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Purpose: Active surveillance (AS) is one of the management options for patients with low-risk and select intermediate-risk prostate cancer (PC). However, factors predicting disease reclassification and conversion to active treatment from a large population of pure Asian cohorts regarding AS are less evaluated. This study investigated the intermediate-term outcomes of patients with localized PC undergoing AS. Materials and Methods: This cohort study enrolled consecutive men with localized non-high-risk PC diagnosed in Taiwan between June 2012 and Jan 2023. The study endpoints were disease reclassification (either pathological or radiographic progression) and conversion to active treatment. The factors predicting endpoints were evaluated using the Cox proportional hazards model. Results: A total of 405 patients (median age: 67.2 years) were consecutively enrolled and followed up with a median of 64.6 months. Based on the National Comprehensive Cancer Network (NCCN) risk grouping, 70 (17.3%), 164 (40.5%), 140 (34.6%), and 31 (7.7%) patients were classified as very low-risk, low-risk, favorable-intermediate risk, and unfavorable intermediate-risk PC, respectively. The 5-year reclassification rates were 24.8%, 27.0%, 18.6%, and 25.3%, respectively. The 5-year conversion rates were 20.4%, 28.8%, 43.6%, and 37.8%, respectively. A prostate-specific antigen density (PSAD) of ≥0.15 ng/mL2 predicted reclassification (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.17–2.88) and conversion (HR 1.56, 95% CI 1.05–2.31). A maximal percentage of cancer in positive cores (MPCPC) of ≥15% predicted conversion (15% to

Tubulin posttranslational modifications (PTMs) modulate the dynamic properties of microtubules and their interactions with other proteins. However, the effects of tubulin PTMs were often revealed indirectly through the deletion of modifying enzymes or the overexpression of tubulin mutants. In this study, we directly edited the endogenous tubulin loci to install PTM-mimicking or -disabling mutations and studied their effects on microtubule stability, neurite outgrowth, axonal regeneration, cargo transport, and sensory functions in the touch receptor neurons of Caenorhabditis elegans. We found that the status of β-tubulin S172 phosphorylation and K252 acetylation strongly affected microtubule dynamics, neurite growth, and regeneration, whereas α-tubulin K40 acetylation had little influence. Polyglutamylation and detyrosination in the tubulin C-terminal tail had more subtle effects on microtubule stability likely by modulating the interaction with kinesin-13. Overall, our study systematically assessed and compared several tubulin PTMs for their impacts on neuronal differentiation and regeneration and established an in vivo platform to test the function of tubulin PTMs in neurons.

Abstract Purpose Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. Methods Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). Results In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. Conclusion This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

SARS-CoV-2 new waves are primarily caused by changes to the spike protein (S), which can substantially decrease the efficacy of vaccines. Therefore, we tested several multivalent mRNA-LNP vaccines, targeting the full-length S proteins of different variants, and identified an optimal combination for protection against VOCs in BALB/c mice. The tested formulations included trivalent (WT + BA.5 + XBB.1.5), pentavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1), and octavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1 + Alpha + Delta + BA.2) vaccines. Among these multivalent vaccines, the pentavalent vaccine showed superior protection for almost all tested variants. Despite this, each multivalent vaccine elicited greater broad-spectrum neutralizing antibodies than the previously evaluated bivalent vaccine (WT + BA.5). Subsequently, we redesigned the multivalent vaccine to efficiently generate neutralizing antibodies against recent VOCs, including EG.5.1. Immunization with the redesigned pentavalent vaccine (WT + EG.5.1 + XBB.1.16 + Delta + BA.5) showed moderate levels of protection against recent Omicron VOCs. Results suggest that the neutralization activity of multivalent vaccines is better than those of the tested bivalent vaccines against WT + BA.5 and WT + EG.5.1. Moreover, the pentavalent vaccine we developed may be highly useful for neutralizing new Omicron VOCs.

