Quantitative measurement of cell-surface displayed proteins based on split-GFP assembly.

BACKGROUND: Microbial cell surface display technology allows immobilizing proteins on the cell surface by fusing them to anchoring motifs, thereby endowing the cells with diverse functionalities. However, the assessment of successful protein display and the quantification of displayed proteins remain challenging. The green fluorescent protein (GFP) can be split into two non-fluorescent fragments, while they spontaneously assemble and emit fluorescence when brought together through complementation. Based on split-GFP assembly, we aim to: (1) confirm the success display of passenger proteins, (2) quantify the number of passenger proteins displayed on individual cells. RESULTS: In this study, we propose two innovative methods based on split-green fluorescent protein (split-GFP), named GFP1-10/GFP11 and GFP1-9/GFP10-11 assembly, for the purpose of confirming successful display and quantifying the number of proteins displayed on individual cells. We evaluated the display efficiency of SUMO and ubiquitin using different anchor proteins to demonstrate the feasibility of the two split-GFP assembly systems. To measure the display efficiency of functional proteins, laccase expression was measured using the split-GFP assembly system by co-displaying GFP11 or GFP10-11 tags, respectively. CONCLUSIONS: Our study provides two split-GFP based methods that enable qualitative and quantitative analyses of individual cell display efficiency with a simple workflow, thus facilitating further comprehensive investigations into microbial cell surface display technology. Both split-GFP assembly systems offer a one-step procedure with minimal cost, simplifying the fluorescence analysis of surface-displaying cells.

DOD-Combo: Bayesian dose finding design in combination trials with meta-analytic-predictive prior.

Combination therapy, a treatment modality that involves multiple treatment agents, has become imperative for improving treatment effectiveness and addressing resistance in the field of oncology. However, determining the most effective dose for these combinations, particularly when dealing with intricate drug interactions and diverse toxicity patterns, presents a substantial challenge. This paper introduces a novel Bayesian dose-finding design for combination therapies with information borrowing, named the DOD-Combo design. Leveraging historical single-agent trials and the meta-analytic-predictive (MAP) power prior, our approach utilizes a copula-type model to connect individual drug priors with joint toxicity probabilities in combination treatments. The MAP power prior allows the integration of information from multiple historical trials, constructing informative priors for each agent. Extensive simulations confirm our method's superior performance compared to combination designs with no information borrowing. By adaptively incorporating historical data, our approach reduces sample sizes and enhances efficiency in selecting the maximum tolerated dose (MTD), effectively addressing the intricate challenges presented by combination trials.

Mucosal vaccine-induced cross-reactive CD8+ T cells protect against SARS-CoV-2 XBB.1.5 respiratory tract infection.

A nasally delivered chimpanzee adenoviral-vectored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (ChAd-SARS-CoV-2-S) is currently used in India (iNCOVACC). Here, we update this vaccine by creating ChAd-SARS-CoV-2-BA.5-S, which encodes a prefusion-stabilized BA.5 spike protein. Whereas serum neutralizing antibody responses induced by monovalent or bivalent adenoviral vaccines were poor against the antigenically distant XBB.1.5 strain and insufficient to protect in passive transfer experiments, mucosal antibody and cross-reactive memory T cell responses were robust, and protection was evident against WA1/2020 D614G and Omicron variants BQ.1.1 and XBB.1.5 in mice and hamsters. However, depletion of memory CD8+ T cells before XBB.1.5 challenge resulted in loss of protection against upper and lower respiratory tract infection. Thus, nasally delivered vaccines stimulate mucosal immunity against emerging SARS-CoV-2 strains, and cross-reactive memory CD8+ T cells mediate protection against lung infection by antigenically distant strains in the setting of low serum levels of cross-reactive neutralizing antibodies.

The Trajectory of Oral Mucositis in Head and Neck Cancer Patients Undergoing Radiotherapy and its Influencing Factors.

