering, Imperial College, London, UK) was used to describe the trend of malignant mesothelioma incidence and to predict the incidence rate and number of cases until the year of 2030. Findings: The crude incidence rates of malignant mesothelioma decreased from 0.22 per 100 000 in 2005 to 0.16 per 100000 in 2015. After age standardization, the incidence rates remained stable over the 11-year period. The trends were mainly caused by aging. The Bayesian APC model showed that increased from 0.14 per 100 000 in 2016 to 0.19 per 100000 in 2030 and the estimated number of new incident cases was predicted to increase to 2775 in 2030. The age-standardized incidence rate would remain steady. Interpretation: The incidence of malignant mesothelioma would remain stable in the next ten years, but due to its high degree of malignancy, the cancer still needs to be taken more attention at. Funding: Ministry of Science and Technology of the People's Republic of China; Beijing Hope Run Special Fund; Chinese Academy of Medical Sciences; Beijing Municipal Health Commission. Conflict of Interest: All authors declare no competing interests.

Background Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear. Methods We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo. Results Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities. Conclusions CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.

Objective Defects in the human solute carrier family 26 member 4 (SLC26A4) gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC26A4 mutations in Chinese patients with CH and analyze the function of the mutations. Methods 273 patients with primary CH were screened for 21 CH candidate genes mutations by targeted next-generation sequencing. All the exons and exon-intron boundaries of SLC26A4 were found and analyzed. The function of 6 missense mutation in SLC26A4 were further investigated in vitro. Results Among 273 patients with CH, 7 distinct SLC26A4 heterozygous mutations (p.S49R, p.I363L, p.R409H, p.T485M, p.D661E, p.H723R, c.919-2A>G) were identified in 10 patients (3.66%, 10/273). In vitro experiments showed that mutation p.I363L, p.R409H,p.H723R affect the membrane location and ion transport of SLC26A4, ,while p.S49R did not.Mutation p.T485M and p.D661E only affect the ion transport, but has no effect on the membrane location. Conclusion Our study indicated that the prevalence of SLC26A4 mutations was 3.66% in the Chinese patients with CH. Five mutations (p.I363L, p.R409H, p.T485M, p.D661E and p.H723R) impaired the membrane location or ion transport function of SLC26A4，which revealed important role of the Ile363,Arg409, Thr485, Asp661, His723 residues in function of SLC26A4. Because these mutations are heterozygous mutations, the pathogenesis of these patients cannot be explained, and the pathogenesis of these patients needs further study.

BACKGROUND Although endoscopy is the gold standard to assess disease activity and infliximab efficacy in inflammatory bowel disease (IBD), the invasive, costly, and time-consuming procedure limits its routine applications. We aimed to investigate the clinical value of serum oncostatin M (OSM) as a surrogate biomarker. METHODS Fifty healthy controls, 34 non-IBD patients, and 189 IBD patients who were pre-infliximab treatment (n = 122) or in infliximab maintenance (n = 67) were enrolled. A chemiluminescence immunoassay (CLIA) was constructed to quantify serum OSM concentrations. Receiver operator characteristic (ROC) curve analysis was used to evaluate the performance of blood biomarkers for IBD management. RESULTS The methodology of CLIA exhibited great analytical performance with a wide linear range of 31.25-25000 pg/mL, a low detection limit of 23.2 pg/mL, acceptable precision, and applicable accuracy. Patients with IBD (121.5 [43.3-249.4] pg/mL, p

Nondipping heart rate (HR), defined as a night/day HR ratio0.90, has been associated with increased mortality in epidemiologic studies. However, its prognostic value in stage 5 chronic kidney disease (CKD5) patients and the effects of parathyroidectomy (PTX) on nondipping HR remain unknown.This case-control study of 162 healthy controls and 502 CKD5 patients was performed between 2011 and 2018, in which CKD5 patients were further divided into non-PTX (n = 186) and severe secondary hyperparathyroidism (SHPT) with PTX (n = 316) subgroups. Each participant underwent 24-hour Holter monitoring for HR ratio. Mortality was followed up in CKD5 patients (median time: 46.0 months).The HR ratio in CKD5 patients was higher than in controls (0.92 ± 0.08 vs 0.81 ± 0.08, P.001), associated with a 44% increase in mortality risk per 0.1 increment (hazard ratio, 1.44; 95% CI: 1.02-2.03; P =.04), and was positively related to serum intact parathyroid hormone levels (P.001). PTX reversed nondipping HR in SHPT patients (n = 50, median time: 6.3 months, P.001). Survival probabilities for PTX (n = 294) were better than non-PTX (n = 47) (hazard ratio, 0.31; 95% CI: 0.14-0.67; P.01) in SHPT patients (serum intact parathyroid hormone500.0 pg/mL).CKD5 patients displayed a nondipping HR pattern, which is a prognostic marker of all-cause mortality. PTX for SHPT patients was associated with a reversal in nondipping HR ratio, which may mediate a better outcome.

AIMS Culprit-plaque morphology [plaque rupture (PR) and plaque erosion (PE)] and high-risk plaques (HRP) identified by optical coherence tomography (OCT) and residual SYNTAX score (rSS) have been reported to influence clinical outcomes. Thus, in this study, we aimed to investigate the prognostic implication of culprit-plaque morphology and rSS for major adverse cardiovascular events (MACE) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS Based on plaque morphology and rSS, 274 STEMI patients were divided into 4 groups: PE/low-rSS (n=61), PE/high-rSS (n=58), PR/low-rSS (n=55), and PR/high-rSS (n=100). According to HRP and rSS, patients were stratified to non-HRP/low-rSS (n=97), non-HRP/high-rSS (n=109), HRP/low-rSS (n=19), and HRP/high-rSS (n=49). MACE was defined as the composite of all-cause death, recurrence of myocardial infarction, stroke, and unplanned revascularization of any coronary artery. RESULTS During the follow-up of 2.2 years, 47 (17.2%) MACE were observed. Patients with PR/high-rSS and HRP/high-rSS presented lower survival probability on revascularization and MACE. In fully adjusted analyses, PR/high-rSS group presented higher MACE risk than PE/low-rSS (HR: 4.80, 95% CI: 1.43-16.11, P=0.025). Patients with non-HRP/high-rSS (HR: 2.90, 95% CI: 1.01-8.38, P=0.049) and HRP/high-rSS (HR: 8.67, 95% CI: 2.67-28.21, P＜0.001) presented higher risk of cardiac events than non-HRP/low-rSS. Adding rSS and HRP to the risk prediction model increased the C-statistic to 0.797 (95% CI: 0.737-0.857), with ΔC-statistic of 0.066 (P=0.002) and the NRI (46.0%, 95% CI: 20.5-56.8%, P＜0.001) and IDI (8.7%, 95% CI: 3.6-18.2%, P＜0.001). CONCLUSION High-risk plaques in combination with rSS enhanced the predictive ability for MACE, indicating culprit-plaque features and residual atherosclerosis burden should be taken into account in risk stratification of STEMI patients.

