A Selective-Tumor-Penetrating Strategy via Unidirectional Direct Transfer for Intravesical Therapy of Bladder Cancer.

A selective tumor-penetrating strategy generally exploits tumor-targeted ligands to modify drugs so that the conjugate preferentially enters tumors and subsequently undergoes transcellular transport to penetrate tumors. However, this process shields ligands from their corresponding targets on the cell surface, possibly inducing an off-target effect during drug penetration at the tumor-normal interface. Herein, we first describe a selective tumor-penetrating drug (R11-phalloidin conjugates) for intravesical therapy of bladder cancer. The intravesical conjugates rapidly translocated across the mucus layer, specifically bound to tumors, and infiltrated throughout the tumor via direct intercellular transfer. Notably, direct transfer from normal cells to tumor cells was unidirectional because the pathways required for direct transfer, termed F-actin-rich tunneling nanotubes, were more unidirectionally extended from normal cells to tumor cells. Moreover, the intravesical conjugates displayed strong anticancer activity and well-tolerated biosafety in murine orthotopic bladder tumor models. Our study demonstrated the potential of a selective tumor-penetrating conjugate for effective intravesical anticancer therapy.

Prehospital stroke care in Singapore.

ABSTRACT: Due to the narrow window of opportunity for stroke therapeutics to be employed, effectiveness of stroke care systems is predicated on the efficiency of prehospital stroke systems. A robust prehospital stroke system of care that provides a rapid and well-coordinated response maximises favourable poststroke outcomes, but achieving this presents a unique set of challenges dependent on demographic and geographical circumstances. Set in the context of a highly urbanised first-world nation with a rising burden of stroke, Singapore's prehospital stroke system has evolved to reflect the environment in which it operates. This review aims to characterise the current state of prehospital stroke care in Singapore, covering prehospital aspects of the stroke survival chain from symptom onset till arrival at the emergency department. We identify areas for improvement and innovation, as well as provide insights into the possible future of prehospital stroke care in Singapore.

Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/ß-catenin signalling pathway.

INTRODUCTION: Vascular calcification, a devastating vascular complication accompanying atherosclerotic cardiovascular disease and chronic kidney disease, increases the incidence of adverse cardiovascular events and compromises the efficacy of vascular interventions. However, effective therapeutic drugs and treatments to delay or prevent vascular calcification are lacking. OBJECTIVES: This study was designed to test the therapeutic effects and mechanism of Moscatilin (also known as dendrophenol) from Dendrobium huoshanense (an eminent traditional Chinese medicine) in suppressing vascular calcification in vitro, ex vivo and in vivo. METHODS: Male C57BL/6J mice (25-week-old) were subjected to nicotine and vitamin D3 (VD3) treatment to induce vascular calcification. In vitro, we established the cellular model of osteogenesis of human aortic smooth muscle cells (HASMCs) under phosphate conditions. RESULTS: By utilizing an in-house drug screening strategy, we identified Moscatilin as a new naturally-occurring chemical entity to reduce HASMC calcium accumulation. The protective effects of Moscatilin against vascular calcification were verified in cultured HASMCs. Unbiased transcriptional profiling analysis and cellular thermal shift assay suggested that Moscatilin suppresses vascular calcification via binding to interleukin 13 receptor subunit A2 (IL13RA2) and augmenting its expression. Furthermore, IL13RA2 was reduced during HASMC osteogenesis, thus promoting the secretion of inflammatory factors via STAT3. We further validated the participation of Moscatilin-inhibited vascular calcification by the classical WNT/ß-catenin pathway, among which WNT3 played a key role in this process. Moscatilin mitigated the crosstalk between WNT3/ß-catenin and IL13RA2/STAT3 to reduce osteogenic differentiation of HASMCs. CONCLUSION: This study supports the potential of Moscatilin as a new naturally-occurring candidate drug for treating vascular calcification via regulating the IL13RA2/STAT3 and WNT3/ß-catenin signalling pathways.

How hydrogen bonding and π-π interactions synergistically facilitate mephedrone adsorption by bio-sorbent: An in-depth microscopic scale interpretation.

