Antitumor Effect and Immunomodulatory Mechanism of "Oncolytic Extracellular Vesicles".

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 vivo and in vivo studies 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.

Joint Effect of Short-Term Exposure to Fine Particulate Matter and Ozone on Mortality: A Time Series Study in 272 Chinese Cities.

Short-term exposure to PM2.5 or O3 can increase mortality risk; however, limited studies have evaluated their interaction. A multicity time series study was conducted to investigate the synergistic effect of PM2.5 and O3 on 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 PM2.5 and O3 with mortality. Modification and interaction effects were explored by stratified analyses and synergistic indexes. Deaths attributable to PM2.5 and O3 were evaluated with or without modification of the other pollutant. The risk of total nonaccidental mortality increased by 0.70% for each 10 µg/m3 increase in PM2.5 when O3 levels were high, compared to 0.12% at low O3 levels. The effect of O3 on total nonaccidental mortality at high PM2.5 levels (1.26%) was also significantly higher than that at low PM2.5 levels (0.59%). Similar patterns were observed for cardiovascular or respiratory diseases. The relative excess risk of interaction and synergy index of PM2.5 and O3 on nonaccidental mortality were 0.69% and 1.31 with statistical significance, respectively. Nonaccidental deaths attributable to short-term exposure of PM2.5 or O3 when 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 PM2.5 and O3 on mortality and suggested underestimations of attributable risks without considering their synergistic effects.

CCDC146 is required for sperm flagellum biogenesis and male fertility in mice.

Multiple morphological abnormalities of the flagella (MMAF) is a severe disease of male infertility, while the pathogenetic mechanisms of MMAF are still incompletely understood. Previously, we found that the deficiency of Ccdc38 might be associated with MMAF. To understand the underlying mechanism of this disease, we identified the potential partner of this protein and found that the coiled-coil domain containing 146 (CCDC146) can interact with CCDC38. It is predominantly expressed in the testes, and the knockout of this gene resulted in complete infertility in male mice but not in females. The knockout of Ccdc146 impaired spermiogenesis, mainly due to flagellum and manchette organization defects, finally led to MMAF-like phenotype. Furthermore, we demonstrated that CCDC146 could interact with both CCDC38 and CCDC42. It also interacts with intraflagellar transport (IFT) complexes IFT88 and IFT20. The knockout of this gene led to the decrease of ODF2, IFT88, and IFT20 protein levels, but did not affect CCDC38, CCDC42, or ODF1 expression. Additionally, we predicted and validated the detailed interactions between CCDC146 and CCDC38 or CCDC42, and built the interaction models at the atomic level. Our results suggest that the testis predominantly expressed gene Ccdc146 is essential for sperm flagellum biogenesis and male fertility, and its mutations might be associated with MMAF in some patients.

Comparative review of novel model-assisted designs for phase I/II clinical trials.

In recent years, both model-based and model-assisted designs have emerged to efficiently determine the optimal biological dose (OBD) in phase I/II trials for immunotherapy and targeted cellular agents. Model-based designs necessitate repeated model fitting and computationally intensive posterior sampling for each dose-assignment decision, limiting their practical application in real trials. On the other hand, model-assisted designs employ simple statistical models and facilitate the precalculation of a decision table for use throughout the trial, eliminating the need for repeated model fitting. Due to their simplicity and transparency, model-assisted designs are often preferred in phase I/II trials. In this paper, we systematically evaluate and compare the operating characteristics of several recent model-assisted phase I/II designs, including TEPI, PRINTE, Joint i3+3, BOIN-ET, STEIN, uTPI, and BOIN12, in addition to the well-known model-based EffTox design, using comprehensive numerical simulations. To ensure an unbiased comparison, we generated 10,000 dosing scenarios using a random scenario generation algorithm for each predetermined OBD location. We thoroughly assess various performance metrics, such as the selection percentages, average patient allocation to OBD, and overdose percentages across the eight designs. Based on these assessments, we offer design recommendations tailored to different objectives, sample sizes, and starting dose locations.

PECSS: Pulmonary Embolism Comprehensive Screening Score to safely rule out pulmonary embolism among suspected patients presenting to emergency department.