Background: Colorectal peritoneal carcinomatosis (CRPC) is a primary cause of death in colorectal cancer (CRC) patients. In the past, computed tomography (CT) has been the primary method used to ev...

Sinomenine (SIN) is commonly used as part of rheumatoid arthritis (RA) therapy in China, but there is still no published evidence of the efficacy of SIN monotherapy. This work investigates the efficacy and safety of SIN in treating RA patients and analyzes the correlation between ornithine level and the alleviation of disease activity in RA patients. In this 24 week, randomized, placebo-controlled, double-blind clinical trial, people with mild to moderate RA were randomly assigned (1:1:1, stratified by hospital) to receive SIN (120 mg, twice daily), methotrexate (MTX) (10 mg per week), or SIN + MTX therapy. The primary outcome was the proportion of patients who achieved a 50% improvement in the American College of Rheumatology (ACR) criteria at week 24 and who showed improvement according to the clinical disease activity index (CDAI). In this prospective subgroup analysis, we also assessed whether the 24 week alterations of disease activity in the treatment group were significantly correlated to the levels of blood ornithine. Of the 135 enrolled participants, 38, 39, and 36 patients were treated with SIN, MTX, and SIN + MTX, respectively. In the SIN-treated group, 52.63% of patients achieved ACR50 after 24 weeks of treatment, which was comparable to the results in the MTX-treated and SIN + MTX-treated groups. Hepatic and gastrointestinal disorders were the main adverse events; however, the ratio of patients suffering from hepatic disorder in the SIN group (1/38) was much lower than that in the MTX (10/39) and SIN + MTX (8/36) groups. A total of 221 serum samples were collected at the four follow-up time points in the three treatments, and the levels of ornithine, citrulline, and arginine were obtained through ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). The serum ornithine level decreased after the 24 week treatment along with a decrease in disease activity, and may reflect therapeutic responses with a sensitivity value of 80%. In conclusion, SIN revealed a comparable efficacy to MTX for treating RA patients, but with fewer side effects. In addition, the serum ornithine level was found for the first time to have a close correlation with the alleviation of RA, which shows the value of this measure as an assessment indicator of drugs in treating RA.

Background/Purpose The long-term disease course and efficacy of maintenance therapies have rarely been investigated in Asian patients with neuromyelitis optica spectrum disorder (NMOSD). Methods Medical records of patients fulfilling the 2015 International Consensus Diagnostic Criteria for NMOSD at three medical centers in Taiwan were systematically analyzed. Linear regression analysis was performed to investigate factors related to annualized relapse rate (ARR); survival analysis was used to estimate the relapse-free intervals among therapies. Results A total of 557 relapses affecting 648 regions (202 optic neuritis, 352 acute myelitis, and 94 brain syndromes) in 204 patients were analyzed during a follow-up period of 69.5 months (range, 1–420). Up to 36.1% of myelitis-onset patients and 24.0% of optic neuritis-onset patients exhibited a limited form disease, defined as having one or more relapses confined to the same region. The median ARR was significantly lower in patients with limited form disease than those with relapses involving multiple regions (0.30 vs. 0.47, respectively). An older age at disease onset was associated with a lower ARR (p = 0.023). Kaplan–Meier analysis showed that the estimated time (months) to next relapse was longest in rituximab-treatment group (58.0 ± 13.2), followed by immunosuppressant (48.5 ± 4.8) or prednisone (29.6 ± 4.6) groups, and shortest in those without maintenance therapy (27.6 ± 4.2) (p = 8.1 × 10−7). Conclusion Limited form disease and older age at disease onset are associated with a lower relapse rate in NMOSD. Compared to no maintenance therapy, rituximab and immunosuppressant significantly reduce the relapse risks.

Vogt-Koyanagi-Harada disease (VKH) is a rare autoimmune disease characterized by diffuse and bilateral uveitis, alopecia, tinnitus, hearing loss, vitiligo and headache. The transcriptional expression pattern of peripheral blood mononuclear cells (PBMC) in VKH remains largely unknown. In this study, mRNA sequencing was conducted in PBMC from VKH patients with active uveitis before treatment (n = 7), the same patients after prednisone combined with cyclosporine treatment (n = 7) and healthy control subjects strictly matched with gender and age (n = 7). We found 118 differentially expressed genes (DEGs) between VKH patients and healthy control subjects, and 21 DEGs between VKH patients before and after treatment. TRIB1 was selected as a potential biomarker to monitor the development of VKH according to the mRNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to predict the possible biological functions and signaling pathways of DEGs. Neutrophil degranulation, peptidase regulator activity, secretory granule membrane, cellular response to peptide, growth factor binding and cell projection membrane were enriched as GO annotations of DEGs. Arachidonic acid metabolism and mitogen-activated protein kinase (MAPK) signaling pathway were potential signaling pathways involved in pathogenesis and drug response of VKH. A protein–protein interaction (PPI) network was constructed by STRING, and colony stimulating factor 1 receptor (CSF1R) was identified as the hubgene of all DEGs by Cytoscape. The cell type presumed to contribute to the aberrant expression of DEGs was analyzed with the use of publicly available single-cell sequencing data of PBMC from a healthy donor and single-cell sequencing dataset of monocytes from VKH patients. Our findings may help to decipher the underlying cellular and molecular pathogenesis of VKH and may lead novel therapeutic applications.