Mephedrone (4-methylmethcathinone, MEPH) exhibited severe ecologic hazards and health detriments. A novel deep eutectic solvent functionalized magnetic ZIF-8/hierarchical porous carbon (DMZH) with excellent selectivity, interference resistance and recyclability, was developed for the rapid adsorption of MEPH. Initially, potential adsorption sites of MEPH were predicted. Then, π-π and hydrogen bonding interactions were proposed and verified from characterizations, comparative experiments and theoretical calculations. The synergistic effects of the hydrogen bonding and π-π interactions increased the adsorption energies from -15.26 kcal⋅mol-1 to -21.83 kcal⋅mol-1, enhanced the degree of π-dissociation, enlarged the π-π isosurface area, extended the van der Waals surface mutual penetration distance, achieving stronger affinity and remarkable adsorption. Furthermore, offset (parallel-displaced) π-π stacking form existed between DMZH and MEPH. DMZH acted as the hydrogen bond donor and MEPH served as the hydrogen bond acceptor to form O-H⋯O and N-H⋯O hydrogen bonding interaction. Profiting from the synergistic effects, DMZH showed satisfactory adsorption for MEPH within 20 min with a maximum adsorption capacity of 3270.11 µg∙g-1, displayed excellent performance in wide pH range of 5∼11 and in the coexistence of multi-chemicals.

The value of ATAD3A as a potential biomarker for bladder cancer.

BACKGROUND: Bladder cancer (BCa) is a highly malignant tumor, and if left untreated, it can develop severe hematuria and tumor metastasis, thereby endangering the patient's life. The purpose of this paper was to detect the expression of ATAD3A in BCa and research the relationship between ATAD3A and pathological features of bladder cancer and the prognosis of patients. METHODS: First, the expression of ATAD3A in BCa and normal bladder tissues was analyzed based on the UALCAN and Oncomine public databases. Second, 491 cases of surgically resected bladder cancer specimens and 110 cases of normal adjacent tissues were immunohistochemically stained. The expression of ATAD3A was quantified, and the value and prognosis of ATAD3A as a biomarker of BCa were evaluated. RESULTS: The expression of ATAD3A in bladder cancer tissues was higher than that in normal bladder mucosa. High expression of ATAD3A was correlated with patient age, tumor size, number of tumors, distant metastasis, lymph node metastasis, lymphovascular invasion, and TNM stage (p < 0.05). Overexpression of ATAD3A is closely related to cancer patient survival. The mean survival time of bladder cancer patients with high ATAD3A expression was shorter than those with low ATAD3A levels. According to the relative comparing result, the high ATAD3A expression herald reduced overall survival in BCa patients. CONCLUSIONS: The abnormal overexpression of ATAD3A may be related to the initiation and progress of bladder cancer. The upregulation of ATAD3A can be used as an effective indicator to diagnose bladder cancer and predict tumor progression. Furthermore, the combination of information from public databases and the results of clinical sample analysis can help us better understand the mechanism of action of molecular oncogenes in bladder cancer.

Research on the Performance of Self-Made Open-Cathode Fuel Cell Stacks under Different Operating Conditions.

The traditional fuel cell power system requires external ventilation and humidification systems for both the anode and cathode, which not only increases the application cost but also restrict its widespread use. In order to further enhance the applicability and reduce the operating costs of fuel cell power systems, this paper investigates the open-cathode proton exchange membrane fuel cell power system. This approach not only lowers the cost but also reduces the weight of the power system, enabling its potential application in a wider range of vehicles. In this study, two versions of the open-cathode fuel cell stacks were developed and performance and stability tests were conducted under various operating conditions. Additionally, tests were carried out with different materials of carbon paper to find a balance between performance and stability. Through the research presented in this paper, the application scope of fuel cells has been expanded, providing valuable insights for their further development.

Multi-Objective NSGA-II Optimization for Broadband Beamforming with Spherical Harmonic Domain Assistance.

