Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Dialysis and Cardiovascular Disease in Patients With Stage 5 Chronic Kidney Disease.

BACKGROUND: No studies have reported the long-term outcomes of initiating sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with estimated glomerular filtration rates less than 20 mL/min/1.73 m2 to predialysis. OBJECTIVE: To compare the risk for dialysis, cardiovascular events, and death between SGLT2i users and nonusers in patients with type 2 diabetes (T2D) and stage 5 chronic kidney disease (CKD). DESIGN: Target trial emulation study. SETTING: Taiwan's National Health Insurance Research Database (NHIRD). PARTICIPANTS: By applying sequential target trial emulation principle, 23 854 SGLT2i users and 23 892 SGLT2i nonusers were selected from the NHIRD for patients with T2D and stage 5 CKD from 1 May 2016 to 31 October 2021. MEASUREMENTS: Conditional Cox proportional hazards models were used to compare the risks for dialysis, hospitalization for heart failure, acute myocardial infarction (AMI), diabetic ketoacidosis (DKA), acute kidney injury (AKI), and all-cause mortality between SGLT2i users and nonusers. RESULTS: In the intention-to-treat model, compared with no SGLT2i use, SGLT2i use was associated with lower risks for dialysis (hazard ratio [HR], 0.34 [95% CI, 0.27 to 0.43]), hospitalization for heart failure (HR, 0.80 [CI, 0.73 to 0.86]), AMI (HR, 0.61 [CI, 0.52 to 0.73]), DKA (HR, 0.78 [CI, 0.71 to 0.85]), and AKI (HR, 0.80 [CI, 0.70 to 0.90]), but there was no difference in the risk for all-cause mortality (HR, 1.11 [CI, 0.99 to 1.24]). The Kaplan-Meier curves and subgroup analyses also showed that initiation of an SGLT2i in stage 5 CKD was associated with a lower risk for long-term dialysis than no SGLT2i use. LIMITATION: This result may not apply to patients without T2D. CONCLUSION: This emulated target trial showed that SGLT2i use was associated with a lower risk for dialysis, cardiovascular events, DKA, and AKI than no SGLT2i use in patients with T2D and stage 5 CKD. PRIMARY FUNDING SOURCE: National Health Research Institutes, Taiwan.

Tranilast alleviates skin inflammation and fibrosis in rosacea-like mice induced by long-term exposure to LL-37.

Rosacea, a prevalent chronic facial inflammatory condition, afflicts millions worldwide. Its multifaceted pathogenesis poses challenges for effective treatment. Tranilast (TR), an analog of a tryptophan metabolite, has demonstrated anti-inflammatory and anti-fibrotic properties across various diseases. Yet, its potential in rosacea treatment remains understudied. Here, we induced rosacea-like symptoms in mice via prolonged LL-37 injections and administered TR intervention. Our findings reveal that TR mitigated skin lesions, reduced skin thickness, and suppressed inflammatory cell infiltration within the dermis of LL-37 mice. Notably, TR downregulated the expression of rosacea-associated inflammatory cytokines (TNF-α, IL-6, IL-1ß, and IL-18) and the antimicrobial peptide CAMP, while also inhibiting NLRP3 inflammasome activation and the TLR4 signaling pathway. Furthermore, TR attenuated LL-37-induced fibrosis and hindered the transforming growth factor-ß1 (TGF-ß1)/Smad2/3 pathway. In summary, our study underscores TR's therapeutic potential in rosacea by mitigating both skin inflammation and fibrosis, thereby offering a promising treatment avenue for this condition.

Differences in antibiotic use between COPD and non-COPD residents based on the health information system.