BACKGROUND Geographic isolation and travel distance to specialist care is a known social determinant of health and contributes to poorer oncology survival outcomes. AIMS Our objective was to compare survival and toxicity outcomes for patients travelling long distances (>50 km) for treatment on clinical trials with local patients (

Transcatheter aortic valve implantation is a fast-growing procedure. Expanding to low-risk patients, it has surpassed surgical aortic valve implantation in frequency and has been associated with excellent outcomes. Stroke is a devastating complication after transcatheter aortic valve implantation. Silent brain infarcts identified by diffusion-weighted magnetic resonance imaging are present in most patients following transcatheter aortic valve implantation. Postoperative delirium and cognitive dysfunction are common neurologic complications. The stroke and silent brain infarcts are likely caused by particulate emboli released during the procedure. Intravascularly positioned cerebral embolic protection devices are designed to prevent debris from entering the aortic arch vessels to avoid stroke. Despite promising design, randomized clinical trials have not demonstrated a reduction in stroke in patients receiving cerebral embolic protection devices. Similarly, the association of cerebral embolic protection devices with silent brain infarcts, post-operative delirium and cognitive dysfunction is uncertain. Monitored anesthesia care or conscious sedation is as safe as general anesthesia and is associated with lower cost but different anesthetic techniques have not been shown to decrease stroke risk, postoperative delirium, or cognitive dysfunction. Anesthesiologists play important roles in providing perioperative care including management of neurologic events in patients undergoing transcatheter aortic valve implantation. Large randomized clinical trials are needed that focus on the correlation between perioperative interventions and neurologic outcomes.

Background: The treatment and survival rate of patients with metastatic prostate cancer (MPCa) remain unsatisfactory. Herein, the authors investigated the clinical value and potential mechanisms of cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) in MPCa to identify novel targets for clinical diagnosis and treatment. Materials and Methods: mRNA microarray and RNA-Seq (n = 1246 samples) data were utilized to estimate CELSR3 expression and to assess its differentiation ability in MPCa. Similar analyses were performed with miRNA-221-3p. Immunohistochemistry performed on clinical samples were used to evaluate the protein expression level of CELSR3 in MPCa. Based on CELSR3 differentially coexpressed genes (DCEGs), enrichment analysis was performed to investigate potential mechanisms of CELSR3 in MPCa. Results: The pooled standard mean difference (SMD) for CELSR3 was 0.80, demonstrating that CELSR3 expression was higher in MPCa than in localized prostate cancer (LPCa). CELSR3 showed moderate potential to distinguish MPCa from LPCa. CELSR3 protein expression was found to be markedly upregulated in MPCa than in LPCa tissues. The authors screened 894 CELSR3 DCEGs, which were notably enriched in the focal adhesion pathway. miRNA-221-3p showed a significantly negative correlation with CELSR3 in MPCa. Besides, miRNA-221-3p expression was downregulated in MPCa than in LPCa (SMD = -1.04), and miRNA-221-3p was moderately capable of distinguishing MPCa from LPCa. Conclusions: CELSR3 seems to play a pivotal role in MPCa by affecting the focal adhesion pathway and/or being targeted by miRNA-221-3p.

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

Parkinson's disease (PD) is an incapacitating neurodegenerative disease. Patients with PD and their caregivers may have interactive effects on each other’s psychological well-being. This study aimed to assess the dyadic dynamics of resilience, fatigue, and suicidal ideation on the depression severity of PD patients and their caregivers. In total, 175 PD patients and 175 caregivers were recruited at a medical center from August 2018 to May 2020. Structural equation modeling (SEM) was used to examine the actor/partner effects on the psychological well-being of both the PD patients and their caregivers. The most common psychiatric diagnoses of both the PD patients (28.6%) and their caregivers (11.4%) were depressive disorders. The PD patients’ and their caregivers’ fatigue, suicidal ideation, and lack of resilience were significantly associated with the severity of their depression, respectively. Interactive effects existed between psychological well-being of individuals with PD and their caregivers. Clinicians must be aware of, and manage, these contributing factors between PD patients and their caregivers in order to prevent them from worsening each other’s depression.

BackgroundSex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren’s syndrome (LS) and non-Löfgren’s syndrome (non-LS).MethodsA meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by an SNP lookup in the UK Biobank (UKB, n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex.ResultsWe identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and ANXA11. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified.ConclusionOur findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis.

As an evolutionarily conserved DNA-sensing machinery in innate immunity, the cGAS-STING pathway has been reported to play an important role in immune surveillance and tumor suppression. Recent evidence suggests an intriguing tumor- and metastasis-promoting effect of this signaling pathway, either in a cancer cell-autonomous or a cancer cell-nonautonomous, bystander cell-mediated manner. Here, we show a new face of cGAS-STING signaling whose activation in a cancer-cell-autonomous response manner confers drug resistance. Targeted or conventional chemotherapy drug treatment induced cancer cell cytosolic DNA accumulation and triggered subsequent cGAS-STING signaling activation in cancer cell lines and the human cell-derived xenograft tumors. This activation promoted an acquisition and maintenance of drug resistance which was prevented and overcome in vitro and in vivo by blockade of STING signaling. This finding highlights a new face of cGAS-STING signaling and an ability of cancer cells to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress and warrants a caution in combining STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.Statement of significancecGAS-STING signaling has long been recognized as playing a key role in triggering antitumor immunity. We reveal a new face of cGAS-STING signaling and an ability of cancer cells autonomously to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress.

Purpose To evaluate the diagnostic performance of swept-source anterior segment optical coherence tomography (SS-OCT) in differentiating eyes with primary angle closure disease (PACD) from eyes of control subjects, as well as eyes with PAC and PAC glaucoma (PACG) from eyes with PAC suspect (PACS) disease. Design Multicenter cross-sectional study. Methods Chinese patients were classified into control, PACS, and PAC/PACG groups. The area under the receiving operating characteristic curve (AUC) from logistic regression models was used to evaluate discriminating ability. Sensitivity and specificity were calculated, and performance of the models was validated using an independent dataset. Results A total of 2928 SS-OCT images from 366 eyes of 260 patients were recruited to develop diagnostic models. The validation dataset included 1176 SS-OCT images from 147 eyes of 143 patients. For distinguishing PACD from control eyes, average anterior chamber depth had the highest AUC (0.94). With a cutoff of 2.2 mm for average anterior chamber depth, the sensitivity and specificity were 90.2% and 85.2% in the training set. For distinguishing PAC/PACG from PACS, a multivariate model had an AUC of 0.83, with sensitivity and specificity of 82.0% and 62.8% in the training set. The validation set confirmed the findings. Conclusions SS-OCT of the anterior segment showed excellent diagnostic performance distinguishing PACD from normal eyes and moderate diagnostic ability distinguishing eyes with PAC/PACG from eyes with PACS. ACD alone may provide a simple and effective way to diagnose PACD from control subjects. As ACD can be obtained using other more available modalities, this has implications for the early diagnosis of PACD.