BACKGROUND: Oral mucositis (OM) is a common and severe side effect of radiotherapy in head and neck cancer (HNC). The study aimed to investigate the longitudinal changes in OM and its influencing factors in patients with HNC during radiotherapy. METHODS: This was a retrospective longitudinal observational study. From July 2022 to March 2023, patients with HNC undergoing radiation therapy were enrolled. OM, oral hygiene, oral infections, oral pain, feeding route, and laboratory indicators were measured at 7 times. The influencing factors of OM were analyzed using generalized estimation equations (GEEs). RESULTS: A total of 160 patients were included in this study. The prevalence of severe OM at T0, T1, T2, T3, T4, T5, and T6 was 0, 0, 2.5%, 9.4%, 26.9%, 24.4%, and 26.9%, respectively. The prevalence of grade 1-2 OM at T0, T1, T2, T3, T4, T5, and T6 was 0, 16.3%, 53.1%, 65.1%, 61.9%, 70.7%, and 71.3%, respectively. Duration of diagnosis, clinical stage, N stage, M stage, surgery, diabetes, radiotherapy dose, oral hygiene, oral infection, oral pain, feeding route, and lymphocyte impacted OM significantly in the GEEs multivariate model. CONCLUSIONS: OM occurs in almost all patients with HNC who undergo radiotherapy. Changes in the severity of OM are a dynamic process, with the severity increasing with the cumulative radiotherapy dose. Specialist oral evaluation and oral care are needed to alleviate the severity of OM in HNC patients.

Propofol Affords No Protection against Delayed Cerebral Ischemia in a Mouse Model of Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is an important contributor to poor outcomes in aneurysmal subarachnoid hemorrhage (SAH) patients. We previously showed that volatile anesthetics such as isoflurane, sevoflurane and desflurane provided robust protection against SAH-induced DCI, but the impact of a more commonly used intravenous anesthetic agent, propofol, is not known. The goal of our current study is to examine the neurovascular protective effects of propofol on SAH-induced DCI. Twelve-week-old male wild-type mice were utilized for the study. Mice underwent endovascular perforation SAH or sham surgery followed one hour later by propofol infusion through the internal jugular vein (2 mg/kg/min continuous intravenous infusion). Large artery vasospasm was assessed three days after SAH. Neurological outcome assessment was performed at baseline and then daily until animal sacrifice. Statistical analysis was performed via one-way ANOVA and two-way repeated measures ANOVA followed by the Newman-Keuls multiple comparison test with significance set at p < 0.05. Intravenous propofol did not provide any protection against large artery vasospasm or sensory-motor neurological deficits induced by SAH. Our data show that propofol did not afford significant protection against SAH-induced DCI. These results are consistent with recent clinical studies that suggest that the neurovascular protection afforded by anesthetic conditioning is critically dependent on the class of anesthetic agent.

BEATS: Bayesian hybrid design with flexible sample size adaptation for time-to-event endpoints.

As the roles of historical trials and real-world evidence in drug development have substantially increased, several approaches have been proposed to leverage external data and improve the design of clinical trials. While most of these approaches focus on methodology development for borrowing information during the analysis stage, there is a risk of inadequate or absent enrollment of concurrent control due to misspecification of heterogeneity from external data, which can result in unreliable estimates of treatment effect. In this study, we introduce a Bayesian hybrid design with flexible sample size adaptation (BEATS) that allows for adaptive borrowing of external data based on the level of heterogeneity to augment the control arm during both the design and interim analysis stages. Moreover, BEATS extends the Bayesian semiparametric meta-analytic predictive prior (BaSe-MAP) to incorporate time-to-event endpoints, enabling optimal borrowing performance. Initially, BEATS calibrates the expected sample size and initial randomization ratio based on heterogeneity among the external data. During the interim analysis, flexible sample size adaptation is performed to address conflicts between the concurrent and historical control, while also conducting futility analysis. At the final analysis, estimation is provided by incorporating the calibrated amount of external data. Therefore, our proposed design allows for an approximation of an ideal randomized controlled trial with an equal randomization ratio while controlling the size of the concurrent control to benefit patients and accelerate drug development. BEATS also offers optimal power and robust estimation through flexible sample size adaptation when conflicts arise between the concurrent control and external data.

Isoflurane Conditioning-Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage-Role of Inducible Nitric Oxide Synthase.

Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning-induced protection against delayed cerebral ischemia in a mouse model of SAH. Methods and Results The experiments used 10- to 14-week-old male wild-type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane 2% for 1 hour. Isoflurane-induced changes in iNOS expression were measured. N-(3-(aminomethyl) benzyl) acetamidine, a highly selective iNOS inhibitor, was injected intraperitoneally immediately after SAH and then daily. Vasospasm, microvessel thrombosis, and neurological assessment was performed. Data were analyzed by 1-way ANOVA and 2-way repeated measures ANOVA followed by Student Newman Keuls comparison test. Statistical significance was set at P<0.05. Isoflurane conditioning downregulated iNOS expression in naïve and SAH mice. N-(3-(aminomethyl) benzyl) acetamidine attenuated large artery vasospasm and microvessel thrombosis and improved neurological deficits in wild-type animals. iNOS knockout mice were significantly resistant to vasospasm, microvessel thrombosis, and neurological deficits induced by SAH. Combining isoflurane with N-(3-(aminomethyl) benzyl) acetamidine did not offer extra protection, nor did treating iNOS knockout mice with isoflurane. Conclusions Isoflurane conditioning-induced delayed cerebral ischemia protection appears to be mediated by downregulating iNOS. iNOS is a potential therapeutic target to improve outcomes after SAH.

Oral health behavior and oral health service utilization among cancer patients in China: A multicenter cross-sectional study.

Purpose: Oral health plays an important role in overall health. But there is scarce information available on oral health behavior and oral health service utilization among cancer patients. This study aimed to evaluate oral health behavior and oral health service utilization among different population groups of cancer patients in China. Methods: A multicenter cross-sectional study in three tertiary hospitals was conducted to explore the oral health behaviors and oral health service utilization of 162 cancer patients in China. Results: We investigated a total of 162 cancer patients, 81 from urban and rural areas, respectively. The participant's ages ranged from 18 and 82 years, mean age was 44.62 years (SD = 15.72). Overall, cancer patients have poor oral health behaviors and limited oral health service utilization. There were statistically significant differences (p < 0.05) between urban and rural cancer patients in terms of oral health behaviors, including brushing methods, the use of fluoride toothpaste, the use of dental floss, dental caries, and bleeding gums while brushing teeth. As for oral health service utilization, there were significant differences (p < 0.05) between urban and rural cancer patients on regular dental cleaning, the reasons for visiting a dental clinic, and whether they took the initiative to learn about oral health. Conclusion: The study findings suggest that cancer patients had poor oral health behaviors and limited oral health service utilization, and rural patients perform poorer than their urban counterparts. Oral health education should be provided to cancer patients to improve their oral health behaviors and oral health service utilization.

Isoflurane Conditioning Provides Protection against Subarachnoid Hemorrhage Induced Delayed Cerebral Ischemia through NF-kB Inhibition.

Delayed cerebral ischemia (DCI) is the largest treatable cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-kB), a transcription factor known to function as a pivotal mediator of inflammation, is upregulated in SAH and is pathologically associated with vasospasm. We previously showed that a brief exposure to isoflurane, an inhalational anesthetic, provided multifaceted protection against DCI after SAH. The aim of our current study is to investigate the role of NF-kB in isoflurane-conditioning-induced neurovascular protection against SAH-induced DCI. Twelve-week-old wild type male mice (C57BL/6) were divided into five groups: sham, SAH, SAH + Pyrrolidine dithiocarbamate (PDTC, a selective NF-kB inhibitor), SAH + isoflurane conditioning, and SAH + PDTC with isoflurane conditioning. Experimental SAH was performed via endovascular perforation. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. Three doses of PDTC (100 mg/kg) were injected intraperitoneally. NF-kB and microglial activation and the cellular source of NF-kB after SAH were assessed by immunofluorescence staining. Vasospasm, microvessel thrombosis, and neuroscore were assessed. NF-kB was activated after SAH; it was attenuated by isoflurane conditioning. Microglia was activated and found to be a major source of NF-kB expression after SAH. Isoflurane conditioning attenuated microglial activation and NF-kB expression in microglia after SAH. Isoflurane conditioning and PDTC individually attenuated large artery vasospasm and microvessel thrombosis, leading to improved neurological deficits after SAH. The addition of isoflurane to the PDTC group did not provide any additional DCI protection. These data indicate isoflurane-conditioning-induced DCI protection after SAH is mediated, at least in part, via downregulating the NF-kB pathway.

Fc-γR-dependent antibody effector functions are required for vaccine-mediated protection against antigen-shifted variants of SARS-CoV-2.

Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with antigenic changes in the spike protein are neutralized less efficiently by serum antibodies elicited by legacy vaccines against the ancestral Wuhan-1 virus. Nonetheless, these vaccines, including mRNA-1273 and BNT162b2, retained their ability to protect against severe disease and death, suggesting that other aspects of immunity control infection in the lung. Vaccine-elicited antibodies can bind Fc gamma receptors (FcγRs) and mediate effector functions against SARS-CoV-2 variants, and this property correlates with improved clinical coronavirus disease 2019 outcome. However, a causal relationship between Fc effector functions and vaccine-mediated protection against infection has not been established. Here, using passive and active immunization approaches in wild-type and FcγR-knockout mice, we determined the requirement for Fc effector functions to control SARS-CoV-2 infection. The antiviral activity of passively transferred immune serum was lost against multiple SARS-CoV-2 strains in mice lacking expression of activating FcγRs, especially murine FcγR III (CD16), or depleted of alveolar macrophages. After immunization with the pre-clinical mRNA-1273 vaccine, control of Omicron BA.5 infection in the respiratory tract also was lost in mice lacking FcγR III. Our passive and active immunization studies in mice suggest that Fc-FcγR engagement and alveolar macrophages are required for vaccine-induced antibody-mediated protection against infection by antigenically changed SARS-CoV-2 variants, including Omicron strains.

Fcγ receptor-dependent antibody effector functions are required for vaccine protection against infection by antigenic variants of SARS-CoV-2.

Emerging SARS-CoV-2 variants with antigenic changes in the spike protein are neutralized less efficiently by serum antibodies elicited by legacy vaccines against the ancestral Wuhan-1 virus. Nonetheless, these vaccines, including mRNA-1273 and BNT162b2, retained their ability to protect against severe disease and death, suggesting that other aspects of immunity control infection in the lung. Although vaccine-elicited antibodies can bind Fc gamma receptors (FcγRs) and mediate effector functions against SARS-CoV-2 variants, and this property correlates with improved clinical COVID-19 outcome, a causal relationship between Fc effector functions and vaccine-mediated protection against infection has not been established. Here, using passive and active immunization approaches in wild-type and Fc-gamma receptor (FcγR) KO mice, we determined the requirement for Fc effector functions to protect against SARS-CoV-2 infection. The antiviral activity of passively transferred immune serum was lost against multiple SARS-CoV-2 strains in mice lacking expression of activating FcγRs, especially murine FcγR III (CD16), or depleted of alveolar macrophages. After immunization with the preclinical mRNA-1273 vaccine, protection against Omicron BA.5 infection in the respiratory tract also was lost in mice lacking FcγR III. Our passive and active immunization studies in mice suggest that Fc-FcγR engagement and alveolar macrophages are required for vaccine-induced antibody-mediated protection against infection by antigenically changed SARS-CoV-2 variants, including Omicron strains.

Assessment of the oral health literacy and oral health behaviors among nurses in China: a cross-sectional study.

PURPOSE: Oral health is important for general health; nurses are expected to possess good oral health awareness and work together for public oral health promotion. The purpose of this study is to investigate oral health literacy (OHL)and oral health behaviors of nurses, and explore the association between oral health literacy with demographic variables and oral health behaviors. METHODS: A cross-sectional study in a tertiary hospital was conducted using a short-form Health Literacy in Dentistry-14 (HeLD-14) and a 16-items oral health behaviors questionnaire. Information about the subjects' demographic details including age, gender, place of residence, marital status, marital status, education level, monthly household income, working experience, etc. were collected. Independent sample t- test, One- way ANOVA, and multivariable regression were used to identify the association of oral health literacy with demographic variables and oral health behaviors. RESULTS: A total number of 317 nursing nurses participated in the survey, with a mean OHL score of 36.72, SD10.531, 21.8% were categorized as good, 34.1% medium and 44.2% poor oral health literacy; monthly household income, self-rated oral health, brushing time, use of fluoride toothpaste, and regular oral examination were signficantly associated with OHL scores. CONCLUSION: The overall oral health literacy of the nurse population is at a moderate to low level. These findings may help to map and design an oral health education intervention to improve oral health literacy amongst nurses, especially nurses with low monthly household income and poor self-assessed oral health status. Nursing administrators and nursing educators should pay more attention to the oral health status of the nurse population.

Oral Health Behaviors and Oral Health-Related Quality of Life Among Dental Patients in China: A Cross-Sectional Study.