BACKGROUND: Pulmonary embolism is a severe cardiovascular disease and can be life-threatening if left untreated. However, the detection rate of pulmonary embolism using existing pretest probability scores remained relatively low and clinical rule out often relied on excessive use of computed tomographic pulmonary angiography. METHODS: We retrospectively collected data from pulmonary embolism suspected patients in Zhongshan Hospital from July 2018 to October 2022. Pulmonary embolism diagnosis and severity grades were confirmed by computed tomographic pulmonary angiography. Patients were randomly divided into derivation and validation set. To construct the Pulmonary Embolism Comprehensive Screening Score (PECSS), we first screened for candidate clinical predictors using univariate logistic regression models. These predictors were then included in a searching algorithm with indicators of Wells score, where a series of points were assigned to each predictor. Optimal D-Dimer cutoff values were investigated and incorporated with PECSS to rule out pulmonary embolism. RESULTS: In addition to Wells score, PECSS identified seven clinical predictors (anhelation, abnormal blood pressure, in critical condition when admitted, age > 65 years and high levels of pro-BNP, CRP and UA,) strongly associated with pulmonary embolism. Patients can be safely ruled out of pulmonary embolism if PECSS ≤ 4, or if 4 < PECSS ≤ 6 and D-Dimer ≤ 2.5 mg/L. Comparing with Wells approach, PECSS achieved lower failure rates across all pulmonary embolism severity grades. These findings were validated in the held-out validation set. CONCLUSIONS: Compared to Wells score, PECSS approaches achieved lower failure rates and better compromise between sensitivity and specificity. Calculation of PECSS is easy and all predictors are readily available upon emergency department admission, making it widely applicable in clinical settings. TRAIL REGISTRATION: The study was retrospectively registered (No. CJ0647) and approved by Human Genetic Resources in China in April 2022. Ethical approval was received from the Medical Ethics Committee of Zhongshan Hospital (NO.B2021-839R).

The influence of congenital and developmental cataract surgery on the ocular surface in a six-month follow-up prospective clinical study.

BACKGROUND: The purpose of this study was to identify changes in tear film function and meibomian gland function in children after congenital/developmental cataract surgery. METHODS: This study enrolled 16 eyes of 16 congenital/developmental cataract patients (mean age: 8.05 ± 1.43 years) who underwent cataract surgery and 16 eyes of 16 normal volunteers (mean age: 8.31 ± 2.18 years). Clinical assessments were conducted preoperatively and at 1 week, 1, 3 and 6 months postoperatively. Symptom questionnaires, non-invasive tear film break-up time, tear meniscus height, corneal fluorescein staining, lid margin abnormality, meibomian gland expressibility, and meibography were assessed. RESULTS: The ocular symptom score was significantly higher in congenital/developmental cataract patients compared to normal controls during the 5 visits (P = 0.009). And the average non-invasive tear film break-up time was significantly lower in congenital/developmental cataract patients compared to normal controls (P = 0.017). The first non-invasive tear film break-up time and average non-invasive tear film break-up time were lowest at 1 month postoperatively compared to baseline levels (P = 0.008 and P = 0.012, respectively). The lid margin score of the upper eyelid was significantly higher in congenital/developmental cataract patients compared to normal controls at 1 week postoperatively (P = 0.027). The meibum expressibility score decreased significantly during the 5 visits (P = 0.024). No significant difference was observed in meibomian gland tortuosity, meibomian gland width, meibomian gland area and meibomian gland length between the congenital/developmental group and normal controls preoperatively and at 6 months postoperatively (P > 0.05). CONCLUSION: Tear film stability and meibomian gland function are worsened transiently after congenital/developmental cataract surgery without accompanying meibomian gland morphological changes.

Status of higher TGF-ß1 and TGF-ß2 levels in the aqueous humour of patients with diabetes and cataracts.