Abstract Background Circulating thyroid-stimulating hormone (TSH) levels within the normal reference range can affect the cardiovascular system. The present study investigated the prognostic value of normal TSH levels in patients presenting with acute myocardial infarction (AMI) following percutaneous coronary intervention (PCI). Methods Between January 2013 and July 2019, 1240 patients with AMI and normal thyroid function were enrolled and classified according to TSH tertile. The trial endpoint was all-cause mortality. The integrated discrimination index (IDI) and the net reclassification index (NRI) were used to assess the combined predictive values of the TSH levels and the Global Registry of Acute Coronary Events (GRACE) scores. Results After a median 44.25-month follow-up, 195 individuals died. Even after covariate adjustment by multivariate Cox regression (HR: 1.56; 95% CI 1.08–2.25; P = 0.017), the patients in the third TSH tertile were at the highest risk of all-cause mortality. A subgroup analysis revealed significant interactions between the TSH levels and the GRACE scores (high risk vs. low/medium risk) (P = 0.019). The addition of the TSH levels to the GRACE scores substantially improved the prediction of all-cause mortality, especially for high-risk patients (NRI = 0.239; IDI = 0.044; C-statistic value range 0.649–0.691; all significant). Conclusions The third TSH tertile is associated with a higher incidence of all-cause mortality than the first TSH tertile in high-risk patients presenting with AMI after PCI.

Abstract Background Sequential infections with SARS-CoV-2 variants such as Alpha, Delta, Omicron and its sublineages may cause high morbidity, so it is necessary to develop vaccines that can protect against both wild-type (WT) virus and its variants. Mutations in SARS-CoV-2’s spike protein can easily alter viral transmission and vaccination effectiveness. Methods In this study, we designed full-length spike mRNAs for WT, Alpha, Delta, and BA.5 variants and integrated each into monovalent or bivalent mRNA-lipid nanoparticle vaccines. A pseudovirus neutralization assay was conducted on immunized mouse sera in order to examine the neutralizing potential of each vaccine. Results Monovalent mRNA vaccines were only effective against the same type of virus. Interestingly, monovalent BA.5 vaccination could neutralize BF.7 and BQ.1.1. Moreover, WT, Alpha, Delta, BA.5, and BF.7 pseudoviruses were broadly neutralized by bivalent mRNA vaccinations, such as BA.5 + WT, BA.5 + Alpha, and BA.5 + Delta. In particular, BA.5 + WT exhibited high neutralization against most variants of concern (VOCs) in a pseudovirus neutralization assay. Conclusions Our results show that combining two mRNA sequences may be an effective way to develop a broadly protective SARS-CoV-2 vaccine against a wide range of variant types. Importantly, we provide the optimal combination regimen and propose a strategy that may prove useful in combating future VOCs.

Collagenous gastritis （CG） is a rare disease characterized by a zone of collagen deposits of > 10 μm in thickness under the gastric mucosal epithelium with inflammatory cell infiltration in the lamina propria. The pathogenesis of CG is still unclear， which may be related to many factors， such as autoimmunity， inflammation and drugs， etc. Clinical manifestations of CG are complex and diverse with a chronic recurrence and prolonged process， which can be divided into child- and adult-onset groups of clinical symptoms. At present， there is no standard treatment for CG. The following therapeutic regimens have been employed including hypoallergenic diet， inhibition of gastric juice secretion， gastrointestinal mucosal protective agent， oral iron agent，glucocorticoid，5-aminosalicylicacid and immunosuppressive agents. However， clinical efficacy and follow-up outcomes are not completely consistent. In this article， research progresses on CG at home and abroad were reviewed.

Abstract To compare clinical outcomes between the use of robotic-assisted laparoscopic radical prostatectomy (RP) and radiotherapy (RT) with long-term androgen deprivation therapy (ADT) in locally advanced prostate cancer (PC), 315 patients with locally advanced PC (clinical T-stage 3/4) were considered for analysis retrospectively. Propensity score-matching at a 1:1 ratio was performed. The median follow-up period was 59.2 months (IQR 39.8–87.4). There were 117 (37.1%) patients in the RP group and 198 (62.9%) patients in the RT group. RT patients were older and had higher PSA at diagnosis, higher Gleason score grade group and more advanced T-stage (all p

