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Enhancing the antitumor immune response and targeting ability of oncolytic viruses will improve the effect of tumor immunotherapy. Through infecting neural stem cells (NSCs) with a capsid dual-modified oncolytic adenovirus (CRAd), we obtained and characterized the “oncolytic extracellular vesicles” (CRAdEV) with improved targeted infection and tumor killing activity compared with CRAd. Both ex vivoand in vivostudies revealed that CRAdEV activated innate immune cells and importantly enhanced the immunomodulatory effect compared to CRAd. We found that CRAdEV effectively increased the number of DCs and activated CD4+and CD8+T cells, significantly increased the number and activation of B cells, and produced higher levels of tumor-specific antibodies, thus eliciting enhanced antitumor activity compared with CRAd in a B16 xenograft immunocompetent mice model. This study provides a novel approach to oncolytic adenovirus modification and demonstrates the potential of “oncolytic extracellular vesicles” in antitumor immunotherapy.

Introduction: Observational studies suggest that different classes of antihypertensive drugs may have different effects on the occurrence of intracranial aneurysms (IA) and subarachnoid hemorrhage (SAH). However, the reported results in previous studies are inconsistent, and randomized data are absent. We performed a two-sample Mendelian randomization (MR) analysis to study the causal effects of genetically determined blood pressure (BP) and genetic proxies for antihypertensive drug classes on the risk of IA and SAH.Materials and methods: Genetic instruments and outcome data were obtained from independent genome-wide association studies (GWAS) or published data, which were exclusively restricted to European ancestry. Causal relationships were identified using inverse-variance weighted MR analyses and a series of statistical sensitivity analyses. The FinnGen consortium was used for repeated analysis to verify results obtained from the above GWAS.Results: Two-sample MR analysis showed that genetically determined Systolic BP, Dystolic BP, and Pulse Pressure were related to a higher risk of IA and SAH. Based on identified single nucleotide polymorphisms (SNPs) that influence the effect of calcium channel blockers (CCB, 42 SNPs), beta-blockers (BB, 8 SNPs), angiotensin-converting enzyme inhibitors (ACEI, 2 SNPs), angiotensin receptor blockers (ARB, 1 SNPs), and thiazides (5 SNPs), genetically determined effect of CCBs was associated with a higher risk of IA (OR, 1.07 [95% CI, 1.03–1.10], p= 5.02 × 10−5) and SAH (OR, 1.06 [95% CI, 1.03–1.09], p= 1.84 × 10−3). No associations were found between other antihypertensive drugs and the risk of IA or SAH. The effect of CCBs on SAH was confirmed in FinnGenconsortium samples (OR, 1.04 [95% CI, 1.00–1.08], p= 0.042).Discussion and conclusion: This MR analysis supports the role of elevated blood pressure in the occurrence of intracranial aneurysms and subarachnoid hemorrhage. However, genetic proxies for calcium channel blockers were associated with an increased risk of intracranial aneurysms and subarachnoid hemorrhage. Further studies are required to confirm these findings and investigate the underlying mechanisms.

Background: The risk and timing of permanent pacemaker implantation (PPMI) after transcatheter aortic valve replacement (TAVR) is still hard to predict. We aimed to analyze the relationship between the compression ratio of a self-expandable valve (SEV) and the need for PPMI after TAVR. Methods: A total of 106 patients who were implanted with the VitaFlow transcatheter aortic valve system and for whom complete imaging information was available were included in this retrospective cohort study. Eight lines perpendicular to the long axis of the SEV were drawn (the top and bottom of the SEV and the intersection of each row of wires) for measurement purposes. The compression ratio was calculated as 1 − (in vivo meridian/in vitro meridian) and compared between patients undergoing and those not undergoing PPMI after adjusting for implantation depth. Multivariable logistic regression and Cox proportional hazards models were used to assess factors associated with the risk and timing of the need for PPMI. Results: Fifteen (14.2%) patients underwent PPMI after TAVR. Patients with a higher mean compression ratio (20%, odds ratio [OR] = 214.82; p< 0.001) and prior right bundle branch block (OR = 51.77; p= 0.015) had a higher risk of the need for PPMI after TAVR. These two factors were also associated with the timing of PPMI, according to the Cox proportional hazards model. Conclusions: The compression ratio of the SEV was positively associated with the risk of PPMI after TAVR, and the association was most significant in the annular and supravalvular planes. The compression ratio may also affect the time to PPMI.

Short-term exposure to PM2.5or O3can increase mortality risk; however, limited studies have evaluated their interaction. A multicity time series study was conducted to investigate the synergistic effect of PM2.5and O3on mortality in China, using mortality data and high-resolution pollutant predictions from 272 cities in 2013–2015. Generalized additive models were applied to estimate associations of PM2.5and O3with mortality. Modification and interaction effects were explored by stratified analyses and synergistic indexes. Deaths attributable to PM2.5and O3were evaluated with or without modification of the other pollutant. The risk of total nonaccidental mortality increased by 0.70% for each 10 μg/m3increase in PM2.5when O3levels were high, compared to 0.12% at low O3levels. The effect of O3on total nonaccidental mortality at high PM2.5levels (1.26%) was also significantly higher than that at low PM2.5levels (0.59%). Similar patterns were observed for cardiovascular or respiratory diseases. The relative excess risk of interaction and synergy index of PM2.5and O3on nonaccidental mortality were 0.69% and 1.31 with statistical significance, respectively. Nonaccidental deaths attributable to short-term exposure of PM2.5or O3when considering modification of the other pollutant were 28% and 31% higher than those without considering modification, respectively. Our results found synergistic effects of short-term coexposure to PM2.5and O3on mortality and suggested underestimations of attributable risks without considering their synergistic effects.

Background: This study aims to develop a post-procedural risk prediction model for permanent pacemaker implantation (PPMI) in patients treated with transcatheter aortic valve replacement (TAVR). Methods: 336 patients undergoing TAVR at a single institution were included for model derivation. For primary analysis, multivariate logistic regression model was used to evaluate predictors and a risk score system was devised based on the prediction model. For secondary analysis, a Cox proportion hazard model was performed to assess characteristics associated with the time from TAVR to PPMI. The model was validated internally via bootstrap and externally using an independent cohort. Results: 48 (14.3%) patients in the derivation set had PPMI after TAVR. Prior right bundle branch block (RBBB, OR: 10.46; p< 0.001), pre-procedural aortic valve area (AVA, OR: 1.41; p= 0.004) and post- to pre-procedural AVA ratio (OR: 1.72; p= 0.043) were identified as independent predictors for PPMI. AUC was 0.7 and 0.71 in the derivation and external validation set. Prior RBBB (HR: 5.07; p< 0.001), pre-procedural AVA (HR: 1.33; p= 0.001), post-procedural AVA to prosthetic nominal area ratio (HR: 0.02; p= 0.039) and post- to pre-procedural troponin-T difference (HR: 1.72; p= 0.017) are independently associated with time to PPMI. Conclusions: The post-procedural prediction model achieved high discriminative power and accuracy for PPMI. The risk score system was constructed and validated, providing an accessible tool in clinical setting regarding the Chinese population.

To evaluate meibomian gland morphology and function in children without ocular discomfort.

To evaluate, using MRI, the extent and pattern of fibrovascular ingrowth into Medpor implants after modified evisceration.