Onion-like doxorubicin-carrying polymeric nanomicelles with tumor acidity-sensitive dePEGylation to expose positively-charged chitosan shell for enhanced cancer chemotherapy.

To effectively promote antitumor potency of doxorubicin (DOX), a regularly used chemotherapy drug, the tumor acidity-responsive polymeric nanomicelles from self-assembly of the as-synthesized amphiphilic benzoic imine-containing PEGylated chitosan-g-poly(lactic-co-glycolic acid) (PLGA) conjugates were developed as vehicles of DOX. The attained PEGylated chitosan-g-PLGA nanomicelles with high PEGylation degree (H-PEG-CSPNs) were characterized to exhibit a "onion-like" core-shell-corona structure consisting of a hydrophobic PLGA core covered by benzoic imine-rich chitosan shell and outer hydrophilic PEG corona. The DOX-carrying H-PEG-CSPNs (DOX@H-PEG-CSPNs) displayed robust colloidal stability under large-volume dilution condition and in a serum-containing aqueous solution of physiological salt concentration. Importantly, the DOX@H-PEG-CSPNs in weak acidic milieu undergoing the hydrolysis of benzoic imine bonds and increased protonation of chitosan shell showed dePEGylation and surface charge conversion. Also, the considerable swelling of protonated chitosan shell within DOX@H-PEG-CSPNs accelerated drug release. Notably, the cellular internalization of DOX@H-PEG-CSPNs by TRAMP-C1 prostate cancer cells under mimic acidic tumor microenvironment was efficiently boosted upon acidity-triggered detachment of PEG corona and exposure of positively-charged chitosan shell, thus augmenting DOX-mediated anticancer effect. Compared to free DOX molecules, the DOX@H-PEG-CSPNs appreciably suppressed TRAMP-C1 tumor growth in vivo, thereby showing great promise in improving DOX chemotherapy.

High-Performance Organic Solar Cells Featuring Double Bulk Heterojunction Structures with Vertical-Gradient Selenium Heterocyclic Nonfullerene Acceptor Concentrations.

In this study, we prepared organic photovoltaics (OPVs) featuring an active layer comprising double bulk heterojunction (BHJ) structures, featuring binary blends of a polymer donor and concentration gradients of two small-molecule acceptors. After forming the first BHJ structure by spin-coating, the second BHJ layer was transfer-printed onto the first using polydimethylsiloxane stamps. A specially designed selenium heterocyclic small-molecule acceptor (Y6-Se-4Cl) was employed as the second acceptor in the BHJ. X-ray photoelectron spectroscopy revealed that the two acceptors formed a gradient concentration profile across the active layer, thereby facilitating charge transportation. The best power conversion efficiencies (PCEs) for the double-BHJ-structured devices incorporating PM6:Y6-Se-4Cl/PM6:Y6 and PM6:Y6-Se-4Cl/PM6:IT-4Cl were 16.4 and 15.8%, respectively; these values were higher than those of devices having one-BHJ structures based on PM6:Y6-Se-4Cl (15.0%), PM6:Y6 (15.4%), and PM6:IT-4Cl (11.6%), presumably because of the favorable vertical concentration gradient of the selenium-containing small-molecule Y6-Se-4Cl in the active layer as well as some complementary light absorption. Thus, combining two BHJ structures with a concentration gradient of the two small-molecule acceptors can be an effective approach for enhancing the PCEs of OPVs.

Adverse outcomes after major surgery in children with intellectual disability.

AIM: To evaluate outcomes after major surgery in children and adolescents with intellectual disability. METHOD: We used 2004 to 2013 claims data from Taiwan's National Health Insurance programme to conduct a nested cohort study, which included 220 292 surgical patients aged 6 to 17 years. A propensity score matching procedure was used to select 2173 children with intellectual disability and 21 730 children without intellectual disability for comparison. Logistic regression was used to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of the postoperative complications and 30-day mortality associated with intellectual disability. RESULTS: Children with intellectual disability had a higher risk of postoperative pneumonia (OR 2.16, 95% CI 1.48-3.15; p<0.001), sepsis (OR 1.67, 95% CI 1.28-2.18; p<0.001), and 30-day mortality (OR 2.04, 95% CI 1.05-3.93; p=0.013) compared with children without intellectual disability. Children with intellectual disability also had longer lengths of hospital stay (p<0.001) and higher medical expenditure (p<0.001) when compared with children with no intellectual disability. INTERPRETATION: Children with intellectual disability experienced more complications and higher 30-day mortality after surgery when compared with children without intellectual disability. There is an urgent need to revise the protocols for the perioperative care of this specific population. WHAT THIS PAPER ADDS: Surgical patients with intellectual disability are at increased risk of postoperative pneumonia, sepsis, and 30-day mortality. Intellectual disability is associated with higher medical expenditure and increased length of stay in hospital after surgical procedures. The influence of intellectual disability on postoperative outcomes is consistent in both sexes and those aged 10 to 17 years. Low income and a history of fractures significantly impacts postoperative adverse events for patients with intellectual disability.

The uremic toxin indoxyl sulfate increases pulmonary vein and atrial arrhythmogenesis.