Objective To evaluate the protective effect and inflammation inhibition mechanism of icariin (ICA) on lung injury in rat model with severe acute pancreatitis (SAP). Methods The rats were randomly divided into sham operation group (sham group), model group (SAP group, 5% sodium taurocholate was retrograde pumped into bile duct according to 0.1 mL/kg through micropump) and experimental group (ICA group, icariin 80 mg/kg intervention was given 2 hours before modeling). There were 6 rats in each group. Twenty-four hours after the establishment of the model, the inferior vena cava blood, pancreatic tissue and lung tissue were collected. The pathological injury of pancreas and lung was observed by HE staining; The activity of amylase, serum IL-6, IL-1β and TNF-α were measured by ELISA; The expression of inflammatory factors IL-6, IL-1β and TNF-α in lung tissue was determined by immunohistochemical staining; And the ratio of phosphorylated JNK/JNK to phosphorylated NF-κB/NF-κB in lung tissue was measured by Western blot. Results The pathological scores of pancreas and lung in SAP group were significantly higher than those in sham group; And the pathological scores of pancreas and lung in ICA group were significantly lower than those in SAP group. Serum amylase activity, serum IL-6, IL-1β and TNF-α content and the expression of IL-6, IL-1β and TNF-α in lung tissue in SAP group were significantly higher than those in sham group; While serum amylase activity, serum IL-6, IL-1β and TNF-α content and the expression of IL-6, IL-1β and TNF-α in lung tissue in ICA group were significantly lower than those in SAP group. The level of phosphorylated JNK and phosphorylated NF-κB in lung tissue of SAP group were significantly higher than those of sham group; While icariin might significantly reduce the level of phosphorylated JNK and phosphorylated NF-κB in lung tissue. Conclusions ICA ameliorates lung injury in SAP rat model by inhibiting acute inflammation response,which is potentially mediated by JNK/NF-κB signal pathway.

Abstract To inhibit the agglomeration of nanotitanium dioxide, a poly (vinyl chloride) (PVC) composite film doped with folic acid-modified titanium dioxide was synthesized and characterized using X-ray powder diffraction, X-ray photoelectron spectroscopy and thermogravimetric analysis coupled with Fourier transform infrared spectroscopy. The average grain size of the folic acid-modified titanium dioxide was found to decrease by 1.3 nm, indicating that the cohesiveness of the nanoparticles is decreased. The lowest temperature for 1.0% thermal decomposition of PVC was determined to be 230.0 °C. The decomposition rate at the peak temperature is found to be 39.6% lower than that of a control sample. The stability of the PVC is improved due to a lower number of surface chlorine atoms as well intermolecular attraction. A mechanism for folic acid modification of titanium dioxide-doped PVC is proposed. After doping, the ester groups in the plasticizer show a significant decrease in the vibration peak intensities observed at 1264 cm−1, 1736 cm−1 and 1106 cm−1. The doped PVC film suppresses the release of CO2, and the strongest vibration peak at 1264 cm−1 is found to be 17.2% lower than that for the blank sample, indicating that doping is beneficial for plasticizer recovery.

Abstract To investigate the value of the star-VIBE sequence in dynamic contrast-enhanced magnetic resonance imaging of esophageal carcinoma under free breathing conditions. From February 2019 to June 2020, 60 patients with esophageal carcinoma were prospectively enrolled to undergo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with the K-space golden-angle radial stack-of-star acquisition scheme (star-VIBE) sequence (Group A) or conventional 3D volumetric-interpolated breath-hold examination (3D-VIBE) sequence (Group B), completely randomized grouping. The image quality of DCE-MRI was subjectively evaluated at five levels and objectively evaluated according to the image signal-to-noise ratio (SNR) and contrast-noise ratio (CNR). The DCE-MRI parameters of volume transfer constant (Ktrans), rate constant (Kep) and vascular extracellular volume fraction (Ve) were calculated using the standard Tofts double-compartment model in the post-perfusion treatment software TISSUE 4D (Siemens). Each group included 30 randomly selected cases. There was a significant difference in subjective classification between the groups (35.90 vs 25.10, p = 0.009). The study showed that both the SNR and CNR of group A were significantly higher than those of group B (p = 0.004 and 0.05). The star-VIBE sequence can be applied in DCE-MRI examination of esophageal carcinoma, which can provide higher image quality than the conventional 3D-VIBE sequence in the free breathing state.

Abstract Longitudinal trends on traumatic cataract wound dehiscence are scant. In this study, we present the characteristics of traumatic cataract wound dehiscence using 15 years of longitudinal trend in one of the largest medical centers in Taiwan for a period when cataract surgeries were gradually shifting from extracapsular cataract extraction (ECCE) to phacoemulsification. All patients with a prior cataract surgery who suffered from blunt open globe trauma between 2001 and 2015 at a tertiary referral center in Taiwan were included. The number of cases per year; type of prior cataract surgery; visual acuity (VA); mechanism and place of injury were analyzed. The risk factors associated with final VA were investigated in patients followed up for ≥ 1 month. Seventy-six eyes of 75 patients were included and all of them were traumatic cataract wound dehiscence with a prior ECCE (65 eyes) or phacoemulsification. The most common mechanism and place of injury was fall and at home in both cataract surgical types. The mean log of the minimal angle resolution (logMAR) of final VA was 2.15 ± 0.88 (ECCE) and 1.61 ± 0.83 (phacoemulsification) (P = .026). The most significant risk factors associated with worse final VA were retinal detachment at the initial visit and low ocular trauma score (both P

