Hierarchical Bayesian modeling of heterogeneous outcome variance in cluster randomized trials.

BACKGROUND: Heterogeneous outcome correlations across treatment arms and clusters have been increasingly acknowledged in cluster randomized trials with binary endpoints, where analytical methods have been developed to study such heterogeneity. However, cluster-specific outcome variances and correlations have yet to be studied for cluster randomized trials with continuous outcomes. METHODS: This article proposes models fitted in the Bayesian setting with hierarchical variance structure to quantify heterogeneous variances across clusters and explain it with cluster-level covariates when the outcome is continuous. The models can also be extended to analyzing heterogeneous variances in individually randomized group treatment trials, with arm-specific cluster-level covariates, or in partially nested designs. Simulation studies are carried out to validate the performance of the newly introduced models across different settings. RESULTS: Simulations showed that overall the newly introduced models have good performance, reporting low bias and approximately 95% coverage for the intraclass correlation coefficients and regression parameters in the variance model. When variances are heterogeneous, our proposed models had improved model fit over models with homogeneous variances. When used to analyze data from the Kerala Diabetes Prevention Program study, our models identified heterogeneous variances and intraclass correlation coefficients across clusters and examined cluster-level characteristics associated with such heterogeneity. CONCLUSION: We proposed new hierarchical Bayesian variance models to accommodate cluster-specific variances in cluster randomized trials. The newly developed methods inform the understanding of how an intervention strategy is implemented and disseminated differently across clusters and can help improve future trial design.

Designing multicenter individually randomized group treatment trials.

In an individually randomized group treatment (IRGT) trial, participant outcomes can be positively correlated due to, for example, shared therapists in treatment delivery. Oftentimes, because of limited treatment resources or participants at one location, an IRGT trial can be carried out across multiple centers. This design can be subject to potential correlations in the participant outcomes between arms within the same center. While the design of a single-center IRGT trial has been studied, little is known about the planning of a multicenter IRGT trial. To address this gap, this paper provides analytical sample size formulas for designing multicenter IRGT trials with a continuous endpoint under the linear mixed model framework. We found that accounting for the additional center-level correlation at the design stage can lead to sample size reduction, and the magnitude of reduction depends on the amount of between-therapist correlation. However, if the variance components of therapist-level random effects are considered as input parameters in the design stage, accounting for the additional center-level variance component has no impact on the sample size estimation. We presented our findings through numeric illustrations and performed simulation studies to validate our sample size procedures under different scenarios. Optimal design configurations under the multicenter IRGT trials have also been discussed, and two real-world trial examples are drawn to illustrate the use of our method.

Pneumocystis jirovecii with high probability detected in bronchoalveolar lavage fluid of chemotherapy-related interstitial pneumonia in patients with lymphoma using metagenomic next-generation sequencing technology.

BACKGROUND: Previous studies achieved low microbial detection rates in lymphoma patients with interstitial pneumonia (IP) after chemotherapy. However, the metagenomic next-generation sequencing (mNGS) is a comprehensive approach that is expected to improve the pathogen identification rate. Thus far, reports on the use of mNGS in lymphoma patients with chemotherapy-related IP remain scarce. In this study, we summarized the microbial detection outcomes of lymphoma patients with chemotherapy-related IP through mNGS testing of bronchoalveolar lavage fluid (BALF). METHODS: Fifteen lymphoma patients with chemotherapy-related IP were tested for traditional laboratory microbiology, along with the mNGS of BALF. Then, the results of mNGS and traditional laboratory microbiology were compared. RESULTS: Of the 15 enrolled patients, 11 received rituximab and 8 were administered doxorubicin hydrochloride liposome. The overall microbial yield was 93.3% (14/15) for mNGS versus 13.3% (2/15) for traditional culture methods (P ≤ 0.05). The most frequently detected pathogens were Pneumocystis jirovecii (12/15, 80%), Cytomegalovirus (4/15, 26.7%), and Epstein-Barr virus (3/15, 20%). Mixed infections were detected in 10 cases. Five patients recovered after the treatment with antibiotics alone without glucocorticoids. CONCLUSION: Our findings obtained through mNGS testing of BALF suggested a high microbial detection rate in lymphoma patients with IP after chemotherapy. Notably, there was an especially high detection rate of Pneumocystis jirovecii. The application of mNGS in patients with chemotherapy-related IP was more sensitive.