Sidelobe suppression is a major challenge in wideband beamforming for acoustic research, especially in high noise and reverberation environments. In this paper, we propose a multi-objective NSGA-II wideband beamforming method based on a spherical harmonic domain for spherical microphone arrays topology. The method takes white noise gain, directional index and maximum sidelobe level as the optimization objectives of broadband beamforming, adopts the NSGA-II optimization strategy with constraints to estimate the Pareto optimal solution, and provides three-dimensional broadband beamforming capability. Our method provides superior sidelobe suppression across different spherical harmonic orders compared to commonly used multi-constrained single-objective optimal beamforming methods. We also validate the effectiveness of our proposed method in a conference room setting. The proposed method achieves a white noise gain of 8.28 dB and a maximum sidelobe level of -23.42 dB at low frequency, while at high frequency it yields comparable directivity index results to both DolphChebyshev and SOCP methods, but outperforms them in terms of white noise gain and maximum sidelobe level, measuring 16.14 dB and -25.18 dB, respectively.

Application of anatomic reconstruction technique for periurethral structure in robotic assisted laparoscopic radical prostatectomy.

Objective: To investigate the outcome of patients underwent anatomic periurethral reconstruction during robotic assisted laparoscopic radical prostatectomy (RARP). Materials and methods: During August 2016 to May 2018, periurethral structure anatomic reconstruction was performed during RARP in 58 consecutive patients. The control group consists of another 50 patients had no reconstruction procedure during RARP. Perioperative data of these patients were collected retrospectively, including operation time, anastomosis time, intraoperative blood loss, duration of indwelling catheter, length of hospital stay, complications, postoperative pathology, and continence outcome at 1,3,6 and 12 months. Results: All cases were successfully performed without conversion to open or laparoscopic surgery. There were no major intraoperative or postoperative complications.The percentage of patients maintain continence in the reconstruction group versus non-reconstruction group: At 1 month 84.5% (49/58)versus 70.0% (35/50), at 3 months 89.7% (52/58)versus 78.0% (39/50), at 6 months 91.3% (53/58)versus 86.0% (43/50) and 1 year after surgery 100.0% (58/58)versus 96.0% (48/50). Reconstruction group showed better continence outcome in 1 and 3 months (P<0.05). There is no statistical differences in 6 month and 1 year. Conclusion: Anatomic reconstruction of periurethral structure during RARP is safe and feasible with reduced duration of indwelling catheter and better continence outcome.

Biobased Intelligent Food-Packaging Materials with Sustained-Release Antibacterial and Real-Time Monitoring Ability.

It has been widely accepted that sustainable polymers derived from renewable resources are able to replace the short-turnover petroleum-based materials and reduce environmental impact in the future. However, their hydrophilic chemical structures rich with oxygen groups could lead to easy growth of bacteria, which greatly limit their applications in packaging materials. Here, we present an intelligent food-packaging material with sustained-release antibacterial and real-time monitoring ability based on totally biobased contents. In detail, sodium alginate with Artemisia argyi emission oil (encapsulated in gelatin-Arabic gum microcapsules) and citric acid-sourced pH-responsive carbon quantum dots (CQDs) are coated on bamboo cellulose papers. The obtained biobased composite material (almost 100% biocarbon content) with antibacterial ability is able to extend the shelf life of fresh shrimps and can be biodegraded. Moreover, owing to the introduction of CQDs, the composite can rapidly (within 1 s) detect slight pH variations (response pH ∼5, 10-9 mol/L of OH-) through an obvious color change (hue value from 305 to 355°). The developed strategy may open up new opportunities in the design of multifunctional biobased composites for intelligent applications.

Association of COVID-19 'circuit breaker' with higher rates of elderly trauma admissions.