Abstract Erectile dysfunction (ED) is mostly due to the lack of blood flow into the penis. In the past 20 years, near-infrared spectroscopy (NIRS) was used in measuring the concentrations and temporal dynamics of different hemoglobin types. However, the dynamics of the light absorption (photoplethysmography; PPG) have not been applied to survey penile hemodynamics and erection quality. This paper compared the use of photoplethysmography (PPG) to study vascular ED with standard penile Doppler ultrasonography. Men diagnosed with vascular ED for at least 6 months and nominated for penile ultrasonography were included. PPG signals were collected during the ultrasound examination. All beat-to-beat PPG waveforms were aligned with the peak and averaged to one representative template waveform for feature analysis, including amplitude differences (APD) index, reflection time index (RTI), augmentation index (AI), and perfusion index (PI). An inverse correlation was found between end-erection amplitude and both erection hardness score (EHS) and resistive index (RI). APD index and EHS as well as the international index of erectile function-5 (IIEF) and RI were positively correlated. RTI and AI were inversely correlated to IIEF and RI. PI was positively correlated to RI. PPG may therefore be useful as a noninvasive, convenient, technique for sexual function evaluation.

Proton pump inhibitors (PPIs) are widely prescribed in medical practice for the treatment of several gastrointestinal disorders. Previous epidemiology studies have reported the association between PPI use and the risk of AKI, although the magnitude of the association between PPIs and the risk of acute kidney injury (AKI) remains uncertain. Therefore, we conducted a meta-analysis to determine the relationship between PPI therapy and the risk of AKI. We systematically searched for relevant articles published before January 2023 on PubMed, Scopus, and Web of Science. In addition, we conducted a manual search of the bibliographies of potential articles. Two independent reviewers examined the appropriateness of all studies for inclusion. We pooled studies that compared the risk of AKI with PPI against their control using a random effect model. The search criteria based on PRISMA guidelines yielded 568 articles. Twelve observational studies included 2,492,125 individuals. The pooled adjusted RR demonstrated a significant positive association between PPI therapy and the risk of AKI (adjusted RR 1.75, 95% CI: 1.40–2.19, p < 0.001), and it was consistent across subgroups. A visual presentation of the funnel plot and Egger’s regression test showed no evidence of publication bias. Our meta-analysis indicated that persons using PPIs exhibited an increased risk of AKI. North American individuals had a higher risk of AKI compared to Asian and European individuals. However, the pooled effect from observational studies cannot clarify whether the observed association is a causal effect or the result of some unmeasured confounding factors. Hence, the biological mechanisms underlying this association are still unclear and require further research.

Abstract Perfect absorbers (PAs) at near infrared allow various applications such as biosensors, nonlinear optics, color filters, thermal emitters and so on. These PAs, enabled by plasmonic resonance, are typically powerful and compact, but confront inherent challenges of narrow bandwidth, polarization dependence, and limited incident angles as well as requires using expensive lithographic process, which limit their practical applications and mass production. In this work, we demonstrate a non-resonant PA that is comprised of six continuous layers of magnesium fluoride (MgF2) and chromium (Cr) in turns. Our device absorbs more than 90% of light in a broad range of 900–1900 nm. In addition, such a planar design is lithography-free, certainly independent with polarization, and presents a further advantage of wide incidence up to 70°. The measured performance of our optimized PA agrees well with analytical calculations of transfer matrix method (TMM) and numerical simulations of finite element method, and can be readily implemented for practical applications.