Xenon postconditioning attenuates neuronal injury after spinal cord ischemia/reperfusion injury by targeting endoplasmic reticulum stress-associated apoptosis.

The purpose of the study is to explore the underlying mechanisms of xenon (Xe) which protects against spinal cord ischemia/reperfusion injury (SCIRI). A SCIRI rat model was induced by abdominal artery occlusion for 85 min and reperfusion. Xe postconditioning (50% Xe) was administered 1 h after 1 h of reperfusion. At reperfusion time points (2, 4, 6, and 24 h), rats were treated with spinal cord scans by MRI to assess the time of peak spinal cord injury after SCIRI. Subsequently, endoplasmic reticulum (ER) stress inhibitor sodium 4-phenylbutyrate (4-PBA) was administered by daily intraperitoneal injection (50 mg/kg) for 5 days before SCIRI. At 4 h after reperfusion, motor function, immunofluorescence staining, hematoxylin and eosin (HE) staining, Nissl staining, TUNEL staining, real-time reverse transcription polymerase chain (RT-PCR) reaction, and western blot analyses were performed to investigate the protective effects of Xe against SCIRI. In the rat I/R model, spinal cord edema peaked at reperfusion 4 h. SCIRI activated ER stress, which was located in neurons. Xe postconditioning remarkably alleviated hind limb motor function, reduced neuronal apoptosis rate, increased the number of normal neurons, and inhibited the expression of ER stress-related protein in spinal cord. Furthermore, the administration of the ER stress inhibitor 4-PBA strongly decreased ER stress-induced apoptosis following SCIRI. Xe postconditioning inhibits ER stress activation, which contributes to alleviate SCIRI by suppressing neuronal apoptosis.

Accounting for expected attrition in the planning of cluster randomized trials for assessing treatment effect heterogeneity.

BACKGROUND: Detecting treatment effect heterogeneity is an important objective in cluster randomized trials and implementation research. While sample size procedures for testing the average treatment effect accounting for participant attrition assuming missing completely at random or missing at random have been previously developed, the impact of attrition on the power for detecting heterogeneous treatment effects in cluster randomized trials remains unknown. METHODS: We provide a sample size formula for testing for a heterogeneous treatment effect assuming the outcome is missing completely at random. We also propose an efficient Monte Carlo sample size procedure for assessing heterogeneous treatment effect assuming covariate-dependent outcome missingness (missing at random). We compare our sample size methods with the direct inflation method that divides the estimated sample size by the mean follow-up rate. We also evaluate our methods through simulation studies and illustrate them with a real-world example. RESULTS: Simulation results show that our proposed sample size methods under both missing completely at random and missing at random provide sufficient power for assessing heterogeneous treatment effect. The proposed sample size methods lead to more accurate sample size estimates than the direct inflation method when the missingness rate is high (e.g., ≥ 30%). Moreover, sample size estimation under both missing completely at random and missing at random is sensitive to the missingness rate, but not sensitive to the intracluster correlation coefficient among the missingness indicators. CONCLUSION: Our new sample size methods can assist in planning cluster randomized trials that plan to assess a heterogeneous treatment effect and participant attrition is expected to occur.

Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway.