Chemical investigation of the culture extract of an endophytic Penicillium citrinum from Dendrobium officinale, afforded nine citrinin derivatives ( 1 – 9 ) and a peptide-polyketide hybrid GKK1032B ( 10 ). The structures of these compounds were determined on the basis of spectroscopic methods. The absolute configurations of 1 and 2 were determined for the first time by calculations of electronic circular dichroism (ECD) data. Among them, GKK1032B ( 10 ) showed significant cytotoxicity against human osteosarcoma cell line MG63 with an IC50 value of 3.49 μmol·L–1, and a primary mechanistic study revealed that it induced the apoptosis of MG63 cells via caspase pathway.

We prospectively investigated the neurological development in infants born from mothers treated with telbivudine (LdT) in the third trimester for prevention of hepatitis B virus (HBV) mother-to-infant transmission. Mothers with high HBV load were assigned to either the LdT group (n = 81, 600 mg of LdT each day from gestational week 28 to delivery) or the Control group (n = 39, untreated). Their infants were followed for 36 months to assess physical and neurological developments with Gesell Developmental Schedule tools. At 12 months after birth, the mean scores in the LdT group for gross motor, fine motor, adaptive, linguistic, and personal social domains were similar to those in the Control group. At 36 months, infants in the LdT group had higher mean scores for gross motor than the Control group (98.42 ± 9.69 vs. 94.54 ± 7.48, P = 0.03). In the LdT group, the rates of normal development were higher for gross motor (96.30% vs. 82.05% P = 0.01) and lower for adaptive (74.07% vs. 92.31% P = 0.02). Multivariate regression analyses showed that exposure to LdT during pregnancy was independently associated with infant’s development in gross motor (OR 6.49, 95% CI 1.37–30.20, P = 0.02) and adaptive (OR 0.18, 95% CI 0.05–0.71, P = 0.01) at 36 months. These results suggest that prenatal LdT exposure might affect neurological development in long-term observation. Abbreviations: LdT: telbivudine; HBV: hepatitis B virus; HBsAg: hepatitis B surface antigen; HBeAg: hepatitis Be antigen; HbsAb: hepatitis B surface antibody; ALT: alanine aminotransferase; NA: nucleoside/nucleotide analog; LAM: lamivudine; MTCT: mother-to-child transmission; GDS: Gesell Developmental Schedule; OR: odds ratio; CI: confidence interval; DQ: developmental quotient; RMB: renminbi; BMI: body mass Index; HBIG: hepatitis B immunoglobulin.

In this work, small self-assembled messenger RNA nanospheres (mRNA-NSs) were successfully prepared by rolling circle transcription on a constructed apoptin plasmid. The self-assembled mRNA-NSs have a uniform diameter of approximately 65 nm, good dispersity in solution, and efficient therapeutic apoptin expression ability. In addition, the mRNA-NSs have a high loading capacity of 8.2% for the antitumor drug doxorubicin (Dox), which can effectively deliver the loaded Dox into 4 T1 cells. Cellular experiments show that Dox-loaded self-assembled messenger RNA nanospheres (mRNA-NSs@Dox) can reduce the viability of 4 T1 breast cancer cells by significantly upregulating Bax protein, thereby inducing the activation of Caspase 3 in 4 T1 cells. In vivo experiments show that mRNA-NSs@Dox can effectively increase the necrosis of tumor tissue, reduce the expression of Ki67, and exhibit a synergistic gene-chemotherapy effect in breast cancer-bearing mice. Taken together, this study successfully prepared self-assembled apoptin messenger RNA nanospheres (mRNA-NSs), which can improve the expression of the therapeutic protein apoptin and exhibit excellent synergistic antitumor effects after loading Dox, providing new ideas for the gene treatment and chemotherapy of breast cancer.

The optimal duration of dual antiplatelet therapy (DAPT) for patients implanted with new-generation drug-eluting stents in East Asians is currently still controversial. The purpose of this meta-analysis was to investigate the efficacy and safety of short-term DAPT in patients with those. In this study, randomized controlled trials from PubMed, EMBASE, and Cochrane Library were searched to compare the efficacy and safety of short-term DAPT (6 months or less) with long-term DAPT (12 months or more) in patients implanted with new-generation drug-eluting stents in East Asian from inception to September 2020. The primary efficacy outcome was all-cause death, the primary safety outcome was major bleeding, and the secondary outcomes included cardiovascular death, myocardial infarction, definite or possible stent thrombosis, and stroke. A total of 6 randomized controlled trials with 15,688 patients met inclusion criteria; there were no significant differences in the incidence of all-cause death [risk ratio (RR), 1.03; 0.76-1.39; P = 0.856)], cardiovascular death (RR, 0.83; 0.55-1.24; P = 0.361), myocardial infarction (RR, 0.97; 0.72-1.31; P = 0.853), definite or possible stent thrombosis (RR, 1.52; 0.83-2.78; P = 0.170), and stroke (RR, 0.90; 0.61-1.31; P = 0.574) between short-term and long-term DAPTs. However, there was a significant difference in the risk of major bleeding (RR, 0.64; 0.49-0.85; P = 0.002) between the 2 groups. Compared with long-term DAPT, the short-term DAPT can reduce the risk of major bleeding without increasing the risk of death or ischemia for East Asians (Registered by PROSPERO, CRD42020213266).

Purpose: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy. Patients and Methods: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses. Results: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0–44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7–21.7)] in the ET group and 14.8 months (12.8–16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71–1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. Conclusions: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.