OBJECTIVES: To compare the differences in antibiotic use between COPD and non-COPD residents, and to explore the effect of COPD on antibiotic use. METHODS: Participants aged 40 years old or over from the Songjiang Adult Cohort were included. Information on prescription and baseline survey was collected based on the health information system. A logit-negative binomial Hurdle model was used to explore correlations between COPD and percentage of antibiotic use and average rate of antibiotic prescribing of different types of antibiotic. Multinomial logistic regression was used to assess the association between COPD and antimicrobial combination therapy and routes of administration. RESULTS: A total of 34576 individuals were included and 1594 (4.6%) were COPD patients. During the 6 years' follow-up, the percentage of antibiotic use for COPD patients was 98.4%, which was 7.88 (95%CI: 5.24-11.85) times of that for non-COPD patients after adjusting for potential confounders. The prescribing rate was 3220 prescriptions (95%CI: 3063.6-3385.2) per 1000 person-years for COPD patients, which was 1.96 (95%CI: 1.87-2.06) times of that for non-COPD patients. Other beta-lactam antibacterials, Macrolides, lincosamides and streptogramins, and quinolone antibacterials were the most commonly used types of antibiotic. Except for aminoglycoside antibacterials, both percentage of antibiotic use and rate of antibiotic prescription were increased in COPD patients. COPD patients were more likely to be prescribed a maximum of two antibiotics (OR=1.34, 95%CI: 1.20-1.50); and were more likely to use antibiotics intravenously (OR=2.77, 95%CI: 2.47-3.11). CONCLUSION: COPD patients were more likely to have increased antibiotic use in a large-scale population-based adult cohort, suggesting COPD patients are a high-priority group for the management of antibiotic use in communities.

Modulating hierarchical learning by high-definition transcranial alternating current stimulation at theta frequency.

Considerable evidence highlights the dorsolateral prefrontal cortex (DLPFC) as a key region for hierarchical (i.e. multilevel) learning. In a previous electroencephalography (EEG) study, we found that the low-level prediction errors were encoded by frontal theta oscillations (4-7 Hz), centered on right DLPFC (rDLPFC). However, the causal relationship between frontal theta oscillations and hierarchical learning remains poorly understood. To investigate this question, in the current study, participants received theta (6 Hz) and sham high-definition transcranial alternating current stimulation (HD-tACS) over the rDLPFC while performing the probabilistic reversal learning task. Behaviorally, theta tACS induced a significant reduction in accuracy for the stable environment, but not for the volatile environment, relative to the sham condition. Computationally, we implemented a combination of a hierarchical Bayesian learning and a decision model. Theta tACS induced a significant increase in low-level (i.e. probability-level) learning rate and uncertainty of low-level estimation relative to sham condition. Instead, the temperature parameter of the decision model, which represents (inverse) decision noise, was not significantly altered due to theta stimulation. These results indicate that theta frequency may modulate the (low-level) learning rate. Furthermore, environmental features (e.g. its stability) may determine whether learning is optimized as a result.

Urban people's preferences for life-sustaining treatment or artificial nutrition and hydration in advance decisions.

BACKGROUND: The Patient Right to Autonomy Act (PRAA), implemented in Taiwan in 2019, enables the creation of advance decisions (AD) through advance care planning (ACP). This legal framework allows for the withholding and withdrawal of life-sustaining treatment (LST) or artificial nutrition and hydration (ANH) in situations like irreversible coma, vegetative state, severe dementia, or unbearable pain. This study aims to investigate preferences for LST or ANH across various clinical conditions, variations in participant preferences, and factors influencing these preferences among urban residents. METHODS: Employing a survey of legally structured AD documents and convenience sampling for data collection, individuals were enlisted from Taipei City Hospital, serving as the primary trial and demonstration facility for ACP in Taiwan since the commencement of the PRAA in its inaugural year. The study examined ADs and ACP consultation records, documenting gender, age, welfare entitlement, disease conditions, family caregiving experience, location of ACP consultation, participation of second-degree relatives, and the intention to participate in ACP. RESULTS: Data from 2337 participants were extracted from electronic records. There was high consistency in the willingness to refuse LST and ANH, with significant differences noted between terminal diseases and extremely severe dementia. Additionally, ANH was widely accepted as a time-limited treatment, and there was a prevalent trend of authorizing a health care agent (HCA) to make decisions on behalf of participants. Gender differences were observed, with females more inclined to decline LST and ANH, while males tended towards accepting full or time-limited treatment. Age also played a role, with younger participants more open to treatment and authorizing HCA, and older participants more prone to refusal. CONCLUSION: Diverse preferences in LST and ANH were shaped by the public's current understanding of different clinical states, gender, age, and cultural factors. Our study reveals nuanced end-of-life preferences, evolving ADs, and socio-demographic influences. Further research could explore evolving preferences over time and healthcare professionals' perspectives on LST and ANH decisions for neurological patients..