BACKGROUND: The mammalian target of rapamycin (mTOR) plays a critical role in controlling cellular homeostasis, and its dysregulation has been implicated in Alzheimer's disease (AD). Presenilin-1 (PS1) mutations account for the most common causes of familial Alzheimer's disease (FAD); however, whether PS1 mutation causes mTOR dysregulation in human neurons remains a key unresolved issue. METHODS: We generated heterozygotes and homozygotes of PS1 F105C knock-in mutation in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9/piggyback-based gene editing and differentiated them into human neurons. Secreted Aß and tau accumulation were determined by ELISA assay, immunofluorescence staining, and western blotting analysis. mTOR signaling was evaluated by western blotting analysis, immunofluorescence staining, and co-immunoprecipitation. Autophagy/lysosome activities were determined by LC3-based assay, LysoTracker Red staining, and DQ-Red BSA staining. RESULTS: Through comparison among these isogenic neurons, PS1 F105C mutant neurons exhibited elevated Aß and tau accumulation. In addition, we found that the response of mTORC1 to starvation decreases in PS1 F105C mutant neurons. The Akt/mTORC1/p70S6K signaling pathway remained active upon EBSS starvation, leading to the co-localization of the vast majority of mTOR with lysosomes. Consistently, PS1 F105C neurons displayed a significant decline in starvation-induced autophagy. Notably, Torin1, a mTOR inhibitor, could efficiently reduce prominent tau pathology that occurred in PS1 F105C neurons. CONCLUSION: We demonstrate that Chinese PS1 F105C mutation causes dysregulation of mTORC1 signaling, contributing to tau accumulation in human neurons. This study on inherited FAD PS1 mutation provides unprecedented insights into our understanding of the molecular mechanisms of AD. It supports that pharmaceutical blocking of mTOR is a promising therapeutic strategy for the treatment of AD.

Dual effects of cardamonin/alpinetin and their acrolein adducts on scavenging acrolein and the anti-bacterial activity from Alpinia katsumadai Hayata as a spice in roasted meat.

Acrolein (ACR) is frequently produced by the thermal degradation of carbohydrates and amino acids and lipid peroxidation in the thermal processing of food. Long-term exposure to ACR can cause various chronic diseases. Here, we screened two high-temperature-resistant ACR inhibitors, cardamonin (CAR) and alpinetin (ALP), which can interconvert without any loss at 100 °C, and were obtained from Alpinia katsumadai Hayata (AKH). They demonstrated the best activity among the six spices investigated and could scavenge ACR generated in roasted pork by forming adducts. After three ACR adducts were prepared, namely CAR-ACR-1, CAR-ACR-2 and ALP-ACR, quantitative analysis showed that the amount of CAR-ACR-1 generated in lean roasted pork with 2% AKH addition reached the minimal inhibitory concentration against Escherichia coli and Staphylococcus aureus, which was 20 times lower than that of CAR, and the higher the generation of ACR, the stronger its antibacterial activity. These results provided well-defined evidence to promote the application of AKH to ACR inhibitors in food processing.

Fabrication of Polyethyleneimine-Functionalized Magnetic Cellulose Nanocrystals for the Adsorption of Diclofenac Sodium from Aqueous Solutions.

Diclofenac sodium (DS), one of the most used non-steroidal anti-inflammatory drugs worldwide, is often detected in wastewater and natural water. This drug is ecotoxic, even at low concentrations. Therefore, it is essential to fabricate low-cost adsorbents that can easily and effectively remove DS from contaminated water bodies. In this study, a polyethyleneimine (PEI)-modified magnetic cellulose nanocrystal (MCNC) was prepared with a silane coupling agent as a bridge. TEM, FTIR, XRD, and VSM were used to demonstrate the successful preparation of MCNC-PEI. This composite adsorbent exhibited efficient DS removal. Furthermore, the adsorption performance of MCNC-PEI on DS was optimal under mildly acidic conditions (pH = 4.5). Adsorption kinetics showed that the adsorption process involves mainly electrostatic interactions. Moreover, the maximum adsorption capacity reached 299.93 mg/g at 25 °C, and the adsorption capacity only decreased by 9.9% after being reused five times. Considering its low cost, low toxicity, and high DS removal capacity, MCNC-PEI could be a promising adsorbent for treating DS-contaminated water.