Purpose: We assessed whether perioperative circulating tumor DNA (ctDNA) could be a biomarker for early detection of molecular residual disease (MRD) and prediction of postoperative relapse in resected non–small cell lung cancer (NSCLC). Experimental Design: Based on our prospective, multicenter cohort on dynamic monitoring of ctDNA in lung cancer surgery patients (LUNGCA), we enrolled 950 plasma samples obtained at three perioperative time points (before surgery, 3 days and 1 month after surgery) of 330 stage I–III NSCLC patients (LUNGCA-1), as a part of the LUNGCA cohort. Using a customized 769-gene panel, somatic mutations in tumor tissues and plasma samples were identified with next-generation sequencing and utilized for ctDNA-based MRD analysis. Results: Preoperative ctDNA positivity was associated with lower recurrence-free survival (RFS; HR = 4.2; P < 0.001). The presence of MRD (ctDNA positivity at postoperative 3 days and/or 1 month) was a strong predictor for disease relapse (HR = 11.1; P < 0.001). ctDNA-based MRD had a higher relative contribution to RFS prediction than all clinicopathologic variables such as the TNM stage. Furthermore, MRD-positive patients who received adjuvant therapies had improved RFS over those not receiving adjuvant therapy (HR = 0.3; P = 0.008), whereas MRD-negative patients receiving adjuvant therapies had lower RFS than their counterparts without adjuvant therapy (HR = 3.1; P < 0.001). After adjusting for clinicopathologic variables, whether receiving adjuvant therapies remained an independent factor for RFS in the MRD-positive population (P = 0.002) but not in the MRD-negative population (P = 0.283). Conclusions: Perioperative ctDNA analysis is effective in early detection of MRD and relapse risk stratification of NSCLC, and hence could benefit NSCLC patient management.

Tumor hypoxia is a common feature in colorectal cancer (CRC), and is associated with resistance to radiotherapy and chemotherapy. Thus, a specifically targeted probe for the detection of hypoxic CRC cells is urgently needed. Carbonic anhydrase 9 (CA9) is considered to be a specific marker for hypoxic CRC diagnosis. Here, a nuclear imaging Indium-111 (111In)-labeled dual CA9-targeted probe was synthesized and evaluated for CA9 detection in in vitro, in vivo, and in human samples. The CA9-targeted peptide (CA9tp) and CA9 inhibitor acetazolamide (AAZ) were combined to form a dual CA9-targeted probe (AAZ-CA9tp) using an automatic microwave peptide synthesizer, which then was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radioisotope (111In) labeling (111In-DOTA-AAZ-CA9tp). The assays for cell binding, stability, and toxicity were conducted in hypoxic CRC HCT15 cells. The analyses for imaging and biodistribution were performed in an HCT15 xenograft mouse model. The binding and distribution of 111In-DOTA-AAZ-CA9tp were detected in human CRC samples using microautoradiography. AAZ-CA9tp possessed good CA9-targeting ability in hypoxic HCT15 cells. The dual CA9-targeted radiotracer showed high serum stability, high surface binding, and high affinity in vitro. After exposure of 111In-DOTA-AAZ-CA9tp to the HCT15-bearing xenograft mice, the levels of 111In-DOTA-AAZ-CA9tp were markedly and specifically increased in the hypoxic tumor tissues compared to control mice. 111In-DOTA-AAZ-CA9tp also targeted the areas of CA9 overexpression in human colorectal tumor tissue sections. The results of this study suggest that the novel 111In-DOTA-AAZ-CA9tp nuclear imaging agent may be a useful tool for the detection of hypoxic CRC cells in clinical practice.

Background As studies on ethnic disparities in metabolic syndrome and its risk factors in Taiwan are still rare, the aims of this study were: (1) to detect the differences in the rates of metabolic syndrome, obesity and health behaviors between two ethnic groups (indigenous Tsou and nonindigenous Han) living in the same area and with similar age and sex distributions; (2) to examine whether ethnicity per se plays a significant role in the occurrence of metabolic syndrome, while taking other risk factors including sociodemographic characteristics, obesity and health behaviors into consideration. Methods This is a cross-sectional study using data from a community survey conducted in Chiayi County in southwestern Taiwan. A frequency matching strategy by age and sex with a ratio of 1 (Tsou) to 3 (Han) was applied to select a comparable sample between both ethnic groups (667 Tsou and 2001 Han) from among the survey participants. Furthermore, participants with cardiometabolic diseases diagnosed before the surveyed day were excluded to avoid confounding any associated risk factors for developing metabolic syndrome (MS). A final analytic sample of 1482 remained. The used information included sociodemographic characteristics, medical histories, health behaviors, and the concentrations of triglycerides, cholesterol, and glucose. Results Indigenous Tsou had significantly higher rates of metabolic syndromes, obesity and unhealthy behaviors than their Han counterparts (MS: 54.0% vs. 29.1%, obesity: 54.0% vs. 23.2%, drinking alcohol: 17.5% vs. 13.6%, and higher intake of fried food: 6.4% vs. 4.4%), even though they were similar in age and sex distributions. The significant risk factors for subsequently developing MS included being indigenous Tsou (adjusted POR = 2.62, P Conclusions There existed ethnic differences in the rates of metabolic syndrome, obesity, and health behaviors. Ethnicity per se did play a significant role in developing MS; in particular indigenous Tsou people had increased risks, suggesting possible biological reasons rooted in their origins that need further exploration. In addition, unhealthy behaviors may potentially have an indirect effect on developing MS via their effect on obesity.

Autophagy has been shown to play an important role in Parkinson's disease. We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson's disease through affecting autophagy. In this study, 6-hydroxydopamine-damaged SH-SY5Y cells were pretreated with a culture medium containing skin-derived precursors differentiated into Schwann cells (SKP-SCs). The results showed that the SKP-SC culture medium remarkably enhanced the activity of SH-SY5Y cells damaged by 6-hydroxydopamine, reduced excessive autophagy, increased tyrosine hydroxylase expression, reduced α-synuclein expression, reduced the autophagosome number, and activated the PI3K/AKT/mTOR pathway. Autophagy activator rapamycin inhibited the effects of SKP-SCs, and autophagy inhibitor 3-methyladenine had the opposite effect. These findings confirm that SKP-SCs modulate the PI3K/AKT/mTOR pathway to inhibit autophagy, thereby exhibiting a neuroprotective effect in a cellular model of Parkinson's disease. This study was approved by the Animal Ethics Committee of Laboratory Animal Center of Nantong University (approval No. S20181009-205) on October 9, 2018.