Early Antiplatelet Resumption and the Risks of Major Bleeding After Intracerebral Hemorrhage.

BACKGROUND: The appropriate timing of resuming antithrombotic therapy after intracerebral hemorrhage (ICH) remains unclear. The aim of this study was to compare the risks of major bleeding between early and late antiplatelet resumption in ICH survivors. METHODS: Between 2008 and 2017, ICH patients were available in the National Health Insurance Research Database. Patients with a medication possession ratio of antiplatelet treatment ≥50% before ICH and after antiplatelet resumption were screened. We excluded patients with atrial fibrillation, heart failure, under anticoagulant or hemodialysis treatment, and developed cerebrovascular events or died before antiplatelet resumption. Finally, 1584 eligible patients were divided into EARLY (≤30 days) and LATE groups (31-365 days after the index ICH) based on the timing of antiplatelet resumption. Patients were followed until the occurrence of a clinical outcome, end of 1-year follow-up, death, or until December 31, 2018. The primary outcome was recurrent ICH. The secondary outcomes included all-cause mortality, major hemorrhagic events, major occlusive vascular events, and ischemic stroke. Cox proportional hazard model after matching was used for comparison between the 2 groups. RESULTS: Both the EARLY and LATE groups had a similar risk of 1-year recurrent ICH (EARLY versus LATE: 3.12% versus 3.27%; adjusted hazard ratio [AHR], 0.967 [95% CI, 0.522-1.791]) after matching. Both groups also had a similar risk of each secondary outcome at 1-year follow-up. Subgroup analyses disclosed early antiplatelet resumption in the patients without prior cerebrovascular disease were associated with lower risks of all-cause mortality (AHR, 0.199 [95% CI, 0.054-0.739]) and major hemorrhagic events (AHR, 0.090 [95% CI, 0.010-0.797]), while early antiplatelet resumption in the patients with chronic kidney disease were associated with a lower risk of ischemic stroke (AHR, 0.065 [95% CI, 0.012-0.364]). CONCLUSIONS: Early resumption of antiplatelet was as safe as delayed antiplatelet resumption in ICH patients. Besides, those without prior cerebrovascular disease or with chronic kidney disease may benefit more from early antiplatelet resumption.

Recent advances in the structure and activation mechanisms of metabolite-releasing Pannexin 1 channels.

Pannexin 1 (PANX1) is a widely expressed large-pore ion channel located in the plasma membrane of almost all vertebrate cells. It possesses a unique ability to act as a conduit for both inorganic ions (e.g. potassium or chloride) and bioactive metabolites (e.g. ATP or glutamate), thereby activating varying signaling pathways in an autocrine or paracrine manner. Given its crucial role in cell-cell interactions, the activity of PANX1 has been implicated in maintaining homeostasis of cardiovascular, immune, and nervous systems. Dysregulation of PANX1 has also been linked to numerous diseases, such as ischemic stroke, seizure, and inflammatory disorders. Therefore, the mechanisms underlying different modes of PANX1 activation and its context-specific channel properties have gathered significant attention. In this review, we summarize the roles of PANX1 in various physiological processes and diseases, and analyze the accumulated lines of evidence supporting diverse molecular mechanisms associated with different PANX1 activation modalities. We focus on examining recent discoveries regarding PANX1 regulations by reversible post-translational modifications, elevated intracellular calcium concentration, and protein-protein interactions, as well as by irreversible cleavage of its C-terminal tail. Additionally, we delve into the caveats in the proposed PANX1 gating mechanisms and channel open-closed configurations by critically analyzing the structural insights derived from cryo-EM studies and the unitary properties of PANX1 channels. By doing so, we aim to identify potential research directions for a better understanding of the functions and regulations of PANX1 channels.

Associations of liver fat content with cardiometabolic phenotypes and outcomes in a multi-ethnic population: Results from the Dallas Heart Study.