In situ growth of ZIF-8 on carboxymethyl chitosan beads for improved adsorption of lead ion from aqueous solutions.

In this study, a method for the in situ growth of zeolitic imidazolate framework-8 (ZIF-8) on carboxymethyl chitosan beads (BCMC) to produce a composite adsorbent (BCMC@ZIF-8) for the removal of Pb2+ from water is proposed. The results revealed that the utilization of the BCMC as a framework enhanced the stability of ZIF-8, and the presence of the latter in the composite improved the removal efficiency of Pb2+ from water. Data from X-ray photoelectron spectroscopy analysis and adsorption kinetics revealed that the adsorption mechanism included diffusion and the sharing/transfer of electrons between BCMC@ZIF-8 and Pb2+. The maximum adsorption capacity of BCMC@ZIF-8 fitted using the Langmuir model was 566.09 mg/g. Results of the experiments on the regeneration of the adsorbent and its stability in water further indicated that BCMC improved the stability of ZIF-8. This study demonstrated that the stability of metal-organic framework (MOF) materials, which exhibited high efficiencies for the removal of heavy metals in water can be improved through fixation of the polymer skeleton. Thus, the present study offers practical and theoretical guidance for the application of MOF materials in water treatment.

CTA Imaging Features Related to Preoperative Coagulopathy in Patients with Stanford Type A Acute Aortic Dissection.

BACKGROUND: Stanford type A acute aortic dissection (TAAAD) is often accompanied by preoperative disorders of coagulation. The study aimed to evaluate the relationship between computed tomography angiography imaging features and preoperative coagulopathy in TAAAD patients. METHODS: This was a single-center retrospective review of adult patients undergoing TAAAD surgery from January 2015 to January 2019 in the Beijing Anzhen Hospital (Beijing, China). Images were obtained using preoperative enhanced computed tomography in 174 patients with TAAAD. Preoperative coagulopathy was defined as the disseminated intravascular coagulation score greater than 5. The patients were divided into coagulopathy and non-coagulopathy groups. Circumferential arc lengths of the false lumen (Fx) and true lumen (Tx) were measured at four planes (ascending aorta, thoracic-descending aorta, descending aorta and abdominal aorta). We define the value of Fx/(Tx+Fx) × 100% as tear index (TI) and take the four planes' averages to weighed the false lumen's size. By analyzing the two groups of clinical data and computed tomography angiography imaging data, potentially related factors were detected by univariate analysis and multivariate binary logistic regression analysis. RESULTS: The incidence of preoperative coagulopathy for TAAAD patients was 12.07%. In adjusted multivariate binary logistic regression analysis, white blood cell count (odds ratio [OR]: 1.204, 95% confidence interval [CI]: 1.035-1.400, P = 0.016); longitude length of aortic dissection (OR: 1.076, 95% CI: 1.016-1.139, P = 0.012); and Tear index (OR = 1.177, 95% CI: 1.075-1.289, P < 0.001) were significant factors related to the occurrence of preoperative coagulopathy for TAAAD. CONCLUSIONS: The incidence of preoperative coagulopathy in TAAAD patients was 12.07%. The longitude length of AD, TI and white blood cell count were significant factors related to preoperative coagulopathy in patients with TAAAD. The significance of imaging and anatomic changes related to coagulopathy are worth further study in TAAAD patients.

Pretreatment Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Prognostic Factors and Reference Markers of Treatment Options for Locally Advanced Squamous Cell Carcinoma Located in the Middle and Upper Esophagus.