Exercise and sport practitioners frequently utilize rating of perceived exertion (RPE) to evaluate the players' psychophysiological strains during training sessions. The subjective rating of physical exertion level during sports training has been shown to have a reciprocal relationship with wellness status during periodic training or competitive seasons. However, the relationship between subjective physical exertions and wellness status during short-term overseas training camps (OTCs) has not been extensively investigated. This study aimed to examine the perceived responses of physical exertions [session-RPE (sRPE), training monotony, and training strain] and wellness status (fatigue, sleep, delayed onset muscle soreness, stress, and mood) measures in elite young adult futsal players from four separate OTCs with different training tasks. Twenty-seven U-20 male national team futsal players voluntarily participated in this study. The players recruited for OTCs were based on their performance during domestic training camps and the tactical demand of the team. The task of each OTCs was defined as: 1) 1st OTC = game-based camp (n = 14); 2) 2nd and 3rd OTC = training-based camp (n = 20 and n = 17, respectively); and 3) 4th OTC = pre-tournament camp (n = 14). The OTCs consisted of 11 training sessions (18.9 hours) and 16 friendly matches (23.8 hours). During daily training sessions and friendly matches, sRPE was used to quantify training load (TL). Additionally, a five-elements general wellness questionnaire was used to evaluate daily wellness status in the morning. The results demonstrated that the mean and sum sRPE in the game-based OTCs were significantly lower compared to the mean sRPE [p < 0.01, effect size (ES) = -4.8; p < 0.01, ES = -2.9] and sum sRPE in the training-based OTCs (p < 0.01, ES = -3.6; p < 0.01, ES = -3.1). The mean (p = 0.01; ES = -2.0) and sum sRPE (p < 0.01; ES = -3.4) in the game-based OTC were also lower than that in the pre-tournament OTC. Conversely, the wellness scores in the game-based OTC were higher compared to the training-based (p = 0.01; ES = 1.8) and the pre-tournament OTCs (p < 0.01; ES = 1.6). There was a negative relationship between mean and sum sRPE and all wellness scores (mean sRPE = r = -0.441 ~ -0.575, p < 0.001; sum sRPE = r = -0.41 ~ -0.559, p < 0.001). Our findings suggested that responses to training sessions, derived from mean and sum sRPE and wellness scores, are dependent upon the task-specific nature of OTCs among elite futsal players. Utilization of mean and sum sRPE and wellness measures to monitor the psychophysiological health during short-term OTCs is recommended.

Acute kidney injury (AKI) is a common syndrome characterized by various etiologies and pathophysiologic processes that deteriorate kidney function. The aim of this study is to identify potential biomarkers in the urine of non-acute kidney injury (non-AKI) and AKI patients through Raman spectroscopy (RS) to predict the advancement in complications and kidney failure. Selected spectral regions containing prominent peaks of renal biomarkers were subjected to partial least squares linear discriminant analysis (PLS-LDA). This discriminant analysis classified the AKI patients from non-AKI subjects with a sensitivity and specificity of 97% and 100%, respectively. In this study, the RS measurements of urine specimens demonstrated that AKI had significantly higher nitrogenous compounds, porphyrin, tryptophan and neopterin when compared with non-AKI. This study’s specific spectral information can be used to design an in vivo RS approach for the detection of AKI diseases.

Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in Drosophila alters chromatin organisation, induces intestinal autophagy through transcriptional regulation, and prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and Wdfy3 transcription, and alters chromatin organisation in the small intestine, suggesting that the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.

Background: Pleural fibrosis is defined as excessive depositions of matrix components that result in pleural tissue architecture destruction and dysfunction. In severe cases, the progression of pleural fibrosis leads to lung entrapment, resulting in dyspnea and respiratory failure. However, the mechanism of pleural fibrosis is poorly understood. Methods: miR-4739 levels were detected by miRNA array and real-time PCR. Real-time PCR, western blotting and immunofluorescence were used to identify the expression profile of indicators related to fibrosis. Target gene of miR-4739 and promoter activity assay was measured by using dual-luciferase reporter assay system. In vivo, pleural fibrosis was evaluated by Masson staining and miR-4739 level was detected by In situ hybridization histochemistry. Findings: We found that bleomycin induced up-regulation of miR-4739 in pleural mesothelial cells (PMCs). Over-regulated miR-4739 mediated mesothelial-mesenchymal transition and increased collagen-I synthesis in PMCs. Investigation on the clinical specimens revealed that high levels of miR-4739 and low levels of bone morphogenetic protein 7 (BMP-7) associated with pleural fibrosis in patients. Then we next identified that miR-4739 targeted and down-regulated BMP-7 which further resulted in unbalance between Smad1/5/9 and Smad2/3 signaling. Lastly, in vivo studies revealed that miR-4739 over-expression induced pleural fibrosis, and exogenous BMP-7 prevented pleural fibrosis in mice. Interpretation: Our data indicated that miR-4739 targets BMP-7 which mediates pleural fibrosis. The miR-4739/BMP-7 axis is a promising therapeutic target for the disease. Fund: The National Natural Science Foundation of China. Keywords: Pleural fibrosis, Pleural mesothelial cells (PMCs), miR-4739, BMP-7, Mesothelial-mesenchymal transition (MMT)