AIMS: To evaluate the associations between liver fat content and cardiometabolic parameters to explore potential threshold values that define metabolically healthy liver fat content, and to examine the association of liver fat content with cardiovascular events as well as its longitudinal progression. METHODS: Participants in the Dallas Heart Study underwent clinical evaluation, including laboratory testing, and liver fat quantification by magnetic resonance spectroscopy (MRS) at baseline (N = 2287) and at follow-up (N = 343) after a mean of 7.3 years. Cardiovascular events were adjudicated (>12 years). RESULTS: The mean age at study entry was 44 years, 47% of participants were men, and 48% were African American. The following cardiometabolic biomarkers worsened across liver fat quintiles (P < 0.0001): body mass index (BMI); waist circumference; prevalence of hypertension; prevalence of diabetes; cholesterol, triglyceride, high-sensitivity C-reactive protein (CRP), leptin and fasting glucose levels; homeostatic model assessment of insulin resistance index (HOMA-IR); coronary artery calcium score; visceral adipose tissue; abdominal subcutaneous adipose tissue; and lower body subcutaneous adipose tissue. Cardiovascular events were comparable across groups defined by tertile of baseline liver fat content. Change in BMI (R = 0.40), waist circumference (R = 0.35), CRP (R = 0.31), alanine aminotransferase (R = 0.27), HOMA-IR (R = 0.26), aspartate transaminase (R = 0.15) and triglycerides (R = 0.12) significantly correlated with change in liver fat content (P < 0.01 for all). CONCLUSION: Clinically relevant metabolic abnormalities were higher across quintiles of liver fat, with increases noted well within normal liver fat ranges, but cardiovascular events were not associated with liver fat content. Longitudinal changes in metabolic parameters, especially adiposity-related parameters, were correlated with change in liver fat content.

Relationship of sleep duration with incident cardiovascular outcomes: a prospective study of 33,883 adults in a general population.

BACKGROUND: Studies on the effect of sleep duration on cardiovascular health have contradictory findings. Underlying health issues may have led to inconsistent results and warrant consideration. We aim to assess the relationship of night sleep duration with incident cardiovascular disease (CVD) in a general population, taking into consideration underlying chronic diseases. METHODS: Data from Shanghai Suburban Adult Cohort and Biobank with a median follow-up of 5.1 years was used, including 33,883 adults aged 20-74 years old. Incident CVD cases were reported and recorded by the Center for Disease Prevention and Control in Songjiang, Shanghai. We used Cox proportional hazard regression models and restricted cubic spline (RCS) analysis to explore the relationship between different sleep groups and sleep duration with incident CVD outcomes, through stratification by gender and age, as well as different health conditions, with adjustments for potential confounders. RESULTS: Long sleep duration (> 9 h) compared to > 7 to ≤ 8 h was associated with overall incident CVD in participants aged ≥ 50 years old: HR(95%CI) = 2.07 (1.15, 3.74) for 50-59y and 1.43 (1.04, 1.93) for 60-74y. RCS analysis showed a J-shaped relationship between sleep and CVD risk in those ≥ 50y, which was confirmed only in those with a chronic health condition. Non-linear relationships between sleep and CVD risk factors, such as BMI, blood glucose and glycated haemoglobin, were observed. CONCLUSIONS: Long sleep duration is associated with increased risk of CVD in people ≥ 50y. However, CVD risk factors and underlying health conditions such as hypertension, and diabetes, may play a driving role in the relationship.

Demographics, employment, and proximity to covid-19 as predictors of preparedness among Taiwanese health social workers.

COVID-19 struck the world violently and cause negative psychological consequences on health professionals. The preparedness of social workers for the pandemic is critical while facing these challenges and pressures. The study aimed to explore what are the roles of demographic, employment, and proximity to Covid-19 in predicting preparedness for the next wave of COVID among social workers in Taiwan. A total of 158 participants were conveniently sampled and multiple regression, univariate analysis, and two-way ANOVA were conducted. The results demonstrated that the demographic and employment variables significantly predicted preparedness, and there were significant differences among demographics on preparedness and an interaction effect between seniority and age. Consequently, middle-aged social workers with junior seniority years may have more difficulties in their preparation for the current situation. The implication of our findings is also discussed.

Association between estimated glomerular filtration rate and 10-year atherosclerotic cardiovascular disease risk among community residents in Shanghai, China.