BACKGROUND: Various inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have been well authenticated to predict clinical outcomes in numerous types of cancer. The optimal treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC) located in the middle or upper region is still inconclusive. The aim of the study was to examine pretreatment NLR and PLR to select from radical surgery or definitive chemoradiotherapy (dCRT) for these patients. The linkage between pretreatment NLR/PLR and prognosis was also analyzed. METHODS: NLR and PLR were calculated in 113 locally advanced ESCC located in the middle or upper esophagus of patients who underwent radical surgery or dCRT between January 2014 and December 2019. A receiver operating characteristic curve was plotted to select the best cut-off value of NLR and PLR for predicting survival. A survival curve was plotted using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were applied to assess predictors for survival. RESULTS: NLR and PLR were associated with the extent of lymph node metastasis (NLR: P = 0.045; PLR: P = 0.002). Additionally, high PLR and recurrence with distant organ metastasis were closely related (P = 0.014), and NLR was related to the tumor stage (P = 0.043). The results of the multivariate analysis revealed that NLR (>2.07) and PLR (>183.06) were independently associated with poor prognosis. It is noteworthy that surgery was associated with a superior OS compared with dCRT in the low NLR population (P = 0.045). CONCLUSION: Low pretreatment NLR patients are fit to undergo radical surgery with a substantial therapeutic benefit. Pretreatment NLR and PLR are independent predictors for patients with locally advanced ESCC located in the middle and upper esophagus who underwent radical surgery or dCRT.

Impact of autologous platelet rich plasma use on postoperative acute kidney injury in type A acute aortic dissection repair: a retrospective cohort analysis.

BACKGROUND: Perioperative coagulopathy and blood transfusion are common in patients undergoing Stanford type A acute aortic dissection (AAD) repair. The autologous platelet-rich plasmapheresis (aPRP) technique is a blood conservation approach to reduce blood transfusions and morbidity in patients at high risk of bleeding. The purpose of this study was to analyze the effect of aPRP on outcomes, especially in postoperative acute kidney injury (post-AKI), in patients undergoing AAD surgery. METHODS: Six hundred sixty patients were divided into aPRP and non-aPRP groups according to aPRP use. The primary endpoint was the difference in the incidence of post-AKI between two groups. The secondary endpoints were risk factors for post-AKI and to assess clinical outcomes. The risk factors associated with post-AKI were calculated, and all outcomes were adjusted by propensity-score matching analysis. RESULTS: A total of 272 patients (41.2%) received aPRP, whereas 388 were in the non-aPRP group. Compared to non-aPRP group, the occurrence of post-AKI increased by 14.1% (p = 0.002) and 11.1% (p = 0.010) with and without propensity adjustment in the aPRP group, respectively. The aPRP group required fewer intraoperative transfusions (p < 0.05) and shortened the duration of mechanical ventilation (p < 0.05) than those in the non-aPRP group. Multiple regression analyses showed that aPRP (odds ratio: 1.729, 95% confidence interval: 1.225-2.440; p < 0.001) was one of the independent risk factors for post-AKI. CONCLUSIONS: The use of aPRP significantly reduced intraoperative blood transfusions and decreased postoperative mortality-adjusted mechanical ventilation. However, aPRP use was independently associated with an increased hazard of post-AKI after adjusting for confounding factors.

In situ formation of tetraphenylethylene nano-structures on microgels inside living cells via reduction-responsive self-assembly.

Controlling the assembly of synthetic molecules in living systems is of significance for their adaptive applications. However, it is difficult to achieve, especially for composite self-assemblies, due to the complexity and dynamic change of the intracellular environment, and there exist technical difficulties for the direct visualization of organic and polymer self-assemblies. Herein, we demonstrate a novel strategy for the in situ formation of self-assembled micro-nano composite structures in a cell milieu using reduction-responsive microgels (MGs) as a platform. The MGs were prepared by a templating and crosslinking method using a synthetic amphiphlic polymer as the basic material and porous CaCO3 microparticles as the template. The aggregation-induced emission (AIE) tetraphenylethylene moieties and reduction-labile disulfide bonds in the MGs were employed as the self-assembly building blocks and triggering sites for the intracellular self-assembly, respectively. In the presence of reductive agents such as glutathione, nano-spikes were gradually formed on the MGs. After the MGs were internalized by cells, the in situ formation of microgel/nano-spike composite structures was evidenced by the enhanced fluorescence intensity and was further confirmed by direct transmission electron microscopy observation. This work provides an effective strategy to cope with the challenging task of achieving and probing controlled self-assembly in a cell milieu, leading to new insights into investigating biological self-assembly and promoting the development of micro-/nanomaterials by learning from nature.