Introduction Preliminary evidence from clinical observations suggests that Tai Chi exercise may offer potential benefits for patients with chronic coronary syndrom (CCS). However, the advantages for CCS patients to practice Tai Chi exercise as rehabilitation have not been rigorously tested and there is a lack of consensus on its benefits. This study aims to develop an innovative Tai Chi Cardiac Rehabilitation Program (TCCRP) for CCS patients and to assess the efficacy, safety and acceptability of the programme.Methods and analysis We propose to conduct a multicentre randomised controlled clinical trial comprising of 150 participants with CCS. The patients will be randomly assigned in a 1:1 ratio into two groups. The intervention group will participate in a supervised TCCRP held three times a week for 3 months. The control group will receive supervised conventional exercise rehabilitation held three times a week for 3 months. The primary and secondary outcomes will be assessed at baseline, 1 month, 3 months after intervention and after an additional 3-month follow-up period. Primary outcome measures will include a score of 36-Item Short Form Survey and Chinese Perceived Stress Scale. The secondary outcome measures will include body composition, cardiopulmonary exercise test, respiratory muscle function, locomotor skills, echocardiogram, New York Heart Association classification, heart rate recovery time and laboratory examination. Other measures also include Seattle Angina Scale, Pittsburgh Sleep Quality Index, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 and Berg Balance Scale. All adverse events will be recorded and analysed.Ethics and dissemination This study conforms to the principles of the Declaration of Helsinki and relevant ethical guidelines. Ethical approval has been obtained from the Ethics Committee of Chinese People’s Libration Army General Hospital (approval number: S2019-060-02). Findings from this study will be published and presented at conferences for widespread dissemination of the results.Trial registration number NCT03936504.

Introduction The aim of this study was to understand the knowledge and current situation of antibiotic use among primary doctors in Sichuan Province, 10 years after the new healthcare reform, to analyze the implementation and impact of the relevant policies of the new healthcare reform, to analyze the reasons for the irrational use of antibiotics, and to provide relevant suggestions for the rational use of antibiotics. Methods From August 2018 to March 2019, five counties (cities) were randomly selected according to the level of urban development and geographical distribution in Sichuan Province, China. Various primary medical institutions and private clinics were randomly selected at different levels. Questionnaires and on-site interviews were conducted to quantitatively analyze doctors’ knowledge of antibiotic use and current situation. Views on antibiotic use were analyzed qualitatively and from multiple perspectives. A total of 492 questionnaires were issued, 430 of which were valid, with an effective recovery rate of 87.4% Results Quantitative analysis showed that 92.1% of 430 doctors surveyed knew the rules and authority of antibiotic use; 83.5% participated in antibiotic knowledge training; 56.7% would abide by guidance on antibiotic use; 72.6% thought that their knowledge of antibiotics needed to be improved. The rank-sum test shows that the cognitive differences of doctors with or without relevant training experience are statistically significant (p=0.018), those with the relevant training were better than the untrained doctors; the cognitive differences of doctors with different working years were statistically significant (p=0.038), and the doctors working under 10 years were better than those with 10–20 years; There was no significant difference in the correct rate of antibiotic use among doctors with different academic qualifications (p=0.077). There was no significant difference in knowing the correct rate of antibiotic use among doctors of different genders (p=0.076). Conclusions Ten years after the introduction of the new healthcare reform policy, the improvement of antibiotic use is still far from the expected goal; the knowledge of antibiotic rational use of doctors in primary medical institutions needs to be strengthened, especially in village clinics and private clinics; joint efforts of doctors, patients and supervisors are needed to promote the rational use of antibiotics.

Abstract We investigate the quantum optical properties of strong light-matter interaction between a quantum emitter and a metallic nanoparticle beyond idealized structures with a smooth surface. Based on the local coupling strength and macroscopic Green’s function, we derived an exact quantum optics approach to obtain the field enhancement and light-emission spectrum of a quantum emitter. Numerical simulations show that the surface roughness has a greater effect on the near-field than on the far-field, and slightly increases the vacuum Rabi splitting on average. Further, we verified that the near-field enhancement is mainly determined by the surface features of hot-spot area.