BACKGROUND AND AIMS: The association between the estimated glomerular filtration rate (eGFR) and atherosclerotic cardiovascular disease (ASCVD) risk is unknown. We aimed to evaluate whether eGFR can be used as a predictor in ASCVD risk assessment. METHODS AND RESULTS: Using baseline data from 28,187 participants from Shanghai Suburban Adult Cohort and Biobank study, we adopted Pooled Cohort Equations (PCEs) and Prediction for ASCVD Risk in China (China-PAR) to estimate 10-year ASCVD risk. Multivariate logistic regression was used to analyze the relationship between 10-year ASCVD risk and eGFR. The receiver operating characteristic (ROC) curve was used to evaluate predictive value of eGFR for 10-year high ASCVD risk. Compared with normal eGFR, both men and women with reduced eGFR had a higher prevalence of ASCVD risk factors. With the decrease of eGFR level, the median of 10-year ASCVD risk gradually increased. For men, the adjusted odds ratios (95% confidence interval (CI)) of 10-year high ASCVD risk by PCEs associated with eGFR (60-74 and <60 mL/min/1.73 m2) were 1.52 (95%CI:1.17-1.99) and 2.51 (95%CI:1.27-4.97). The corresponding result was significant only for eGFR < 60 mL/min/1.73 m2, OR of 1.57 (1.14-2.18) for women. Using China-PAR, the adjusted OR of 10-year high risk associated with eGFR < 60 mL/min/1.73 m2 was 1.82 (1.40-2.38) in men. ROC indicated that eGFR has a good predictive value for 10-year high ASCVD risk. CONCLUSION: eGFR may be an important risk factor in predicting and stratifying ASCVD risk. Consideration should be given to integrating eGFR into existing risk assessment tools to improve predictive performance.

Association between four nontraditional lipids and ischemic stroke: a cohort study in Shanghai, China.

BACKGROUND: The correlation between nontraditional lipids and ischemic stroke (IS) is inconsistent and controversial. This study aimed to examine the association of four nontraditional lipids with IS risk in Chinese adults. METHODS: This prospective community-based cohort study was performed in Songjiang District, Shanghai, China. The study began in 2016 and included 34,294 participants without stroke before the investigation. The association between nontraditional lipids (nonhigh-density lipoprotein cholesterol [non-HDL-C], total cholesterol/high-density lipoprotein cholesterol [TC/HDL-C], triglyceride [TG]/HDL-C, and low-density lipoprotein cholesterol [LDL-C]/HDL-C) and IS was studied with multivariate Cox regression models. The dose-response associations between these four serum lipids and IS were explored using restricted cubic spline (RCS) analysis. RESULTS: There were a total of 458 IS cases with 166,380 person-years of follow-up. Compared with the lowest tertiles, the highest tertiles of the nontraditional blood lipids showed greater IS risk after controlling for potential confounders. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were as follows: TC/HDL-C, 1.63 (1.28-2.07); TG/HDL-C, 1.65 (1.28-2.13); LDL-C/HDL-C, 1.51 (1.18-1.92); and non-HDL-C, 1.43 (1.13-1.81). The fully adjusted RCS curves presented a nonlinear relationship, and the risk increased when the TC/HDL-C, TG/HDL-C, and LDL-C/HDL-C levels were > 3.47, > 0.92, and > 1.98, respectively. CONCLUSIONS: This community-based cohort study presents a positive association between the four nontraditional lipids and IS incidence. Maintaining relatively low lipid ratios can be beneficial for preventing stroke. Nontraditional lipids can be considered targets for managing blood lipids.

Bazi Bushen capsule attenuates cognitive deficits by inhibiting microglia activation and cellular senescence.