Introduction: In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus emerged and caused a worldwide pandemic, leading to measures being imposed by many countries to reduce its transmission. Singapore implemented the 'circuit breaker', which restricted all movements except for access to necessities and healthcare services. We aimed to investigate the impact of lockdown measures on the pattern of trauma and its effects. Methods: An observational, retrospective, single-centre descriptive study was conducted using the trauma registry in Singapore General Hospital. It included patients above 18 years old who presented to the emergency department with trauma and were subsequently admitted. Patients admitted from 1 February 2020 to 31 July 2020 and those admitted during the same timeframe in 2019 were studied. Subgroup analyses were performed for patients aged ≥65 years and those <65 years. Results: A total of 1,037 patients were included for analysis. A 17.6% increase in trauma presentations was seen from 2019 to 2020. Patients aged ≥65 years accounted for the rise in admissions. The predominant mechanism of injury was falls at home for older patients and vehicular accidents in patients <65 years. There were no significant differences in injury severity score, intensive care/high-dependency unit admission rates, length of stay, mortality rate, and subsequent need for inpatient rehabilitation. Conclusion: Our study provided information on differences in trauma presentations before and during the COVID-19 pandemic. Further studies are required to better inform on additional precautionary measures needed to reduce trauma and improve safety during future lockdowns and pandemics.

Adsorption of amphetamine on deep eutectic solvents functionalized graphene oxide/metal-organic framework nanocomposite: Elucidation of hydrogen bonding and DFT studies.

The efficient and selective removal of amphetamine (AMP) from water bodies is significant for environmental remediation. In this study, a novel strategy for screening deep eutectic solvent (DES) functional monomers was proposed based on density functional theory (DFT) calculations. Using magnetic GO/ZIF-67 (ZMG) as substrates, three DES-functionalized adsorbents (ZMG-BA, ZMG-FA, and ZMG-PA) were successfully synthesized. The isothermal results showed that the DES-functionalized materials introduced more adsorption sites and mainly contributed to the formation of hydrogen bonds. The order of the maximum adsorption capacity (Qm) was as follows: ZMG-BA (732.110 µg⋅g-1) > ZMG-FA (636.518 µg⋅g-1) > ZMG-PA (564.618 µg⋅g-1) > ZMG (489.913 µg⋅g-1). The adsorption rate of AMP on ZMG-BA was the highest (98.1%) at pH 11, which could be explained by the less protonation of -NH2 from AMP being more favorable for forming hydrogen bonds with the -COOH of ZMG-BA. The strongest affinity of the -COOH of ZMG-BA for AMP was reflected in the most hydrogen bonds and the shortest bond length. The hydrogen bonding adsorption mechanism was fully explained by experimental characterization (FT-IR, XPS) and DFT calculations. Frontier Molecular Orbital (FMO) calculations showed that ZMG-BA had the lowest HOMO-LUMO energy gap (Egap), the highest chemical activity and the best adsorption capability. The experimental results agreed with the results of theoretical calculations, proving the validity of the functional monomer screening method. This research offered fresh suggestions for the functionalized modification of carbon nanomaterials to achieve effective and selective adsorption for psychoactive substances.

Enhanced adsorption of 3,4-methylenedioxymethamphetamine by magnetic graphene oxide-polydopamine nanohybrid modified zeolitic imidazolate framework-67 and its micro-mechanism: Experiments and calculations.

Exploring the structure-dependent adsorption mechanism of contaminants in wastewater is beneficial to high-efficiency adsorbents design and environmental remediation. In this study, emerging porous material of zeolitic imidazolate framework-67 (ZIF-67) has been modified by the magnetic graphene oxide-polydopamine nanohybrid (mGOP) to obtain three-dimensional ZIF-67/mGOP through an in-situ growth strategy, which was applied to adsorb 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in wastewater. A combination of characterizations, experiments (pH, humic acid and ion strength effect) and quantum chemical calculations revealed the microscopic adsorption mechanism involves each single component, of which the hydrogen bond (O/N…HO) and π-π electron donor acceptor (π-π EDA) interactions of mGOP endowed favourable adsorption of ZIF-67/mGOP, and mechanisms of the pore filling and Co-O chelation of ZIF-67 played synergistic effect. Such nanocomposite as a ZIFs-based adsorbent exhibited ultra-high porosity (total pore volume = 0.4033 cm3/g) and specific surface area (995.22 m2/g), revealed the heterogeneity and multilayer adsorption properties, and obtained a theoretical maximum adsorption capacity of 159.845 µg/g which higher than that of mZIF-67 alone. Overall, this work provided an effective strategy for rationally modulate ZIFs-based composites and exploration of adsorption mechanism.