BACKGROUND: Transforming growth factor (TGF) is a cytokine that acts on the proliferation, migration, differentiation, and apoptosis of cells and the accumulation of extracellular matrix components. Very few studies have precisely evaluated the concentration of TGF-ß in the aqueous humour (AH) of diabetic and cataract (DMC) eyes due to the low expression of proteins in the AH or other reasons. The concentrations of TGF-ß1, -ß2, and -ß3 in the AH of the DMC group were compared with those of the age-related cataract (ARC) group. METHODS: We collected AH and lens epithelium samples from 33 DMC patients and 36 ARC patients. Luminex liquid suspension chip detection was applied to detect the concentration of TGF-ß1, -ß2, and -ß3 in the AH samples. The expression of TGFB1/2/3 in lens epithelium samples was determined by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The concentrations of TGF-ß1 and TGF-ß2 in AH samples of DMC eyes were higher than those of ARC eyes. The differences in TGF-ß1 and TGF-ß2 between the two groups were statistically significant (P value = 0.001 for TGF-ß1, P value = 0.023 for TGF-ß2). The difference of the correlation between TGF-ß1 and glycosylated haemoglobin was significant (P value = 0.011, and Pearson correlation coefficient = 0.306). The difference of the correlation between TGF-ß2 and glycosylated haemoglobin was significant (P value = 0.026, and Pearson correlation coefficient = 0.269). The mRNA expression levels of TGFB1 and TGFB2 were upregulated in DMC epithelium samples compared with ARC epithelium samples. The differences in TGFB1 and TGFB2 between the two groups were statistically significant (P value for TGFB1 = 0.041, P value for TGFB2 = 0.021). CONCLUSIONS: The concentrations of TGF-ß1 and TGF-ß2 in AH samples were significantly higher in DMC eyes than in ARC eyes. The higher the glycosylated haemoglobin was, the higher the concentrations of TGF-ß1 and -ß2 were. The mRNA expression of TGFB1 and TGFB2 was significantly upregulated in DMC epithelial samples compared with ARC epithelial samples, suggesting the proinflammatory status of the anterior chamber of DMC eyes.

TGF-ß/Smad Signalling Activation by HTRA1 Regulates the Function of Human Lens Epithelial Cells and Its Mechanism in Posterior Subcapsular Congenital Cataract.

Congenital cataract is the leading cause of blindness among children worldwide. Patients with posterior subcapsular congenital cataract (PSC) in the central visual axis can result in worsening vision and stimulus deprivation amblyopia. However, the pathogenesis of PSC remains unclear. This study aims to explore the functional regulation and mechanism of HTRA1 in human lens epithelial cells (HLECs). HTRA1 was significantly downregulated in the lens capsules of children with PSC compared to normal controls. HTRA1 is a suppression factor of transforming growth factor-ß (TGF-ß) signalling pathway, which plays a key role in cataract formation. The results showed that the TGF-ß/Smad signalling pathway was activated in the lens tissue of PSC. The effect of HTRA1 on cell proliferation, migration and apoptosis was measured in HLECs. In primary HLECs, the downregulation of HTRA1 can promote the proliferation and migration of HLECs by activating the TGF-ß/Smad signalling pathway and can significantly upregulate the TGF-ß/Smad downstream target genes FN1 and α-SMA. HTRA1 was also knocked out in the eyes of C57BL/6J mice via adeno-associated virus-mediated RNA interference. The results showed that HTRA1 knockout can significantly upregulate p-Smad2/3 and activate the TGF-ß/Smad signalling pathway, resulting in abnormal proliferation and irregular arrangement of lens epithelial cells and leading to the occurrence of subcapsular cataract. To conclude, HTRA1 was significantly downregulated in children with PSC, and the downregulation of HTRA1 enhanced the proliferation and migration of HLECs by activating the TGF-ß/Smad signalling pathway, which led to the occurrence of PSC.

Annexin A5 is essential for PKCθ translocation during T-cell activation.

T-cell activation is a critical part of the adaptive immune system, enabling responses to foreign cells and external stimulus. In this process, T-cell antigen receptor (TCR) activation stimulates translocation of the downstream kinase PKCθ to the membrane, leading to NF-κB activation and thus transcription of relevant genes. However, the details of how PKCθ is recruited to the membrane remain enigmatic. It is known that annexin A5 (ANXA5), a calcium-dependent membrane-binding protein, has been reported to mediate PKCδ activation by interaction with PKCδ, a homologue of PKCθ, which implicates a potential role of ANXA5 involved in PKCθ signaling. Here we demonstrate that ANXA5 does play a critical role in the recruitment of PKCθ to the membrane during T-cell activation. ANXA5 knockout in Jurkat T cells substantially inhibited the membrane translocation of PKCθ upon TCR engagement and blocked the recruitment of CARMA1-BCL10-MALT1 signalosome, which provides a platform for the catalytic activation of IKKs and subsequent activation of canonical NF-κB signaling in activated T cells. As a result, NF-κB activation was impaired in ANXA5-KO T cells. T-cell activation was also suppressed by ANAX5 knockdown in primary T cells. These results demonstrated a novel role of ANXA5 in PKC translocation and PKC signaling during T-cell activation.

Analysis of multivariate longitudinal substance use outcomes using multivariate mixed cumulative logit model.