Perioperative risk factors predict one-year mortality in patients with acute type-A aortic dissection.

OBJECTIVE: The goal of this study was to analyze perioperative risk factors to predict one- year mortality after operation for acute type A aortic dissection (AAD). METHODS: A total of 121 consecutive patients undergoing Stanford type A AAD surgery in Beijing Anzhen Hospital were enrolled. Preoperative clinical and laboratory data from patients were collected. RESULTS: Multivariable Cox regression analysis showed that significant factors associated with increased one-year mortality were elder age (year) (hazard ratio (HR) 1.0985; 95% confidence interval (CI) 1.0334-1.1677), intraoperative blood transfusion ≥2000 mL (HR 8.8081; 95% CI 2.3319-33.2709), a higher level of serum creatinine (µmol/L) at postoperative one day (HR 1.0122; 95% CI 1.0035-1.0190) and oxygenation index (OI) < 200 (mmHg) at the end of surgery (HR 5.7575; 95% CI 1.1695-28.3458). CONCLUSION: In this study, perioperative risk factors to predict one-year prognosis are age, intraoperative blood transfusion ≥2000 mL, postoperative OI < 200 mmHg and level of postoperative serum creatinine. The results aid in the comprehension of surgical outcomes and assist in the optimization of treatment strategies for those with perioperative risk factors to decrease one-year mortality.

Morphogenesis and Optoelectronic Properties of Supramolecular Assemblies of Chiral Perylene Diimides in a Binary Solvent System.

Chiral supramolecular structures are attracting great attention due to their specific properties and high potential in chiral sensing and separation. Herein, supramolecular assembling behaviors of chiral perylene diimides have been systematically investigated in a mixed solution of tetrahydrofuran and water. They exhibit remarkably different morphologies and chiral aggregation behaviors depending on the mixing ratio of the solvents, i.e., the fraction of water. The morphogenesis and optoelectronic properties of chiral supramolecular structures have been thoroughly studied using a range of experimental and theoretical methods to investigate the morphological effects of chiral supramolecular assemblies on the electrical performances and photogenerated charge-carrier behaviors. In addition, chiral perylene diimides have been discriminated by combining vibrational circular dichroism with theoretical calculations, for the first time. The chiral supramolecular nanostructures developed herein strongly absorb visible spectral region and exhibit high photoresponsivity and detectivity, opening up new opportunities for practical applications in optoelectronics.

Deciphering the binding behaviours of BSA using ionic AIE-active fluorescent probes.

The binding behaviours of a transport protein, bovine serum albumin (BSA), in its native, unfolding and refolding states have been probed by monitoring the emission changes of two exogenous AIE-active fluorescent probes, M2 and M3, which are designed to be anionic and cationic, respectively. Due to their AIE properties, both M2 and M3 display emission enhancement when bound to the hydrophobic cavity of BSA. The binding site of M2 and M3 is found to be subdomain IIA. Then, the BSA + M2 and BSA + M3 systems are utilized to fluorescently signal the conformation changes of BSA caused by various external stimuli, including thermally or chemically induced denaturation. The data confirmed the multi-step unfolding process and the existence of a molten-globule intermediate state. The unfolding process consists of the rearrangement of subdomain IIA, the exposure of a negatively charged binding site in domain I that prefers interacting with cationic species, and the transformation of the molten-globule intermediate into the final random coil. The anionic and cationic modifications of the probes enable us to observe that electrostatic interactions play a role in the folding and unfolding of BSA.

A macrocyclic 1,4-bis(4-pyridylethynyl)benzene showing unique aggregation-induced emission properties.

A box-like macrocycle based on 1,4-bis(4-pyridylethynyl)benzene was derived in high yield. The macrocyclic fluorogen shows unique aggregation-induced emission properties.