Abstract The levels of serum S100B were elevated in patients with ischemic stroke (IS), which may be a novel biomarker for diagnosing IS. The aim of this study was to investigate the association of S100B polymorphisms and serum S100B with IS risk. We genotyped the S100B polymorphisms rs9722, rs9984765, rs2839356, rs1051169 and rs2186358 in 396 IS patients and 398 controls using polymerase chain reaction-single base extension (SBE-PCR). Serum S100B levels were measured by enzyme-linked immunosorbent assay (ELISA). Rs9722 was associated with an increased risk of IS (AA vs. GG: adjusted OR = 2.172, 95% CI, 1.175–4.014, P = 0.013; dominant: adjusted OR = 1.507, 95% CI, 1.071–2.123, P = 0.019; recessive: adjusted OR = 1.846, 95% CI, 1.025–3.323, P = 0.041; additive: adjusted OR=1.371, 95% CI, 1.109-1.694, P = 0.003). The A-C-C-C-A haplotype was associated with an increased risk of IS (OR = 1.325, 95% CI, 1.035–1.696, P = 0.025). In addition, individuals carrying the rs9722 GA/AA genotypes had a higher serum S100B compared with the rs9722 GG genotype in IS patients (P = 0.018). Our results suggest that the S100B gene rs9722 polymorphism may contribute to the susceptibility of IS, probably by promoting the expression of serum S100B.

The purpose of this study was to test the feasibility of utilizing the established perimenopausal fatigue self-management scale (P-MFSMS) to evaluate perimenopausal Taiwanese women’s vulnerability to fatigue syndrome. A cross-sectional study design was adopted to survey 220 perimenopausal Taiwanese women with a mean age of 51.8 ± 4.64 years and a mean body mass index of 23.07 ± 3.04 kg/m2, 75.9% of whom were married, 52.3% had a college education or above, 80.4% had salaries, 81.3% had small families, and 96.4% were not using hormone therapy. The P-MFSMS consists of 25 questions based on six categories: (1) strive to maintain work energy and efficiency; (2) seek self-help from medical resources (doctor shopping); (3) strive to maintain the normal operation of the family (seeking help and support from family or significant other); (4) make time for activities or exercise in busy life; (5) slow down or adjust lifestyle; (6) frustration. For all of these six categories, the minimum loading of each question on the factor was calculated to be over 0.50, with a Cronbach’s α of 0.78 and a corrected total-item correlation of >0.50. The goodness of fit of the model was determined to be acceptable, with a chi-square/df value of χ2 = 503.45 and df = 260), a root mean square error of approximation (RMSEA) value of 0.065 (0.90. There was no statistically significant difference in the difficulty between perimenopausal and postmenopausal women utilizing differential item function (DIF) analysis. Taken together, the 25-question P-MFSMS may be a potentially valid and reliable instrument for suitably evaluating perimenopausal Taiwanese women’s vulnerability to fatigue syndrome. Future studies will be conducted to test the effectiveness of the P-MFSMS for evaluating perimenopausal Taiwanese women’s vulnerability to fatigue syndrome in clinical practice.

Abstract Glioma is the most common and aggressive type of brain tumor. While long non-coding RNAs (lncRNAs) are clearly more abundant in human brain than protein-coding genes, the specific roles of lncRNAs and mechanisms underlying their dysregulation in glioma remain unclear. Here, we focused on lncRNAs that are differentially expressed in brain tumor and their potential biological functions. LOC441204, a novel non-coding RNA gene displaying high expression in clinical specimens of brain tumor and significant upregulation in glioma cell lines in microarray analyses, was selected for further study. Notably, knockdown of LOC441204 suppressed tumor cell proliferation in two glioma cell lines. Moreover, LOC441204-induced tumor cell growth was mediated the stabilization of β-catenin pathway. Briefly, LOC441204 bound to β-catenin preventing its degradation, resulting in downstream p21 repression and cdk4 activation to enhance glioma cell proliferation. Collectively, our findings indicate a pro-oncogenic role of LOC441204 in tumor cell growth through activation of the β-catenin/p21/cdk4 cascade to act as a potential diagnostic marker or therapeutic target in brain tumor.