BACKGROUND: Chronic kidney disease (CKD) is associated with a higher incidence of atrial fibrillation (AF) with unclear mechanisms. Indoxyl sulfate (IS) accumulates in CKD patients. IS increases oxidative stress, which contributes to the genesis of AF. The arrhythmogenic effect of IS is unclear. METHODS: Conventional microelectrodes recorded the action potentials (AP) of isolated rabbit left atrium (LA), right atrium (RA), pulmonary vein (PV), and sinoatrial nodes (SANs) before and after treatment with IS with and without an antioxidant (ascorbic acid). Confocal microscopy with fluorescence and whole-cell patch clamp were used to evaluate intracellular calcium in isolated PV cardiomyocytes with and without IS. RESULTS: Compared to the control, IS induced more PV delayed afterdepolarizations at 0.1, 1, 10, and 100 µM, and induced more PV burst firings at 1, 10, and 100 µM. In contrast, IS (10 and 100 µM) reduced the SAN spontaneous beating rate. IS (100 µM) significantly shortened LA AP durations, but not RA. IS (100 µM)-treated PV cardiomyocytes had a similar calcium transient and sarcoplasmic reticulum calcium content, but a larger calcium leak than control PV cardiomyocytes. Burst pacing and isoproterenol induced a greater AF occurrence (50% vs. 100%; P = 0.009) and a longer AF duration (26 ± 9 vs. 5 ± 3 seconds; P < 0.05) in the LA (n = 8) with IS (100 µM) than without IS. Moreover, ascorbic acid (1 mM) attenuated the effects of IS on the LA, PV, and SANs. CONCLUSION: IS increases PV and atrial arrhythmogenesis through oxidative stress. They may contribute to the occurrence of AF in CKD patients.

The impact of age on the electrophysiological characteristics and different arrhythmia patterns in patients with Wolff-Parkinson-White syndrome.

INTRODUCTION: Information about the impact of age on the electrophysiological characteristics of accessory pathways (APs) in patients with Wolff-Parkinson-White (WPW) syndrome remains limited. METHODS AND RESULTS: A total of 1,885 consecutive patients (mean age 43 ± 17 years, male 61.5%) with WPW syndrome who were referred to the tertiary center for an electrophysiological study and radiofrequency catheter ablation were investigated. The patients were divided into 4 groups based on their age (Group 1: <20; Group 2: 20-39; Group 3: 40-59; Group 4: ≧60 years old). With age, more left-sided APs (53.2%, 67.7%, 71.7%, 75.7%, P < 0.001) and a longer duration of the arrhythmia (4.3 ± 2.8 years, 10.1 ± 7.0 years, 12.4 ± 10.9 years, 14.0 ± 12.4 years, P < 0.001) were noted. The incidence of concealed APs (53.5%, 53.0%, 57.8%, 60.9%, P = 0.01), and orthodromic atrioventricular (AV) reentrant tachycardia (92.4%, 94.2%, 96.5%, 96.3%, P = 0.023) increased with age. The tachycardia cycle length, antegrade (275.5 ± 42.2 ms, 286.7 ± 62.7 ms, 302.5 ± 66.5 ms, 315.2 ± 80.2 ms, P < 0.001) and retrograde AP effective refractory periods (APERPs) (254.0 ± 42.5 ms, 263.3 ± 51.8 ms, 274.5 ± 100.5 ms, 292.7 ± 57.0 ms, P < 0.001), atrial ERP, antegrade AV node effective refractory period (AVNERP), and ventricular effective refractory period (VERP) lengthened as the age increased. The incidence of decremental APs, multiple APs, and a catecholamine response were similar. The duration of the catheter ablation, total fluoroscopy time, acute success rate, complication rate, and incidence of a secondary procedure were similar between the different age groups. CONCLUSION: The electrophysiological characteristics and pattern of the arrhythmic attack associated with the AP changed with age.

The impact of age on the electroanatomical characteristics and outcome of catheter ablation in patients with atrial fibrillation.

BACKGROUND: Previous studies have indicated that atrial fibrillation (AF) in patients over the age of 60 at diagnosis is a risk factor for a substantial increase in cardiovascular events. However, information about the impact of age on the atrial substrate and clinical outcome after catheter ablation of AF is limited. METHODS: This study included 350 patients (53 ± 12 years, 254 males) who underwent circumferential pulmonary vein isolation (CPVI) of AF, guided by a NavX mapping system. The subjects were divided into three groups according to their age, as follows: Group I: age ≤50 (n = 141), Group II: age = 51-64 (n = 149) and Group III: age ≥65 years old (n = 60). The mean voltage and total activation time of the individual atria were obtained by using a NavX mapping system before ablation. Several parameters, including the gender, AF duration, and left atrial (LA) diameter were analyzed. RESULTS: The younger age group had a significantly smaller LA diameter (Group I vs Group II vs Group III, 36.89 ± 7.11 vs 39.16 ± 5.65 vs 40.77 ± 4.95 mm, P = 0.002) and higher LA bipolar voltage (2.09 ± 0.83 vs 1.73 ± 0.73 vs 1.86 ± 0.67 mV, respectively, P = 0.024), compared with the older AF patients. The LA bipolar voltage exhibited a significant reduction when the patients became older, however, that did not occur in the right atrium. The incidence of an AF recurrence was higher in the older age group than in the younger age groups. A subgroup of patients with lone AF was analyzed and age was found to be an independent predictor of the AF recurrence after receiving the first CPVI in the multivariable model (P < 0.05). CONCLUSIONS: Age has a significant impact on the LA substrate properties and outcome of the catheter ablation of AF.