Xiaoying Ning, Dingwei Zhang, Yuan Wang, Jia Huo, Ying Huang, Ying Guo, Zhengxiao Li, Yanfei Zhang Department of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xian, Shaanxi Province, People’s Republic of ChinaCorrespondence: Zhengxiao Li; Yanfei ZhangDepartment of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xian, Shaanxi Province, 710004, People’s Republic of ChinaTel/Fax +86-29-87679301Email lizhengxiao1979@163.com; zhangyanfei723@163.comPurpose: Psoriasis is a systemic, chronic and inflammatory condition. The exact pathogenesis is unclear. The abnormal expression of Wnt5a pathway in psoriasis vulgaris has been confirmed. Whether it is related to the severity of psoriasis is unclear.Methods: Thirty-eight skin lesions from psoriasis vulgaris patients and 22 healthy adult skin tissues were taken. The semi-quantitative immunohistochemistry score of Wnt5a, Frizzled5 and Frizzled2 was evaluated under a microscope by two independent dermatologists. Psoriasis area and severity index (PASI) score system was used to evaluate the disease severity.Results: The average PASI score of the patients was 16.25 ± 7.8, and the average duration of disease was 19.6 ± 10.4 months. Wnt5a, Frizzled5 and Frizzled2 were highly expressed in psoriasis lesions. The semi-quantitative immunohistochemistry scores of Wnt5a, Frizzled5 and Frizzled2 were positively correlated with PASI scores (r = 0.71, r = 0.46, r = 0.65, respectively, all P-value < 0.01), but not correlated with duration of disease (r = 0.11, r = 0.17, r = 0.29, respectively, all P-value > 0.05). There were significant positive correlations between Wnt5a and Frizzled5 (r = 0.57, P-value < 0.01), as well as Wnt5a and Frizzled2 (r = 0.59, P-value < 0.01).Conclusion: Wnt5a and its receptors play an important role in pathogenesis of psoriasis vulgaris and are positively correlated with the severity of psoriasis, and may be one of the immunohistochemical predictors of the severity of the disease.Keywords: psoriasis vulgaris, Wnt5a, PASI, Frizzled5, Frizzled2

Ying-Tao Lin,1 Ying Chen,2 Tian-Xiu Liu,3 Fang Kuang,1 Ping Huang1 1Administration Office of Drug Clinical Trial, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of China; 2Management Office of Science and Technology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, People’s Republic of China; 3Department of Thoracic Radiotherapy, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, People’s Republic of ChinaCorrespondence: Ping HuangAdministration Office of Drug Clinical Trial, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of ChinaTel +86 13960908650Fax +86 0591 62752517Email 1967217973@qq.comPurpose: The aim of this study was to assess the cost-effectiveness of camrelizumab immunotherapy versus docetaxel or irinotecan chemotherapy as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC), which was evaluated in the ESCORT trial.Materials and Methods: A partitioned survival model was developed to reflect the costs and effectiveness of the ESCORT trial. The clinical efficacy data, safety data, and health-related costs and utilities were derived from published data from clinical trials or health administration departments in China. Adverse event-related costs, drug administration, and other expenses were derived from a single center of Fujian Medical University Cancer Hospital in 2021. All survival analyses were performed with SPSS software. Overall survival was estimated with the Kaplan–Meier method, and progression-free survival was estimated with the life table method. Sensitivity analyses were conducted to assess the uncertainty of the model. Incremental cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) were calculated.Results: Camrelizumab therapy had 0.232 QALYs at an incremental cost of USD$9959.44 compared with the chemotherapy group with 0.158 QALYs at an incremental cost of USD$8601.67. The ICER was USD$18393.12/QALY. Probabilistic sensitivity analyses showed that when the willingness-to-pay threshold reached USD$31200/QALY, which is nearly three times the Chinese gross domestic product per capita, camrelizumab had an 80% possibility of being cost-effective versus docetaxel or irinotecan chemotherapy.Conclusion: Camrelizumab is a cost-effective option compared with docetaxel or irinotecan chemotherapy in patients with advanced ESCC as second-line therapy in China.Keywords: camrelizumab, chemotherapy, cost-effectiveness, esophageal squamous cell carcinoma

Objective: To explore whether there is a specific clinical effect of acupuncture in the treatment of chronic prostatitis. Methods: A total of 52 patients with chronic prostatitis were randomly divided into an acupuncture group (24 cases) and a placebo acupuncture group (28 cases). During the treatment, 1 case was dropped out in the placebo acupuncture group and 51 patients accomplished the clinical trial finally in two groups. In the acupuncture group, Shenshū (肾俞BL23), Zhōngliao (中髎BL33), Huiyang (会阳BL35) and Sānyīnjiāo (三阴交SP6) were selected. In the placebo acupuncture group, the non-meridian points located lateral to BL23, BL33, BL35 and SP6 were selected respectively. The duration of treatment was 8 weeks in each group. In the first 4 weeks of treatment, the treatment was given once every two days, three times weekly. In the last 4 weeks of treatment, the treatment was given once every three days, twice a week. Totally, 20 acupuncture treatments were required in the whole trial. Before treatment, in week 4 and 8 of treatment and in follow-up, National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score and the comprehensive effect were evaluated in the two groups successively. Results: In week 4 and 8 of treatment, NIH-CPSI score in the acupuncture group was lower than that before treatment respectively (both P Conclusion: Acupuncture relieves pelvic pain and urination symptoms and has a certain of long-term effect in patients with chronic prostatitis.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide, with an individual lifetime risk of approximately 37% in the United States. Broadly defined as a supraventricular tachyarrhythmia with disorganized atrial activation, AF results in an increased risk of stroke, heart failure, valvular heart disease, and impaired quality of life, and confers a significant burden on the health of individuals and society. AF in the perioperative setting is common and a significant source of perioperative morbidity and mortality worldwide. The latest iteration of the European Society of Cardiology AF guidelines published in 2020 provide the clinician a valuable road map for the management of this arrythmia. This expert review will comprehensively analyze the 2020 European Society of Cardiology guidelines and provide perioperative management tools for the clinician.