Abstract Background Although vertebrates are bilaterally symmetric organisms, their internal organs are distributed asymmetrically along a left-right axis. Disruption of left-right axis asymmetric patterning often occurs in human genetic disorders. In zebrafish embryos, Kupffer’s vesicle, like the mouse node, breaks symmetry by inducing asymmetric expression of the Nodal-related gene, spaw, in the left lateral plate mesoderm (LPM). Spaw then stimulates transcription of itself and downstream genes, including lft1, lft2, and pitx2, specifically in the left side of the diencephalon, heart and LPM. This developmental step is essential to establish subsequent asymmetric organ positioning. In this study, we evaluated the role of krüppel-like factor 8 (klf8) in regulating left-right asymmetric patterning in zebrafish embryos. Methods Zebrafish klf8 expression was disrupted by both morpholino antisense oligomer-mediated knockdown and a CRISPR-Cas9 system. Whole-mount in situ hybridization was conducted to evaluate gene expression patterns of Nodal signalling components and the positions of heart and visceral organs. Dorsal forerunner cell number was evaluated in Tg(sox17:gfp) embryos and the length and number of cilia in Kupffer’s vesicle were analyzed by immunocytochemistry using an acetylated tubulin antibody. Results Heart jogging, looping and visceral organ positioning were all defective in zebrafish klf8 morphants. At the 18–22 s stages, klf8 morphants showed reduced expression of genes encoding Nodal signalling components (spaw, lft1, lft2, and pitx2) in the left LPM, diencephalon, and heart. Co-injection of klf8 mRNA with klf8 morpholino partially rescued spaw expression. Furthermore, klf8 but not klf8△zf overexpressing embryos showed dysregulated bilateral expression of Nodal signalling components at late somite stages. At the 10s stage, klf8 morphants exhibited reductions in length and number of cilia in Kupffer’s vesicle, while at 75% epiboly, fewer dorsal forerunner cells were observed. Interestingly, klf8 mutant embryos, generated by a CRISPR-Cas9 system, showed bilateral spaw expression in the LPM at late somite stages. This observation may be partly attributed to compensatory upregulation of klf12b, because klf12b knockdown reduced the percentage of klf8 mutants exhibiting bilateral spaw expression. Conclusions Our results demonstrate that zebrafish Klf8 regulates left-right asymmetric patterning by modulating both Kupffer’s vesicle morphogenesis and spaw expression in the left LPM.

Hindsight bias (HB) is the tendency to retrospectively exaggerate one's foresight knowledge about the outcome of an event. Cognitive processes influenced by newly obtained outcome information are used to explain the HB phenomenon, but the neural correlates remain unknown. This study investigated HB in the context of election results using a memory design and functional magnetic resonance imaging for the first time. Participants were asked to predict and recall the percentage of votes obtained by (pairs of) candidates before and after an election. The results revealed that 88% of participants showed HB by recalling that their predictions were closer to the actual outcomes than they really were; and participants had HB for 38% of the events. The HB effect was associated with activation in the medial superior frontal gyrus and bilateral inferior frontal gyrus (IFG), which have been implicated in updating an old belief due to new information and is similar to the process of reconstruction bias. Furthermore, participants with a greater HB effect showed greater activation of the left IFG. In conclusion, we successfully observed the HB phenomenon in election results, and our imaging results suggested that the HB phenomenon might involve reconstruction bias.

Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.

Background: Appropriate expression and regulation of the transcriptome, which mainly comprise of mRNAs and lncRNAs, are important for all biological and cellular processes including the physiological activities of bone microvascular endothelial cells (BMECs). Through an intricate intracellular signaling systems, the transcriptome regulates the pharmacological response of the cells. Although studies have elucidated the impact of glucocorticoids (GCs) cell-specific gene expression signatures, it remains necessary to comprehensively characterize the impact of lncRNAs to transcriptional changes. Methods: BMECs were divided into two groups. One was treated with GCs and the other left untreated as a paired control. Differential expression was analyzed with GeneSpring software V12.0 (Agilent, Santa Clara, CA, USA) and hierarchical clustering was conducted using Cluster 3.0 software. The Gene Ontology (GO) analysis was performed with Molecular Annotation System provided by CapitalBio Corporation. Results: Our results highlight the involvement of genes implicated in development, differentiation and apoptosis following GC stimulation. Elucidation of differential gene expression emphasizes the importance of regulatory gene networks induced by GCs. We identified 73 up-regulated and 166 down-regulated long noncoding RNAs, the expression of 107 of which significantly correlated with 172 mRNAs induced by hydrocortisone. Conclusions: Transcriptome analysis of BMECs from human samples was performed to identify specific gene networks induced by GCs. Our results identified complex RNA crosstalk underlying the pathogenesis of steroid-induced necrosis of femoral head.