CONTEXT: Bazi Bushen capsule (BZBS) has anti-ageing properties and is effective in enhancing memory. OBJECTIVE: To find evidence supporting the mechanisms and biomarkers by which BZBS functions. MATERIALS AND METHODS: Male C57BL/6J mice were randomly divided into five groups: normal, ageing, ß-nicotinamide mononucleotide capsule (NMN), BZBS low-dose (LD-BZ) and BZBS high-dose (HD-BZ). The last four groups were subcutaneously injected with d-galactose (d-gal, 100 mg/kg/d) to induce the ageing process. At the same time, the LD-BZ, HD-BZ and NMN groups were intragastrically injected with BZBS (1 and 2 g/kg/d) and NMN (100 mg/kg/d) for treatment, respectively. After 60 days, the changes in overall ageing status, brain neuron morphology, expression of p16INK4a, proliferating cell nuclear antigen (PCNA), ionized calcium-binding adapter molecule 1 (Iba1), postsynaptic density protein 95 (PSD95), CD11b, Arg1, CD206, Trem2, Ym1 and Fizz1, and the senescence-associated secretory phenotype (SASP) factors were observed. RESULTS: Compared with the mice in the ageing group, the HD-BZ mice exhibited obvious improvements in strength, endurance, motor coordination, cognitive function and neuron injury. The results showed a decrease in p16INK4a, Iba1 and the upregulation of PCNA, PSD95 among brain proteins. The brain mRNA exhibited downregulation of Iba1 (p < 0.001), CD11b (p < 0.001), and upregulation of Arg1 (p < 0.01), CD206 (p < 0.05), Trem2 (p < 0.001), Ym1 (p < 0.01), Fizz1 (p < 0.05) and PSD95 (p < 0.01), as well as improvement of SASP factors. CONCLUSIONS: BZBS improves cognitive deficits via inhibition of cellular senescence and microglia activation. This study provides experimental evidence for the wide application of BZBS in clinical practice for cognitive deficits.

Changes in the gut microbiota: a possible factor influencing peripheral blood immune indexes in non-obese diabetic mice.

Intestinal flora changes were found in patients and animals with type 1 diabetes (T1D). However, few studies have provided any explicit clues of changes in highly disease related commensal microbiota before disease onset and their relationships with disordered peripheral immune cells. We conducted 16S rRNA microbiota analysis of non-obese diabetic (NOD) mice from weaning to diabetes onset to identify highly disease related microbes and performed Spearman correlation analysis between anomalous flora and peripheral immune cells. We found NOD mice had increased exclusive bacteria and decreased community richness or diversity, besides, with the features of decreased abundance of Bacteroidetes and increased abundance of Firmicutes, Proteobacteria or Deferribacteres and remarkable fluctuations of genus relative abundance. Furthermore, kinds of highly T1D related genus and their strong correlations with peripheral immune cells, especially neutrophils, were discovered. Microbial changes in NOD mice differed from that of ICR mice and highly disease associated microbes have strong correlations with the peripheral neutrophil ratio, which provide evidence that neutrophils are possibly involved in the pathogenesis of T1D.

Catheter Ablation Compared with Medical Therapy for Atrial Fibrillation with Heart Failure: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Background: The optimal strategy for patients with coexisting atrial fibrillation (AF) and heart failure (HF) was not settled. Our purpose was to conduct a systematic review and meta-analysis of randomized controlled trials to evaluate the effect of catheter ablation compared with medical therapy for AF on mortality, HF hospitalization, left ventricular (LV) function, and quality of life among patients with HF and AF. Materials and Methods: We searched Pubmed (1966 to September 20, 2019), EMBASE (1966 to September 20, 2019), the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov for randomized controlled trials with a comparison of catheter ablation for AF with medical therapy among patients with coexisting AF and HF. Risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI) was used as a measure of the effect of catheter ablation versus medical therapy on endpoints. Our final analysis included 6 randomized control trials with 775 patients. Results: Pooled results from the random-effects model showed that compared with medical therapy for AF, catheter ablation was associated with reduced all-cause mortality (RR 0.52, 95%Cl, 0.35 to 0.76) and HF hospitalization (RR 0.56, 95%Cl, 0.44 to 0.71), as well as increased LV ejection fraction (LVEF), distance walked in six minutes, and improvements in quality of life. Conclusions: This updated meta-analysis showed that compared to medical therapy, catheter ablation for AF was associated with significant benefits in several key clinical and biomarker endpoints, including reductions in all-cause mortality and HF hospitalization.

Timing of the first cannulation and survival of arteriovenous grafts in hemodialysis patients: a multicenter retrospective cohort study.