Deep insight into selective adsorption behavior and mechanism of novel deep eutectic solvent functionalized bio-sorbent towards methcathinone: Experiments and DFT calculation.

This work designed and synthesized novelly selective, highly efficient and friendly environmental biochar nanomaterial (ZMBC@ChCl-EG) by screening suitable deep eutectic solvent (DES) as the functional monomer via Density Functional Theory (DFT). The prepared ZMBC@ChCl-EG achieved the highly efficient adsorption of methcathinone (MC) and exhibited excellent selectivity as well as good reusability. Selectivity analysis concluded that the distribution coefficient value (KD) of ZMBC@ChCl-EG towards MC was 3.247 L/g, which was about 3 times higher than that of ZMBC, corresponding to stronger selective adsorption capacity. The studies of isothermal and kinetics indicated that ZMBC@ChCl-EG had an excellent adsorption capacity towards MC and the adsorption was mainly chemically controlled. In addition, DFT was used to calculate the binding energies between MC and each component. The binding energies were -10.57 kcal/mol for ChCl-EG/MC, -3.15∼-9.51 kcal/mol for BCs/MC, -2.33 kcal/mol for ZIF-8/MC, respectively, suggesting that DES played a major role in enhancing methcathinone adsorption. Lastly, the adsorption mechanisms were revealed by variables experiment combined with characterizations and DFT calculation. The main mechanisms were hydrogen bonding and π-π interaction.

Growth differentiation factor 15 is dispensable for acetaminophen-induced liver injury in mice.

Acetaminophen (APAP)-induced liver injury (AILI) has been recognized as a pivotal contributor to drug-induced liver failure in Western countries, but its molecular mechanism remains poorly understood. Growth differentiation factor 15 (GDF15) is a pleiotropic factor that alleviates non-alcoholic liver steatohepatitis, liver fibrosis and liver injury. The aim of the present study was to examine the possibility whether GDF15 confers protection against AILI. We found that the gene expression of Gdf15 was increased significantly after APAP overdose in mice. Next, the role of Gdf15 in AILI was evaluated by hepatic Gdf15 overexpression (using adeno-associated virus serotype 8), injection with recombinant human GDF15 (rhGDF15) and Gdf15 knockout mice after challenge with APAP. A marked elevation of Gdf15 was observed after AILI. However, there were no significant differences in AILI-related liver injury and JNK phosphorylation after Gdf15 overexpression, rhGDF15 injection or Gdf15 deficiency. Together, we conclude that, despite a noticeable elevation of Gdf15 level after AILI, Gdf15 is dispensable for APAP-induced AILI. Our study further suggests that genomic analysis of mRNA expression after APAP overdose is of limited relevance unless followed up by a functional analysis of candidate genes in vivo.

The cause analysis of benign uretero-ileal anastomotic stricture after radical cystectomy and urinary diversion.

Background: Benign uretero-ileal anastomotic stricture (UIAS) is a major complication following radical cystectomy (RC) and ileal orthotopic bladder substitution, and it can occur in combination with other complications. But risk factors for patients with UIAS have not been well described. Material and methods: We retrospectively reviewed 198 patients treated with RC for bladder cancer from 2014 to 2019 at the Zhejiang Provincial People's Hospital. Patient demographic and clinical variables were examined to determine the risk factors associated with UIAS by univariate and multivariate logistic regression analysis. Results: A total of 180 patients into the group standards and in all 360 uretero-ileal anastomoses. Among the above cases, 22 patients developed UIAS, including 10 cases of left UIAS, nine cases of right UIAS, and three cases of bilateral UIAS. There was no difference in demographic, operative, or perioperative variables between patients with and without UIAS. In a multivariate analysis, after adjusting for gender, age, surgical methods, and underlying diseases, intraoperative or postoperative blood transfusion (HR = 0.144, P <0.01), postoperative urinary tract infection (HR = 3.624, P <0.01), and extracorporeal bladder anastomosis (HR = 3.395, P = 0.02) significantly increased the risk of UIAS. Conclusions: In our experience, intraoperative or postoperative blood transfusion, postoperative urinary tract infection, and extracorporeal neobladder anastomoses increased the risk of UIAS after radical cystectomy and ileal orthotopic bladder substitution surgery. Further studies with larger samples are necessary to validate this result.