BACKGROUND: Longitudinal assessments of usage are often conducted for multiple substances (e.g., cigarettes, alcohol and marijuana) and research interests are often focused on the inter-substance association. We propose a multivariate longitudinal modeling approach for jointly analyzing the ordinal multivariate substance use data. METHODS: We describe how the binary random slope logistic regression model can be extended to the multi-category ordinal outcomes. We also describe how the proportional odds assumption can be relaxed by allowing differential covariate effects on different cumulative logits for multiple outcomes. Data are analyzed from a P01 study that evaluates the usage levels of cigarettes, alcohol and marijuana repeatedly across 8 measurement waves during 7 consecutive years. RESULTS: 1263 subjects participated in the study with informed consent, among whom 56.6% are females. Males and females show significant differences in terms of the time trend for substance use. Specifically, males showed steeper trends on cigarette and marijuana use over time compared to females, while less so for alcohol. For all three substances, age effects appear to be different for different cumulative logits, indicating the violation of proportional odds assumption. CONCLUSIONS: The multivariate mixed cumulative logit model offers the most flexibility and allows one to examine the inter-substance association when proportional odds assumption is violated.

Substance use behaviors in adolescent and young adult cancer patients: Associations with mental and physical health.

OBJECTIVE: Cancer diagnosis in adolescents and young adults (AYAs) coincides with the developmental initiation of substance use and emergence of affective disturbance. We examined substance use behaviors and risk-stratified associations with mental and physical health, as well as objective indicators of tobacco and cannabis use and concordance with self-report and medical records. METHODS: AYAs were 15 to 39 years at cancer diagnosis and ≥18 years and ≥6 months postdiagnosis at study enrollment. Risk-stratified groups included nonsmoker/nondrinker, nonsmoker/drinker, smoker/drinker. Assessments included demographics, past year tobacco, alcohol, and cannabis use, depression, anxiety, sleep, and physical activity. Urine analysis provided biochemical verification of tobacco and cannabis use. RESULTS: Participants included 100 AYAs (60% male) with primarily hematological cancers (88%). Past year alcohol, tobacco, and cannabis use prevalence rates were 80%, 15%, and 33%, respectively. A minority (non-users) refrained from both alcohol and tobacco (20%), while most were exclusively alcohol users (65%) or alcohol and tobacco co-users (15%). Relative to other sub-groups, co-users reported more depressive and anxious symptoms, while non-users reported more physical activity. More frequent tobacco and cannabis use were associated with more depressive and anxious symptoms, while more frequent alcohol use was associated with lower physical activity. There were no group differences or associations with sleep quality. There was considerable discordance between tobacco use self-report, biochemical verification, and medical record documentation. CONCLUSIONS: Substance use among AYAs is common and detrimental to mental and physical health, especially among more frequent users and co-users, highlighting the need for early assessment and intervention.

The Joint i3+3 (Ji3+3) design for phase I/II adoptive cell therapy clinical trials.

Adoptive cell therapy (ACT), such as chimeric antigen receptor (CAR) T-cell therapy, has demonstrated promising therapeutic effects with potentially non-monotonic dose-response curves. Building upon the i3 + 3 design for cytotoxic agents [1], we propose a new method - joint i3 + 3 (Ji3 + 3) that takes into account of both safety and efficacy outcomes in making dosing recommendations. This allows for efficient dose escalation and identification of biological optimal dose of ACTs which may not be cytotoxic. The Ji3 + 3 design is rule based, easy to understand for clinicians, and is simple to implement. Simulation results show that Ji3 + 3 outperforms existing designs when monotonic dose-response assumption is violated, and still achieves comparable performance when the assumption holds. The simplicity and superior operating characteristics make Ji3 + 3 a good candidate for phase I/II ACT dose-finding trials in the clinical community when toxicity and efficacy are both considered as binary endpoints.

Comparison of two intense pulsed light patterns for treating patients with meibomian gland dysfunction.