Objective: To compare the difference in the clinical therapeutic effect on dysmenorrhea in the patients with adenomyosis between acupuncture and ibuprofen sustained release capsules. Methods: A total of 40 patients were randomized into an acupuncture group and an ibuprofen group, 20 cases in each one. The treatment was given consecutively for 3 menstrual cycles and the follow-up lasted for 2 menstrual cycles. The score of visual analogue scale (VAS) at the most painful time during menstruation, menstrual flow, the score of COX menstrual symptom scale (CMSS) and the score of endometriosis health profile-5 (EHP-5), as well as the patients’ satisfaction and acceptance were compared between the two groups. Results: Three menstrual cycles after treatment, the VAS score at the most painful time, menstrual flow, CMSS score and EHP-5 score were all lower than those before treatment in either group, with statistical significance (all P 0.05), the menstrual flow was lower (P > 0.05), CMSS score was higher (P 0.05). The score of the patients’ satisfaction and acceptance in the acupuncture group were all higher than the ibuprofen group (both P Conclusion: Acupuncture is effective for analgesia and symptom-relief and the long-term effect is superior to the oral administration of ibuprofen.

Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states.In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting.The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed.The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol.Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.

Background: A variety of emerging medical imaging technologies based on artificial intelligence have been widely applied in many diseases, but they are still limitedly used in the cerebrovascular field even though the diseases can lead to catastrophic consequences. Objective: This work aims to discuss the current challenges and future directions of artificial intelligence technology in cerebrovascular diseases through reviewing the existing literature related to applications in terms of computer-aided detection, prediction and treatment of cerebrovascular diseases. Methods: Based on artificial intelligence applications in four representative cerebrovascular diseases including intracranial aneurysm, arteriovenous malformation, arteriosclerosis and moyamoya disease, this paper systematically reviews studies published between 2006 and 2021 in five databases: National Center for Biotechnology Information, Elsevier Science Direct, IEEE Xplore Digital Library, Web of Science and Springer Link. And three refinement steps were further conducted after identifying relevant literature from these databases. Results: For the popular research topic, most of the included publications involved computer-aided detection and prediction of aneurysms, while studies about arteriovenous malformation, arteriosclerosis and moyamoya disease showed an upward trend in recent years. Both conventional machine learning and deep learning algorithms were utilized in these publications, but machine learning techniques accounted for a larger proportion. Conclusion: Algorithms related to artificial intelligence, especially deep learning, are promising tools for medical imaging analysis and will enhance the performance of computer-aided detection, prediction and treatment of cerebrovascular diseases.

Background The transcription factor NFIL3 exerts comprehensive effects on the immune system. Previous studies revealed that NFIL3 is related to the function and development of different immune cell subsets. Experimental autoimmune encephalomyelitis (EAE) is mediated by immune cells which results in inflammatory demyelination in the central nervous system (CNS). However, how NFIL3 affects EAE has not been thoroughly studied. Objectives The current study aimed to investigate how NFIL3 affects EAE, especially the changes of T cells and dendritic cells as well as the crosstalk between them. Methods We used NFIL3-/- mice and C57BL/6J mice (wildtype) to establish MOG35-55-induced EAE. The clinical scores were recorded daily. The immune cells within and outside the CNS of EAE mice were analyzed by flow cytometry. Histology was used to evaluated the neuroinflammation and demyelination in the CNS. Besides, CD11c+ dendritic cells (DCs) were cocultured with T cells and the interplay was measured. Results At the peak of EAE, Th17 cells decreased within the CNS accompanying with lower clinical scores and milder neuroinflammation and demyelination in NFIL3 knockout EAE mice. Outside the CNS, PD-1 and ICOS on CD4+T cells increased, whereas Th2, Th9, CD8+CD103+T cells and GM-CSF+CD4+T cells decreased. Besides, the pro-inflammatory capacity of NFIL3-/- CD11c+ dendritic cells was impaired while the anti-inflammatory capacity was promoted. Conclusions This study suggests that NFIL3 deficiency could alleviate MOG35-55-induced EAE through regulating different immune cell subsets, which is not only related with adaptive immunity and innate immunity, but also related with the cross-talk between them, especially CD4+ T cells and CD11c+ dendritic cells.

Background/purpose Morbidity and mortality from typhoid and paratyphoid fever remain an important problem for public health authorities in developing countries. In countries with lower incidences, most cases occur in travelers who visit regions in which typhoid and paratyphoid fever are highly endemic. The aim was to evaluate the source and transmission dynamics of typhoid and paratyphoid fever in Taiwan by using genomic analysis. Methods During 2012–2019, 15 clinical isolates of Salmonella Typhi and S. Paratyphi A were collected. Demographic and clinical information of the infections were analyzed. We performed whole genome sequencing and evolutionary analysis on these isolates. Results Clinical and microbiological data from 7 S. Typhi and 8 S. Paratyphi A isolates in Taiwan showed epidemiological and bacterial genomic link to the infection in South and Southeast Asia. The Taiwanese typhoidal isolates also share highly similar genomes with those collected from UK, indicating global circulation of the typhoidal clones. Local transmission of the imported but indigenized international clones was observed. Mutations occurring at gyrA 83 aa, including S83Y and S83F, were identified in the ciprofloxacin-resistant strains. Conclusion Due to the advance of global transportation and communication, the transmission mode of infectious disease has been modified. Domestic typhoid and paratyphoid fever caused by international resistant clones can occur in low-incidence countries. Genome analysis showed that the indigenous clone originally imported from other countries has been circulating in Taiwan for over a decade.