Comprehensive proteomic and metabolomic analysis uncover the response of okra to drought stress.

The response of okra to drought stress is very complicated, and the molecular mechanisms underlying this process remains ambiguous up to now. In this study, different degrees of water-stress responses of okra leaf were explained by using transcriptomics and metabolomic approaches. The photosynthesis and glycometabolism in okra leaf were both adversely affected by drought stress, leading to inhibition of the carbohydrate metabolic process, and then influencing the secondary plant metabolism. Further, drought stress disturbed amino acid metabolism, especially for the tyrosine-derived pathway as well as arginine and proline metabolism, which have been shown to be significantly enriched under water withholding conditions based on multi-omics conjoint analysis (transcriptome, proteome and metabolome). In-depth analysis of the internal linkages between differentially expressed transcripts, proteins, and metabolites decidedly indicate that tyrosine metabolism could confer tolerance to drought stress by influencing carbon and nitrogen metabolism. These findings provide a whole framework of the regulation and relationships of major transcripts and peptides related to secondary metabolism, particularly, the role of critical proteins and metabolite involved in the change of amino acid metabolism in response to drought stress.

Comparative study on the clinical effect of preparing neobladder with different lengths of ileum.

Objective: To investigate the relationship between orthotopic U-shaped ileal neobladder volume and bladder function. To investigate the correlation between the volume of the radical cystectomy and the U-shaped ileal neobladder in situ and the function of the bladder. Methods: The clinical data of patients undergoing in orthotopic U-shaped neobladder in our hospital were retrospectively analyzed. They were divided into two groups according to the length of the retained ileum. Group 1: The length of the ileum was 25-35cm (including 35cm), and the second group: the length of the ileum was 35-45cm. The basic information, cushion usage, urodynamic examination and complications of the two groups were obtained. Results: A total of 88 patients were included in the study, including 33 in the first group and 55 in the second group. There was no statistical difference in general data, lymph node collection, lymph node positive rate, positive margin rate, postoperative pathological stage, pathological grade, pathological type, intraoperative blood loss, blood transfusion, postoperative hospital stay, and complications between the two groups of patients. significance. Although the usage of urine pads in group 1 was more than that in group 2 in the short term after operation (P<0.05), it started from the third year after operation. Patients in group 1 used less cushion than group 2 (P<0.05). Urodynamic examination was performed on the patients, and the bladder function of group 1 maintained satisfactory time longer than that of group 2. The total number of deaths in the two groups was 12 and 23, respectively. The 5-year overall survival (OS) rate of group 1 was 53.60%, and the 5-year overall survival rate of group 2 was 52.9%. Conclusions: A new bladder formed by cutting the ileum with a length of 25-35 cm (including 35cm) has a longer time to maintain good bladder function than cutting the ileum with a length of 35-45 cm to produce a new bladder.

The incidence and risk factors of chronic kidney disease after radical nephrectomy in patients with renal cell carcinoma.