PURPOSE: The objective of this was to determine the efficacy of different patterns of intense pulsed light (IPL) therapy in patients with meibomian gland dysfunction (MGD). MATERIALS AND METHOD: IPL treatment was administered in 124 eyes of 62 patients with MGD-associated dry eye disease (DED). These patients were divided randomly into two groups treated with different IPL patterns. The first group was treated with "Optimal Pulse Technology" (OPT) (n = 29) and received three consecutive treatments (10-14 J/cm2) with three weeks between treatments. The other group was treated with "Intense Regulated Pulsed Light" (IRPL) (n = 33) and received four treatments (9-13 J/cm2) on days (D)1, D15, D45, and D75. The Ocular Surface Disease Index (OSDI), fluorescein breakup time (FTBUT), first and the average of noninvasive keratograph tear breakup times (NIKBUT), Schirmer I tests, conjunctival hyperemia, corneal fluorescent staining (CFS), tear meniscus height (TMH), MG secretion, and dropout were examined before each treatment and at one and three months after treatment. RESULTS: Compared to baseline, the clinical symptoms and signs in both groups were significantly improved at one and three months after IPL treatment. However, compared to the IRPL group, the OPT-treated group showed significant improvement in the clarity of MG secretions (P = 0.001), the number of MGs yielding clear or cloudy liquid secretions (P < 0.001), the total MG secretion score (P < 0.001) in lower eyelid, the lid margin score in upper (P < 0.001) and lower eyelids (P = 0.013), the first NIKBUT (P = 0.009), and FTBUT (P = 0.006). CONCLUSIONS: These results suggest that IPL has significant clinical value in treating patients with MGD. OPT IPL treatment was more effective in improving MG function in lower eyelids and partial tear film signs than IRPL IPL treatment. TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov, and the clinical trial accession number is NCT02481167.

A 3-level Bayesian mixed effects location scale model with an application to ecological momentary assessment data.

Ecological momentary assessment studies usually produce intensively measured longitudinal data with large numbers of observations per unit, and research interest is often centered around understanding the changes in variation of people's thoughts, emotions and behaviors. Hedeker et al developed a 2-level mixed effects location scale model that allows observed covariates as well as unobserved variables to influence both the mean and the within-subjects variance, for a 2-level data structure where observations are nested within subjects. In some ecological momentary assessment studies, subjects are measured at multiple waves, and within each wave, subjects are measured over time. Li and Hedeker extended the original 2-level model to a 3-level data structure where observations are nested within days and days are then nested within subjects, by including a random location and scale intercept at the intermediate wave level. However, the 3-level random intercept model assumes constant response change rate for both the mean and variance. To account for changes in variance across waves, as well as clustering attributable to waves, we propose a more comprehensive location scale model that allows subject heterogeneity at baseline as well as across different waves, for a 3-level data structure where observations are nested within waves and waves are then further nested within subjects. The model parameters are estimated using Markov chain Monte Carlo methods. We provide details on the Bayesian estimation approach and demonstrate how the Stan statistical software can be used to sample from the desired distributions and achieve consistent estimates. The proposed model is validated via a series of simulation studies. Data from an adolescent smoking study are analyzed to demonstrate this approach. The analyses clearly favor the proposed model and show significant subject heterogeneity at baseline as well as change over time, for both mood mean and variance. The proposed 3-level location scale model can be widely applied to areas of research where the interest lies in the consistency in addition to the mean level of the responses.

Fibrovascular ingrowth into porous polyethylene orbital implants (Medpor) after modified evisceration.

PURPOSE: To evaluate, using MRI, the extent and pattern of fibrovascular ingrowth into Medpor implants after modified evisceration. METHODS: Contrast T1-weighted images were performed in 21 patients within 1.5- to69-month intervals after modified evisceration with primary Medpor implantation. In 6 patients, the images were obtained separately following 1- and 5-minute delays after contrast administration. RESULTS: No grade I enhancement occurred in these series. Grade II was observed in 2 patients (9.09%), grade III in 8 patients (36.36%), grade IV in 9 patients (40.91%), and grade V in 3 patients (13.64%). Significant correlation existed between the grade of enhancement and the postevisceration interval (r = 0.483, p = 0.023 < 0.05). The images demonstrated an enhancement pattern that started at the unwrapped posterior pole and anterior location of rectus muscles with progressive centripetal vascularization toward the center of the implant. At the early stage of recovery, the fibrous connective tissue was thick in front of Medpor spheres. In the 5-minute delay images of 6 patients, 2 patients failed to exhibit further enhancement; 2 patients exhibited enlarged and homogeneous enhancement; and 2 patients revealed more intense enhancement patterns. The medical ethics committee of Zhongshan Ophthalmic Center approved the study. CONCLUSIONS: Fibrovascular ingrowth into Medpor implants was satisfactory after the modified evisceration and correlated with the duration of the implants. The double layers of sclera effectively prevented the implant extrusion and exposure. The authors recommend waiting at least 5 minutes before obtaining MR images after contrast administration.

Comparison of deep anterior lamellar keratoplasty and penetrating keratoplasty with respect to postoperative corneal sensitivity and tear film function.