Background Gait abnormalities from neuromuscular conditions like cerebral palsy (CP) limit mobility and negatively affect quality of life. Increasing walking speed and stride length are essential clinical goals in the treatment of gait disorders from CP. Research question. How does over-ground gait training with an untethered ankle exoskeleton providing adaptive assistance affect mobility-related spatiotemporal outcomes and lower-extremity muscle activity in people with CP? Methods A diverse cohort of individuals with CP (n = 6, age 9–31, Gross Motor Function Classification System Level I – III) completed four over-ground training sessions (98 ± 17 min of assisted walking) and received pre- and post-training assessments. On both assessments, participants walked over-ground with and without the exoskeleton while we recorded spatiotemporal outcomes and muscle activity. We used two-tailed paired t-tests to compare all parameters pre- and post-training, and between assisted and unassisted conditions. Results Following training, walking speed increased 0.24 m/s (p = 0.006) and stride length increased 0.17 m (p = 0.013) during unassisted walking, while walking speed increased 0.28 m/s (p = 0.023) and stride length increased 0.15 m (p = 0.002) during exoskeleton-assisted walking. Exoskeleton training improved stride-to-stride repeatability of soleus and vastus lateralis muscle activation by up to 51 % (p ≤ 0.046), while the amount of integrated stance-phase muscle activity was similar across visits and conditions. Relative to baseline, post-training walking with the exoskeleton resulted in a soleus activity pattern that was 39 % more similar to the typical pattern from unimpaired individuals (p Significance This study demonstrates acute spatiotemporal and neuromuscular benefits from over-ground training with adaptive ankle exoskeleton assistance, and provides rationale for completion of a longer randomized controlled training protocol.

Aim Familial hypercholesterolemia (FH) is an underdiagnosed autosomal dominant genetic disorder characterized by high levels of plasma low-density lipoprotein cholesterol (LDL-C) from birth. This study aimed to assess the genetic identification of FH in children with high LDL-C levels who are identified in a universal pediatric FH screening in Kagawa, Japan. Method In 2018 and 2019, 15,665 children aged 9 or 10 years underwent the universal lipid screening as part of the annual health checkups for the prevention of lifestyle-related diseases in the Kagawa prefecture. After excluding secondary hyper-LDL cholesterolemia at the local medical institutions, 67 children with LDL-C levels of ≥ 140 mg/dL underwent genetic testing to detect FH causative mutations at four designated hospitals. Results The LDL-C levels of 140 and 180 mg/dL in 15,665 children corresponded to the 96.3 and 99.7 percentile values, respectively. Among 67 children who underwent genetic testing, 41 had FH causative mutations (36 in the LDL-receptor, 4 in proprotein convertase subtilisin/kexin type 9, and 1 in apolipoprotein B). The area under the curve of receiver operating characteristic curve predicting the presence of FH causative mutation by LDL-C level was 0.705, and FH causative mutations were found in all children with LDL-C levels of ≥ 250 mg/dL. Conclusion FH causative mutations were confirmed in almost 60% of the referred children, who were identified through the combination of the lipid universal screening as a part of the health checkup system and the exclusion of secondary hyper-LDL cholesterolemia at the local medical institutions.

Photothermal therapy has the characteristics of minimal invasiveness, controllability, high efficiency, and strong specificity, which can effectively make up for the toxic side effects and tumor resistance caused by traditional drug treatment. However, due to the limited tissue penetration of infrared light, it is difficult to promote and apply in clinical practice. The eye is the only transparent tissue in human, and infrared light can easily penetrate the eye tissue, so it is expected that photothermal therapy can be used to treat fundus diseases. Here in, a new nano-platform assembled by liposome and indocyanine green (ICG) was used to treat retinoblastoma. ICG was assembled in liposomes to overcome some problems of ICG itself. For example, ICG is easily quenched, self-aggregating and instability. Moreover, liposomes can prevent free ICG from being cleared through the systemic circulation. The construction of the nano-platform not only ensured the stability of ICG in vivo, but also realized imaging-guided photothermal therapy, which created a new strategy for the treatment of retinoblastoma.

BACKGROUND Atherosclerosis and vascular inflammatory response have been considered as risk factors for non-typhoidal Salmonella (NTS) vascular infection. The study aims to assess the risk of vascular infection by measuring atherosclerosis severity, NTS vascular infection (NTSVI) score, and serum levels of inflammatory markers in people with NTS bacteremia. METHODS A prospective observational study was conducted in two medical centers and two regional hospitals. Adults aged ≥50 years with NTS bacteremia who underwent computed tomography (CT) scan for revealing vascular infections were enrolled. The degree of atherosclerosis was scaled by a calcium score determined by a CT scan. Serum concentrations of inflammatory biomarkers were determined in the patients enrolled in a medical center. RESULTS Fourteen (20.3%) of 69 patients with NTS bacteremia had vascular infections. Calcium scores over the thoracic (12,540 vs. 3,261, P = 0.0005) and abdominal (9755 vs. 3,461, P = 0.0006) aorta of those with vascular infections were higher than those without vascular infection. All vascular infections were present in the high-risk group (NTSVI score ≥1), yielding a sensitivity of 100% and specificity of 30.9%. Among 17 low-risk patients (NTSVI score

The BRCA1-PALB2-BRCA2 axis, or the BRCA pathway, plays key roles in genome stability maintenance and suppression of breast and several other cancers. Due to frequent p53 mutations in human BRCA1 breast cancers and mouse mammary tumors from Brca1, Brca2 and Palb2 conditional knockout models, it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis. Here, we studied tumor development in mice with a mutation in Palb2 that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds. Rather than mammary tumors, Palb2 and Trp53 compound mutant mice developed, with greatly reduced latencies, lymphomas and sarcomas that are typically associated with germline Trp53 inactivation. Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of Trp53 single mutant and Palb2;Trp53 compound mutant mice. These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development, possibly without altering the fundamental tumorigenic processes.

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

BACKGROUND Lung cancer with direct cardiac invasion (LCCI+) exerts a significant influence on the survival of patients. There is a paucity of comparative research into the prognosis of advanced lung cancer with and without direct cardiac invasion. METHOD In this study, 50 LCCI+ patients and 50 sex-, age-, and TNM stage-matched patients without direct cardiac invasion (LCCI-) were retrospectively analysed. LCCI+ was defined as lung cancer directly invading the heart by penetrating mediastinum or extending into the atrium via the pulmonary vein. The study endpoint was all-cause death. In this study, the survival time was defined as the time from the first detection of direct cardiac invasion to the end of the event. RESULTS During a median follow-up period of 31 months, all-cause death occurred in 44 patients (88.0%) in the LCCI+ group and in 36 patients (72.0%) in the LCCI- group; the overall survival (OS) time among patients in the LCCI+ group was significantly lower compared with those in the LCCI- group (5.0 [interquartile range (IQR), 2.0-12.0] vs 13.8 [IQR, 4.0-18.4] months; p