Background and Purpose: Oral health plays an important role in overall health. But little is known about the problems with oral health behaviors and oral health-related quality of life (OHRQoL) among dental patients in China. This study aimed to investigate oral health behaviors and OHRQoL, as well as to examine the effects of oral health behaviors and associated factors on OHRQoL among dental patients. Methods: This cross-sectional study was conducted from June 2022 to July 2022 in the Department of Stomatology of the First Mobile General Hospital of Armed Police, Hebei, China. The five-item short form of the Oral Health Impact Profile (OHIP-5) was used to evaluate OHRQoL. Oral health behaviors were assessed by a 16-items oral health behavior questionnaire, and socio-demographic data were collected by a socio-demographic questionnaire. The t-test, one-way ANOVA, and multiple linear regression analysis were used to investigate the associations between the study variables. Results: 186 participants were included in the study. The average age of the participants was 24.62 years (SD = 10.67). The mean OHIP-5 score was 4.31 (SD =3.35). Oral health-related quality of life differed significantly by smoking history, history of alcohol consumption, work status, economic pressure, self-rated oral health status, daily brushing frequency, dental caries condition, and whether they take the initiative to learn about oral health. Multivariate analysis found that the self-rated oral health status and work status were significantly associated with the OHIP scores. The retired people and those with poor self-rated oral health displayed poor OHRQoL. Conclusion: In general, dental patients' oral health needs to be improved, the majority of patients reported practicing poor oral health behaviors, among which the retired population and hose with poor self-rated oral health showed poor OHRQoL. OHRQoL in dental patients is a complex issue associated with social and behavioral factors.

Multi-omics analyses reveal MdMYB10 hypermethylation being responsible for a bud sport of apple fruit color.

Apple bud sports offer a rich resource for clonal selection of numerous elite cultivars. The accumulation of somatic mutations as plants develop may potentially impact the emergence of bud sports. Previous studies focused on somatic mutation in the essential genes associated with bud sports. However, the rate and function of genome-wide somatic mutations that accumulate when a bud sport arises remain unclear. In this study, we identified a branch from a 10-year-old tree of the apple cultivar 'Oregon Spur II' as a bud sport. The mutant branch showed reduced red coloration on fruit skin. Using this plant material, we assembled a high-quality haplotype reference genome consisting of 649.61 Mb sequences with a contig N50 value of 2.04 Mb. We then estimated the somatic mutation rate of the apple tree to be 4.56 × 10 -8 per base per year, and further identified 253 somatic single-nucleotide polymorphisms (SNPs), including five non-synonymous SNPs, between the original type and mutant samples. Transcriptome analyses showed that 69 differentially expressed genes between the original type and mutant fruit skin were highly correlated with anthocyanin content. DNA methylation in the promoter of five anthocyanin-associated genes was increased in the mutant compared with the original type as determined using DNA methylation profiling. Among the genetic and epigenetic factors that directly and indirectly influence anthocyanin content in the mutant apple fruit skin, the hypermethylated promoter of MdMYB10 is important. This study indicated that numerous somatic mutations accumulated at the emergence of a bud sport from a genome-wide perspective, some of which contribute to the low coloration of the bud sport.

PMED: Optimal Bayesian Platform Trial Design with Multiple Endpoints.

In oncology drug development, indication selection and optimal dose identification are the primary objectives for the early phase of clinical trials and could significantly impact the probability of success. Master protocols, e.g., basket trial, umbrella trial, and platform trial, have become popular in practice considering the connection of trial designs with multiple indications and treatment candidates. They also enable the optimization of operational resources and maximize the capability of data-driven decision-making. However, most of the available designs are developed with the efficacy endpoint only for treatment effect estimation and testing, without consideration of the safety end point. Thus, it often lacks a comprehensive quantitative framework to allow optimal treatment selection, which could put future development at risk. We propose an optimal Bayesian platform trial design with multiple end points (PMED) to characterize the overall benefit-risk profile. The design is further extended to allow treatment and indication selection within and across arms, with continuous monitoring on multiple interim analyses for futility. In addition, we propose dynamic borrowing across arms to increase the efficiency and accuracy of estimation given the level of similarity across arms. A hierarchical hypothesis structure is utilized to achieve optimal indication and treatment combination selection by controlling family-wise error. Through simulation studies, we show that PMED is a robust design under the studied scenarios with superb power and controlled family-wise error rate.