BACKGROUND: Radical nephrectomy (RN) is the standard treatment for localized renal cell carcinoma. The decrease in nephrons from RN could lead to postoperative chronic kidney disease (CKD). In this study, we aim to investigate the incidence and risk factors for CKD in patients who have received RN. METHODS: A Total of 1233 patients underwent radical nephrectomy in Zhejiang Provincial People's Hospital from January 2010 to December 2018. Those who had an abnormal renal function before surgery or were lost to follow-up were excluded. Five hundred patients were enrolled in the end. eGFR was calculated using the abbreviated MDRD equation. CKD was defined as eGFR less than 60 ml/min/1.73m2. The incidence of postoperative CKD was estimated using the Kaplan-Meier method. The independent risk factors for CKD occurrence were determined through logistic multivariate regression analysis. RESULTS: Patients were followed up for a median of 40 month (3-96 months), with CKD occurring in 189 cases. The 5-year cumulative incidence of CKD was 43.4%. There was a significant difference between these189 patients and the remaining patients without post nephrectomy CKD in terms of age, sex, weight, and preoperative eGFR(P<0.05). Multivariate regression analysis showed that age (OR = 1.038, 95%CI = 1.002-1.076), preoperative eGFR of the contralateral kidney (OR = 0.934, 95%CI = 0.884-0.988) and Immediate postoperative eGFR (OR = 0.892, 95%CI = 0.854-0.931) were independent risk factors for postoperative CKD. CONCLUSIONS: The incidence of CKD after radical nephrectomy was not uncommon. Age, preoperative eGFR of the contralateral kidney and Immediate postoperative eGFR are independent risk factors for postoperative CKD.

R11 modified tumor cell membrane nanovesicle-camouflaged nanoparticles with enhanced targeting and mucus-penetrating efficiency for intravesical chemotherapy for bladder cancer.

Intravesical chemotherapy is generally used in the clinic for treating bladder cancer (BCa), but its efficacy is limited due to the permeation barrier and side effects caused by the off-targeting of normal urothelial cells. In this study, BCa cell-derived membrane nanovesicles were used as drug carriers, and their homologous tumor-targeting capacity was utilized. A BCa-targeting hendeca-arginine peptide was functionalized onto the nanovesicles to impart a mucus-penetrating ability and thus overcome the permeation barrier. The tumor-targeting and mucus-penetrating nanovesicles were stable in urine, were highly permeable to the glycosaminoglycan layer, and specifically targeted BCa. The vesicles were internalized through caveolin-mediated endocytosis, were transported to nonlysosome-localized intracellular regions, and efficiently infiltrated bladder tumor spheroids. In in vivo intravesical chemotherapy, the nanovesicles achieved chemo-resection in murine orthotopic BCa models. This BCa-targeting and mucus-penetrating drug delivery system may be promising for the intravesical chemotherapy of BCa.

Nationwide study of the characteristics of frequent attenders with multiple emergency department attendance patterns.

INTRODUCTION: The burden of frequent attenders (FAs) of emergency departments (EDs) on healthcare resources is underestimated when single-centre analyses do not account for utilisation of multiple EDs by FAs. We aimed to quantify the extent of multiple ED use by FAs and to characterise FAs. METHODS: We reviewed nationwide ED attendance in Singapore data from 1 January 2006 to 31 December 2018 (13 years). FAs were defined as patients with ≥4 ED visits in any calendar year. Single ED FAs and multiple ED FAs were patients who attended a single ED exclusively and ≥2 distinct EDs within the year, respectively. Mixed ED FAs were patients who attended a mix of a single ED and multiple EDs in different calendar years. We compared the characteristics of FAs using multivariable logistic regression. RESULTS: We identified 200,130 (6.3%) FAs who contributed to1,865,704 visits (19.6%) and 2,959,935 (93.7%) non-FAs who contributed to 7,671,097 visits (80.4%). After missing data were excluded, the study population consisted of 199,283 unique FAs. Nationwide-linked data identified an additional 15.5% FAs and 29.7% FA visits, in addition to data from single centres. Multiple ED FAs and mixed ED FAs were associated with male sex, younger age, Malay or Indian ethnicity, multiple comorbidities, median triage class of higher severity, and a higher frequency of ED use. CONCLUSION: A nationwide approach is needed to quantify the national FA burden. The multiple comorbidities and higher frequency of ED use associated with FAs who visited multiple EDs and mixed EDs, compared to those who visited a single ED, suggested a higher level of ED burden in these subgroups of patients. The distinct characteristics and needs of each FA subgroup should be considered in future healthcare interventions to reduce FA burden.