Arteriovenous graft (AVG) is an important vascular access route in hemodialysis patients. The optimal waiting time between AVG creation and the first cannulation is still undetermined, therefore the current study investigated the association between ideal timing for cannulation and AVG survival. This retrospective cohort study used data from the Taiwan National Health Insurance Database, which included 6,493 hemodialysis patients with AVGs between July 1st 2008 and June 30th 2012. The waiting cannulation time was defined as the time from the date of shunt creation to the first successful cannulation. Patients were categorized according to the waiting cannulation time of their AVGs as follows: ≤30 days, between 31 and 90 days, between 91 and 180 days, and >180 days. The primary outcome was functional cumulative survival, measured as the time from the first cannulation to shunt abandonment. The AVGs which were cannulated between 31 and 90 days (reference group) after construction had significantly superior functional cumulative survival compared with those cannulated ≤30 days (adjusted HR = 1.651 with 95% CI 1.482-1.839; p < 0.0001) and >180 days (adjusted HR = 1.197 with 95% CI 1.012-1.417; p = 0.0363) after construction. An analysis of the hazard ratios in patients with different demographic characteristics, revealed that the functional cumulative survival of AVGs in most groups was better when they received cannulation >30 days after construction. Consequently, in order to achieve the best long-term survival, AVGs should be cannulated at least 1 month after construction, but you should avoid waiting for >3 months.

Recent development of AAV-based gene therapies for inner ear disorders.

Gene therapy for auditory diseases is gradually maturing. Recent progress in gene therapy treatments for genetic and acquired hearing loss has demonstrated the feasibility in animal models. However, a number of hurdles, such as lack of safe viral vector with high efficiency and specificity, robust deafness large animal models, translating animal studies to clinic etc., still remain to be solved. It is necessary to overcome these challenges in order to effectively recover auditory function in human patients. Here, we review the progress made in our group, especially our efforts to make more effective and cell type-specific viral vectors for targeting cochlea cells.

Correction: Recent development of AAV-based gene therapies for inner ear disorders.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Preparation of Highly Swelling/Antibacterial Cross-Linked N-Maleoyl-Functional Chitosan/Polyethylene Oxide Nanofiber Meshes for Controlled Antibiotic Release.

Due to the cell affinity of chitosan (CS) and the hydrophilicity of polyethylene oxide (PEO), CS/PEO composited nanofiber meshes (NFMs) have been extensively used as wound healing dressings for skin tissue regeneration. Nonetheless, numerous innate drawbacks of the NFM system such as the use of toxic spinning solvents and cross-linkers, moderate water regain capacity, and lack of triggered release function significantly hampered their biomedical applications. In order to enhance their performances in promoting cell growth and preventing bacterial infection, highly swelling cross-linked N-maleoyl-functional chitosan (MCS)/PEO NFMs have been developed as the next-generation CS/PEO NFM system through an acid-free electrospinning process and a UV-irradiated cross-linked treatment without the use of aldehyde-containing cross-linkers. With the simultaneous introduction of ethylene oxide chains and disulfide bonds in the cross-linkages, this new NFM system displays enhanced swelling capability, antibacterial ability, triggered antibiotic release, and high biocompatibility. These biomedical merits enable the new NFM systems to be utilized as tissue scaffolds, especially for functional wound healing dressings.

Ginsenoside CK-loaded self-nanomicellizing solid dispersion with enhanced solubility and oral bioavailability.

Ginsenoside compound K (CK) is a major ginsenoside metabolite of protopanaxadiol, which exhibits numerous pharmacological activity such as cardioprotective and antidiabetic. However, the therapeutic application of CK is hampered by its physicochemical characteristics and low oral bioavailability (BA). The present work aims at the preparation of CK to improve its dissolution and enhance the oral BA for the management of arrhythmia by using self-nanomicellizing solid dispersion system (SSD). The formulations were characterized by advanced techniques like DSC, XRD, FTIR, SEM and XRD. In the in vivo pharmacokinetic study, UPLC-MS/MS was used to measure the concentration of CK in plasma. Mapping Lab was applied in the experiment of perfused intact hearts to determine the ventricular rate and ventricular conduction velocity. The solubility of CK-SSD8 was 4658.11 ± 6.66 µg/ml, which is 130-fold than free CK, and the dissolution rate was faster than any other dosage forms. The average diameters of CK-SSD were smaller than 100 nm. The in vivo pharmacokinetic study revealed that the AUC(0-24) of CK-SSD8 formulation was 2.02-fold higher than pure CK. Moreover, the study performed to evaluate the efficiency in arrhythmia treatment showed a reduced ventricular rate and ventricular conduction velocity. Thus, CK-SSD could serve as potential carrier candidate in improving the clinical application of CK.