PURPOSE: To investigate tear film function, central and peripheral corneal sensitivity and corneal subbasal nerve morphology in the cornea after deep anterior lamellar keratoplasty (DALK) compared with penetrating keratoplasty (PK). METHODS: This prospective study compared the changes in 16 eyes of 16 patients who underwent DALK (DALK group) with those in 28 eyes of 28 patients who underwent PK (PK group). Thirty healthy volunteers were also included as controls. Tear functions were evaluated using tear break-up time (TBUT), tear meniscus height (TMH) and corneal fluorescein staining. Corneal sensation was measured with a Cochet-Bonnet esthesiometer. Corneal subbasal nerve morphology was evaluated using in vivo confocal microscopy (IVCM). The patients were examined 1, 3, 6, 9 and 12 months after keratoplasty. RESULTS: Postoperatively, TMH recovered significantly faster in the DALK group than in the PK group (p < 0.05), and the postoperative TBUT was much higher in the DALK group compared with the PK group (p < 0.05). Central and peripheral corneal sensitivity remained lower in both the PK and DALK groups at 12 months after surgery compared with the control group (p < 0.05). The peripheral corneal sensitivity of the host cornea was significantly higher than the central corneal sensitivity (p < 0.05). No significant difference was found in corneal sensitivity between the PK and DALK groups. There was no significant correlation between corneal sensitivity and tear film function after PK or DALK. CONCLUSIONS: Tear film function was restored more rapidly after DALK compared with PK, but there was no significant difference in corneal sensitivity between PK and DALK.

Comparisons of clinical scoring systems among suspected pulmonary embolism patients presenting to emergency department.

Introduction: Pulmonary embolism (PE) is among the most severe cardiovascular disorders worldwide. Timely and appropriate diagnosis of PE remains an important step in reducing PE related mortality and morbidity. Methods: In this retrospective single-center cohort study, we comprehensively compared the screening performances of several clinical scoring systems (Wells score [WS], Revised Geneva score [RGS], WS + d-Dimer [D-D], RGS + D-D, WS + PE rule-out criteria [PERC] and RGS + PERC) among PE suspected patients. Failure rates across different PE severity grades as well as overall sensitivity/specificity were considered in evaluating each screening strategy. Results: A total of 3437 patients were included in this study and 698 of them were diagnosed with PE. Patients with and without PE were similar in demographics, while significantly different in respiration-related characteristics. Compared with WS or RGS alone, Integrating PERC or D-D with WS or RGS significantly decreased the failure rates across all PE severity grades, and increased the overall sensitivity from 88.5% and 87.2% to 96.3% and 94.8% (D-D) to 99.4% and 99.6% (PERC), respectively. However, compared with other four scoring approaches, using WS or RGS alone increased the specificity from 8.3% and 7.2%, 38.3% and 21.3%, to 63.5% and 34.8%, respectively, and increased the AUC from 0.54 to 0.54, 0.70 and 0.69, to 0.8 and 0.76, respectively. In general, all screening approaches achieved better performances among PE patients with respiratory distress compared to those without respiratory distress. Conclusion: Combining PERC or D-D with WS or RGS, and the presence of respiratory distress provide significantly better PE rule-out performances.

Genetically determined blood pressure, antihypertensive medications, and risk of intracranial aneurysms and aneurysmal subarachnoid hemorrhage: A Mendelian randomization study.

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.

Mean compression ratio of a self-expandable valve is associated with the need for pacemaker implantation after transcatheter aortic valve replacement.

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.

Augmentation of scleral glycolysis promotes myopia through histone lactylation.

Myopia is characterized of maladaptive increases in scleral fibroblast-to-myofibroblast transdifferentiation (FMT). Scleral hypoxia is a significant factor contributing to myopia, but how hypoxia induces myopia is poorly understood. Here, we showed that myopia in mice and guinea pigs was associated with hypoxia-induced increases in key glycolytic enzymes expression and lactate levels in the sclera. Promotion of scleral glycolysis or lactate production induced FMT and myopia; conversely, suppression of glycolysis or lactate production eliminated or inhibited FMT and myopia. Mechanistically, increasing scleral glycolysis-lactate levels promoted FMT and myopia via H3K18la, and this promoted Notch1 expression. Genetic analyses identified a significant enrichment of two genes encoding glycolytic enzymes, ENO2 and TPI1. Moreover, increasing sugar intake in guinea pigs not only induced myopia but also enhanced the response to myopia induction via the scleral glycolysis-lactate-histone lactylation pathway. Collectively, we suggest that scleral glycolysis contributes to myopia by promoting FMT via lactate-induced histone lactylation.