A Reduced Starch Level in Plants at Early Stages of Infection by Viruses Can Be Considered a Broad-Range Indicator of Virus Presence.

The diagnosis of virus infection can facilitate the effective control of plant viral diseases. To date, serological and molecular methods for the detection of virus infection have been widely used, but these methods have disadvantages if applied for broad-range and large-scale detection. Here, we investigated the effect of infection of several different plant RNA and DNA viruses such as cucumber mosaic virus (CMV), tobacco mosaic virus (TMV), potato virus X (PVX), potato virus Y (PVY) and apple geminivirus on starch content in leaves of Nicotiana benthamiana. Analysis showed that virus infection at an early stage was generally associated with a reduction in starch accumulation. Notably, a reduction in starch accumulation was readily apparent even with a very low virus accumulation detected by RT-PCR. Furthermore, we also observed that the infection of three latent viruses in propagative apple materials was associated with a reduction in starch accumulation levels. Analysis of transcriptional expression showed that some genes encoding enzymes involved in starch biosynthesis were downregulated at the early stage of CMV, TMV, PVX and PVY infections, suggesting that virus infection interferes with starch biosynthesis in plants. Our findings suggest that assessing starch accumulation levels potentially serve as a broad-range indicator for the presence of virus infection.

Sevoflurane and Desflurane Exposures Following Aneurysmal Subarachnoid Hemorrhage Confer Multifaceted Protection against Delayed Cerebral Ischemia.

Numerous studies have demonstrated the ability of isoflurane conditioning to provide multifaceted protection against aneurysmal subarachnoid hemorrhage (SAH)-associated delayed cerebral ischemia (DCI); however, preclinical studies have not yet examined whether other commonly used inhalational anesthetics in neurological patients such as sevoflurane or desflurane are also protective against SAH-induced neurovascular deficits. We therefore sought to identify the potential for sevoflurane and desflurane conditioning to protect against DCI in an endovascular perforation mouse model of SAH. Neurological function was assessed daily via neuroscore. Large artery vasospasm and microvessel thrombosis were assessed three days after SAH or sham surgery. Four groups were examined: Sham, SAH + room air, SAH + 2% Sevoflurane, and SAH + 6% Desflurane. For the SAH groups, one hour after surgery, mice received 2% sevoflurane, 6% desflurane, or room air for one hour. We found that conditioning with sevoflurane or desflurane attenuated large artery vasospasm, reduced microvessel thrombosis, and improved neurologic function. Given their frequent clinical use and strong safety profile in patients (including those with SAH), these data strongly support further studies to validate these findings in preclinical and clinical studies and to elucidate the mechanisms by which these agents might be acting.

Propensity-score-based meta-analytic predictive prior for incorporating real-world and historical data.

As the availability of real-world data sources (eg, EHRs, claims data, registries) and historical data has rapidly surged in recent years, there is an increasing interest and need from investigators and health authorities to leverage all available information to reduce patient burden and accelerate both drug development and regulatory decision making. Bayesian meta-analytic approaches are a popular historical borrowing method that has been developed to leverage such data using robust hierarchical models. The model structure accounts for various degrees of between-trial heterogeneity, resulting in adaptively discounting the external information in the case of data conflict. In this article, we propose to integrate the propensity score method and Bayesian meta-analytic-predictive (MAP) prior to leverage external real-world and historical data. The propensity score methodology is applied to select a subset of patients from external data that are similar to those in the current study with regards to key baseline covariates and to stratify the selected patients together with those in the current study into more homogeneous strata. The MAP prior approach is used to obtain stratum-specific MAP prior and derive the overall propensity score integrated meta-analytic predictive (PS-MAP) prior. Additionally, we allow for tuning the prior effective sample size for the proposed PS-MAP prior, which quantifies the amount of information borrowed from external data. We evaluate the performance of the proposed PS-MAP prior by comparing it to the existing propensity score-integrated power prior approach in a simulation study and illustrate its implementation with an example of a single-arm phase II trial.

Role of SIRT1 in Isoflurane Conditioning-Induced Neurovascular Protection against Delayed Cerebral Ischemia Secondary to Subarachnoid Hemorrhage.

We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD-dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning-induced neurovascular protection against SAH-induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX-527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX-527, a selective SIRT1 inhibitor, 10 mg/kg was injected intraperitoneally immediately after SAH in the EX-527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX-527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway.