An ensemble data assimilation modeling system for operational outdoor microalgae growth forecasting.

Microalgae have received increasing attention as a potential feedstock for biofuel or biobased products. Forecasting the microalgae growth is beneficial for managers in planning pond operations and harvesting decisions. This study proposed a biomass forecasting system comprised of the Huesemann Algae Biomass Growth Model (BGM), the Modular Aquatic Simulation System in Two Dimensions (MASS2), ensemble data assimilation (DA), and numerical weather prediction Global Ensemble Forecast System (GEFS) ensemble meteorological forecasts. The novelty of this study is to seek the use of ensemble DA to improve both BGM and MASS2 model initial conditions with the assimilation of biomass and water temperature measurements and consequently improve short-term biomass forecasting skills. This study introduces the theory behind the proposed integrated biomass forecasting system, with an application undertaken in pseudo-real-time in three outdoor ponds cultured with Chlorella sorokiniana in Delhi, California, United States. Results from all three case studies demonstrate that the biomass forecasting system improved the short-term (i.e., 7-day) biomass forecasting skills by about 60% on average, comparing to forecasts without using the ensemble DA method. Given the satisfactory performances achieved in this study, it is probable that the integrated BGM-MASS2-DA forecasting system can be used operationally to inform managers in making pond operation and harvesting planning decisions.

Combining Radiotherapy with Immunotherapy in Cervical Cancer: Where Do We Stand and Where Are We Going?

OPINION STATEMENT: Combining immunotherapy and radiotherapy as a treatment strategy for cervical cancer has attracted increasing attention. The primary objective of this review is to provide an up-to-date summary of the knowledge regarding the combined use of radiotherapy and immunotherapy for treating cervical cancer. This review discusses the biological rationale combining immunotherapy with radiotherapy in a clinical setting and presents supporting evidence for the combination strategy based on both safety and effectiveness data. Additionally, we discuss the potential and challenges of combining radiotherapy and immunotherapy in clinical practice.

Real-time ensemble microalgae growth forecasting with data assimilation.

Accurate short-range (e.g., 7 days) microalgae growth forecasts will be beneficial for both the production and harvesting of microalgae. This study developed an operational microalgae growth forecasting system comprised of the Huesemann Algae Biomass Growth Model (BGM), the Modular Aquatic Simulation System in Two Dimensions (MASS2) hydrodynamic model, and ensemble data assimilation (DA). The novelty of this study is the use of ensemble DA to sequentially update the BGM model's initial condition (IC) with the assimilation of measured biomass optical density to improve short-range biomass forecasting skills. The forecasting system was run in pseudo-real-time and validated against observed Monoraphidium minutum 26B-AM growth in two outdoor pond cultures located in Mesa, Arizona, United States. We found the DA forecasting system could improve the 7-day microalgae forecasting skill by about 85% on average compared to model forecasts without DA. These results suggest the potential accuracy of biomass growth forecasts may be sufficient to inform real-time operational decisions, such as pond operation and harvest planning, for commercial-scale microalgae production.

Development and evaluation of an efficient heterologous gene knock-in reporter system in Lactococcus lactis.

BACKGROUND: Lactococcus lactis is a food grade probiotics and widely used to express heterologous proteins. Generally, target genes are knocked into the L. lactis genome through double-crossover recombination to express heterologous proteins stably. However, creating marker-less heterologous genes knocked-in clones is laborious. In this study, an efficient heterologous gene knock-in reporter system was developed in L. lactis NZ9000. RESULTS: Our knock-in reporter system consists of a temperature-sensitive plasmid pJW and a recombinant L. lactis strain named NZB. The pJW contains homologous arms, and was constructed to knock-in heterologous genes at a fixed locus of NZ9000 genome. lacZ (ß-galactosidase) gene was knocked into the chromosome of NZ9000 as a counter-selective marker through the plasmid pJW to generate NZB. The engineered NZB strain formed blue colonies on X-Gal plate. The desired double-crossover mutants formed white colonies distinctive from the predominantly blue colonies (parental and plasmid-integrated clones) when the embedded lacZ was replaced with the target heterologous genes carried by pJW in NZB. CONCLUSIONS: By using the system, the heterologous gene knocked-in clones are screened by colony phenotype change rather than by checking colonies individually. Our new knock-in reporter system provides an efficient method to create heterologous genes knocked-in clones.

Next-Generation Intensity-Duration-Frequency Curves for Diverse Land across the Continental United States.

The current methods for designing hydrological infrastructure rely on precipitation-based intensity-duration-frequency curves. However, they cannot accurately predict flooding caused by snowmelt or rain-on-snow events, potentially leading to underdesigned infrastructure and property damage. To address these issues, next-generation intensity-duration-frequency (NG-IDF) curves have been developed for the open condition, characterizing water available for runoff from rainfall, snowmelt, and rain-on-snow. However, they lack consideration of land use land cover (LULC) factors, which can significantly affect runoff processes. We address this limitation by expanding open area NG-IDF dataset to include eight vegetated LULCs over the continental United States, including forest (deciduous, evergreen, mixed), shrub, grass, pasture, crop, and wetland. This NG-IDF 2.0 dataset offers a comprehensive analysis of hydrological extreme events and their associated drivers under different LULCs at a continental scale. It will serve as a useful resource for improving standard design practices and aiding in the assessment of infrastructure design risks. Additionally, it provides useful insights into how changes in LULC impact flooding magnitude, mechanisms, timing, and snow water supply.

Evaluation of retinal vascularization in retinopathy of prematurity regressed after intravitreal ranibizumab monotherapy or without treatment based on fluorescein angiography.

To investigate the fluorescein angiography (FA) findings and compare the extent of retinal vascularization in retinopathy of prematurity (ROP), recovered after intravitreal ranibizumab (IVR) monotherapy and those regressed spontaneously. Infants with a history of ROP who underwent FA between April 2018 and November 2021 were retrospectively included. The patients were divided into two groups based on whether they had received IVR (IVR group) or had ROP that regressed spontaneously without treatment (untreated group). The differences between the two groups in zone II ROP were also compared, to equalize the subgroups as much as possible in terms of disease severity. FA findings were recorded. The extent of vascularization was measured by the ratio of the distance from the center of the disk to the border of the vascularized zone (DB) and the distance from the center of the disk to the center of the fovea (DF). The width of the persistent avascular retina (PAR) was counted by disc diameters (DD). One hundred and ten eyes of 55 infants were included in the IVR group and 76 eyes of 38 babies in the untreated group. The ratio of abnormal shape of vessels was significantly higher in the IVR group than in the untreated group (50.9% vs. 35.5%; P = 0.038), while the linear choroidal filling pattern, tortuosity of vessels over the posterior pole, dye leakage, anomalous branching of vessels, circumferential vessels, arteriovenous shunt, abnormal capillary bed, and macular abnormalities were similarly. There was a smaller temporal DB/DF ratio (4.48 vs. 4.63; P = 0.003) and greater PAR (2.63 vs. 1.76; P < 0.001) in the IVR group compared to the untreated group. In zone II ROP, the progression of retinal vascularization was significantly larger in the IVR group than that in the untreated group (P = 0.003), while no statistical differences were observed in FA features, the DB/DF ratio, and PAR between the two subgroups. The residual vascular abnormalities and PAR may be common results of ROP regression. The DB/DF ratio of 4.0 temporally and 3.3 nasally could be used as the preliminary indicators for safe retinal vascularization in the completion of ROP regression.

Microglia-Derived Spp1 Promotes Pathological Retinal Neovascularization via Activating Endothelial Kit/Akt/mTOR Signaling.

Pathological retinal neovascularization (RNV) is the main character of ischemic ocular diseases, which causes severe visual impairments. Though retinal microglia are well acknowledged to play important roles in both physiological and pathological angiogenesis, the molecular mechanisms by which microglia communicates with endothelial cells (EC) remain unknown. In this study, using single-cell RNA sequencing, we revealed that the pro-inflammatory secreted protein Spp1 was the most upregulated gene in microglia in the mouse model of oxygen-induced retinopathy (OIR). Bioinformatic analysis showed that the expression of Spp1 in microglia was respectively regulated via nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor 1α (HIF-1α) pathways, which was further confirmed through in vitro assays using BV2 microglia cell line. To mimic microglia-EC communication, the bEnd.3 endothelial cell line was cultured with conditional medium (CM) from BV2. We found that adding recombinant Spp1 to bEnd.3 as well as treating with hypoxic BV2 CM significantly enhanced EC proliferation and migration, while Spp1 neutralizing blocked those CM-induced effects. Moreover, RNA sequencing of BV2 CM-treated bEnd.3 revealed a significant downregulation of Kit, one of the type III tyrosine kinase receptors that plays a critical role in cell growth and activation. We further revealed that Spp1 increased phosphorylation and expression level of Akt/mTOR signaling cascade, which might account for its pro-angiogenic effects. Finally, we showed that intravitreal injection of Spp1 neutralizing antibody attenuated pathological RNV and improved visual function. Taken together, our work suggests that Spp1 mediates microglia-EC communication in RNV via activating endothelial Kit/Akt/mTOR signaling and is a potential target to treat ischemic ocular diseases.

Characterizing uncertainty in Community Land Model version 5 hydrological applications in the United States.

Land surface models such as the Community Land Model Version 5 (CLM5) are essential tools for simulating the behavior of the terrestrial system. Despite the extensive application of CLM5, limited attention has been paid to the underlying uncertainties associated with its hydrological parameters and how these uncertainties affect water resource applications. To address this long-standing issue, we use five meteorological datasets to conduct a comprehensive hydrological parameter uncertainty characterization of CLM5 over the hydroclimatic gradients of the conterminous United States. Key datasets produced from the uncertainty characterization experiment include: a benchmark dataset of CLM5 default hydrological performance, parameter sensitivities for 28 hydrological metrics, and large-ensemble outputs for CLM5 hydrological predictions. The presented datasets will assist CLM5 calibration and support broad applications, such as evaluating drought and flood vulnerabilities. The datasets can be used to identify the hydroclimatological conditions under which parametric uncertainties demonstrate substantial effects on hydrological predictions and clarify where further investigations are needed to understand how hydrological prediction uncertainties interact with other Earth system processes.

Improving Microalgal Biomass Productivity Using Weather-Forecast-Informed Operations.

The operation of microalgal cultivation systems, such as culture dilution associated with harvests, affects biomass productivity. However, the constantly changing incident light and ambient temperature in the outdoor environment make it difficult to determine the operational parameters that result in optimal biomass growth. To address this problem, we present a pond operation optimization tool that predicts biomass growth based on future weather conditions to identify the optimal dilution rate that maximizes biomass productivity. The concept was tested by comparing the biomass productivities of three dilution scenarios: standard batch cultivation (no dilution), fixed-rate dilution (harvest 60% of the culture every three days), and weather-forecast-informed dilution. In the weather-forecast-informed case, the culture was diluted daily, and the dilution ratio was optimized by the operation optimization tool according to the future 24 h weather condition. The results show that the weather-forecast-informed dilution improved the biomass productivity by 47% over the standard batch cultivation and 20% over the fixed-rate dilution case. These results demonstrate that the pond operation optimization tool could help pond operators to make decisions that maximize biomass growth in the field under ever-changing weather conditions.

Datasets for characterizing extreme events relevant to hydrologic design over the conterminous United States.

Despite the close linkage between extreme floods and snowmelt, particularly through rain-on-snow (ROS), hydrologic infrastructure is mostly designed based on standard precipitation Intensity-Duration-Frequency curves (PREC-IDF) that neglect snow processes in runoff generation. For snow-dominated regions, such simplification could result in substantial errors in estimating extreme events and infrastructure design risk. To address this long-standing problem, we applied the Next Generation IDF (NG-IDF) technique to estimate design basis extreme events for different durations and return periods in the conterminous United States (CONUS) to distinctly represent the contribution of rain, snowmelt, and ROS events to the amount of water reaching the land surface. A suite of datasets were developed to characterize the magnitude, trend, seasonality, and dominant mechanism of extreme events for over 200,000 locations. Infrastructure design risk associated with the use of PREC-IDF was estimated. Accuracy of the model simulations used in the analyses was confirmed by long-term snow data at over 200 Snowpack Telemetry stations. The presented spatially continuous datasets are readily usable and instrumental for supporting site-specific infrastructure design.

Twelve-year profile of screening results of retinopathy of prematurity at a tertiary care institute in Northwest China.

AIM: To report the changes in detection rate and characteristics of retinopathy of prematurity (ROP) in infants, during a 12-year period in Northwest China. METHODS: The medical records of infants were retrospectively collected and reviewed using an established clinical database. The detection rate and severity of ROP were compared between two consecutive periods (P1: 2008-2013, P2: 2014-2019). Gender, gestational age (GA), birth weight (BW), multiple births, delivery pattern, and postmenstrual age of the first fundus screen were analyzed in all visiting infants. RESULTS: During the 12-year study period, 7832 infants were initially included; among them, 1266 (16.16%) were diagnosed with ROP, 441 of whom (5.63%) developed severe ROP. Throughout the study period, the total number of infants being screened showed a trend of slight fluctuation after a rapid increase; however, an annual increase was observed in the number of infants diagnosed with ROP and severe ROP. The proportion of each stage at the first screening of infants with ROP was stable. The detection rate of ROP increased from 2.33% in 2008 to 16.18% in 2010, decreased to 10.73% in 2014, and then increased to 27.47% in 2019. For severe ROP, the detection rate gradually increased from 0 in 2008 to 12.49% in 2019. Among the infants with ROP, 96 (7.58%) did not meet the screening criteria set by the Chinese Medical Association in 2014 (GA<32wk, or BW<2000 g); among them, 14 (1.11%) needed treatment because of severe ROP. CONCLUSION: From 2008 to 2019, the detection rates of ROP and severe ROP in infants screened in Northwest China were 16.16% and 5.63%, respectively. The characteristics of the ROP infants were similar to those in other middle-income regions. The "tertiary prevention network of ROP" is a potentially effective screening approach.

Observation on the effect of periodontal treatment on patients with combined periodontal-pulpal lesions.

OBJECTIVE: To evaluate the effect of periodontal treatment on combined periodontal-pulpal lesions. METHODS: A total of 327 patients with periodontal-pulpal lesions (360 affected teeth) were selected, and all affected teeth were treated with a complete root canal, and assigned into group A (periodontal treatment group, 180 affected teeth) and group B (non-periodontal treatment group, 180 affected teeth). Group A received periodontal basic treatment for 2 weeks after the completion of root canal treatment; 6 weeks later, if there were still more than 5 mm periodontal pockets and bleeding after detection, flap treatment was performed. Group B received root canal treatment and supragingival scaling. Follow-up was conducted at 3, 6, 12 and 24 months after surgery by observing the periodontal depth (PD), alveolar bone resorption and tooth mobility (TM). RESULT: In group A, the PDs before operation and 2 years after operation were (5.966±1.877) mm and (5.133±1.935) mm, and the PD was significantly decreased. In group B, the PDs before operation and 2 years after operation were (5.533±1.856) mm and (6.167±1.927) mm, and the PD was increased. There was no statistical difference in preoperative TM between the two groups (P>0.05). Two years after operation, TM in group A was significantly lower than that in group B (P<0.05). In terms of X-ray performance, there was no significant change in alveolar bone resorption in group A two years after operation compared with that before operation (P>0.05); two years after operation, alveolar bone resorption in group B was significantly reduced compared with that before operation (P<0.05). CONCLUSION: Periodontal treatment is a promising technique for patients with combined periodontal-pulpal lesions.

Clinical Features of Spontaneous Regression of Retinopathy of Prematurity in China: A 5-Year Retrospective Case Series.

Purpose: The aim of this study is to explore the clinical features of spontaneous regression of retinopathy of prematurity (ROP) in China, including fundus appearance, time course, and affecting factors. Methods: Data of pediatric patients in whom ROP spontaneously regressed without treatment were collected, including general demographics, medical history, zones and stages of ROP, and changes of fundus appearance. The fundus manifestations of spontaneous regression in ROP were systematically summarized. Meanwhile, the time course of spontaneous regression in ROP was further analyzed, including the onset time, completion time, and duration of regression, which were all compared across different ROP zones and stages. The associated factors were analyzed by survival analysis for their correlation with delayed regression for the first time. Results: Two hundred thirty-seven eyes of 237 pediatric patients were included. The fundus manifestations of regression differed across stages. Lesions gradually subsided, and the retinal vessels gradually vascularized completely. However, despite ROP regression, some abnormalities remained. We observed avascular retina in the temporal periphery (19.0%), increased vascular branching (6.8%), retinal pigmentary changes (6.8%), and smaller angle between the upper and lower temporal retinal vessel trunks (3.0%). Acute ROP started to regress at a median 40 weeks of postmenstrual age (PMA) and completely regressed by median 49.0 weeks of PMA. The median duration for regression was 8.5 weeks. The zone II ROP and stage 3 ROP had a later time for onset and completion of regression, and longer duration. Anemia and retinal hemorrhage (RH) were identified as independent risk factors for delayed regression by survival analysis. Conclusions: During spontaneous regression, the fundus appearance is diverse, and the retinal vessels gradually vascularized completely. The time course of regression differs depending on the ROP zone and stage. Anemia and RH are independent risk factors for delayed regression. Further research of the natural course of the regression of ROP is needed to help design effective screening and follow-up plans.

Identification of a Ferroptosis-Related Long Noncoding RNA Prognostic Signature and Its Predictive Ability to Immunotherapy in Hepatocellular Carcinoma.

Background: Immune checkpoint blockers (ICBs) are increasingly being used to treat patients with advanced hepatocellular carcinoma (HCC), but only a third of these patients are sensitive to ICBs. Emerging evidence suggests that ferroptosis could be a novel target for antitumor treatment, and combined treatment with ferroptosis inducers might enhance sensitivity to immunotherapy. However, there is a lack of information on the crosstalk between ferroptosis-related lncRNAs and anti-tumor immunity. Therefore, we aim to explore prognostic value of ferroptosis-related lncRNAs and clarify potential role in ICBs of HCC. Methods: We obtained mRNA and lncRNA expression data from two independent cohorts (TCGA and GEO database). Univariate Cox, the least absolute shrinkage and selection operator (Lasso) algorithm and multivariate Cox analysis were used to construct a lncRNA signature, which was evaluated using the area under the receiver operating characteristic curve (AUC) and Kaplan-Meier curves. Tumor-infiltrating cell (TIC) profiling and the tumor immune dysfunction and exclusion (TIDE) algorithm were used to validate the signature model and immunotherapy. Finally, we adopted RT-PCR assay to evaluate the differential expression of lncRNAs in HCC tissues in our hospital. Results: The ferroptosis-related lncRNA signature included five lncRNAs, most of which were positively correlated with clinical stage and grade. The signature could stratify patients into two risk groups, with the high-risk group associated with a shorter overall survival (OS, p < 0.05) in TCGA-LIHC and GSE76427. Besides, the AUCs of the 1-, 3-, and 5-years OS were 0.772, 0.707, and 0.666, respectively. Gene set enrichment analysis (GESA) of lncRNAs revealed enrichment of oncogenic and immune-related pathways. The TIC profiling indicated a close correlation between the signature and immune cells. Furthermore, the high-risk group had a better response to immunotherapy than low-risk group. RT-PCR demonstrated these five lncRNAs were upregulated in cancerous tissue than normal tissues. Conclusions: The ferroptosis-related lncRNA signature could accurately predict the OS of HCC patients and may serve as an independent clinical factor for patients' outcomes. Ferroptosis-related lncRNAs may remodel the tumor microenvironment (TME) and affect the anti-cancer ability of ICBs, and therefore, could potentially act as an indicator for the response to immunotherapy in HCC.

Repetitive Transcranial Magnetic Stimulation Promotes Neural Stem Cell Proliferation and Differentiation after Intracerebral Hemorrhage in Mice.

Repetitive transcranial magnetic stimulation (rTMS) is a physical treatment applied during recovery after intracerebral hemorrhage (ICH). With in vivo and in vitro assays, the present study sought to investigate how rTMS influences neural stem cells (NSCs) after ICH and the possible mechanism. Following a collagenase-induced ICH, adult male C57BL/6 J mice were subjected to rTMS treatment every 24 h for 5 days using the following parameters: frequency, 10 Hz; duration, 2 s; wait time, 5.5 s; 960 trains (500 µV/div, 5 ms/div, default setting). Brain water content and neurobehavioral score were assessed at days 1, 3, and 5 after ICH. The proliferation and differentiation of NSCs were observed using immunofluorescence staining for Nestin, Ki-67, DCX, and GFAP on day 3 after ICH, and rTMS treatment with the same parameters was applied to NSCs in vitro. We found that rTMS significantly reduced brain edema and alleviated neural functional deficits. The mice that underwent ICH recovered faster after rTMS treatment, with apparent proliferation and neuronal differentiation of NSCs and attenuation of glial differentiation and GFAP aggregation. Accordingly, proliferation and neuronal differentiation of isolated NSCs were promoted, while glial differentiation was reduced. In addition, microarray analysis, western blotting assays, and calcium imaging were applied to initially investigate the potential mechanism. Bioinformatics showed that the positive effect of rTMS on NSCs after ICH was largely related to the MAPK signaling pathway, which might be a potential hub signaling pathway under the complex effect exerted by rTMS. The results of the microarray data analysis also revealed that Ca2+ might be the connection between physical treatment and the MAPK signaling pathway. These predictions were further identified by western blotting analysis and calcium imaging. Taken together, our findings showed that rTMS after ICH exhibited a restorative effect by enhancing the proliferation and neuronal differentiation of NSCs, potentially through the MAPK signaling pathway.

Development of cryptotanshinone-loaded pellets for angina chronotherapy: In vitro/in vivo prediction and evaluation.

The clinical manifestations of variant angina is unevenly distributed during the 24 h, thus the in vivo performance of drugs should be tailored according to the angina circadian rhythm. Cryptotanshinone (CTN) is one of the representative bioactive lipid-soluble components of Danshen which has been commonly used for cardiovascular diseases such as angina pectoris. The aim of this study was to develop a novel CTN sustained-released pellets (CTN-SRPs) to precisely synchronize the CTN plasma concentrations with predicted occurrence of angina pectoris for angina chronotherapy. A deconvolution-based method was applied to develop and optimize the CTN-SRPs. The plasma concentration-time curve of CTN immediate-released formulation after oral administration in rats was used as the weight function. The predicted plasma concentration-time curve of CTN-SRPs simulated according to the incidence of variant angina during 24 h was used as the response function. Then the desired drug release profile of CTN-SRPs was calculated based on deconvolution using weight function and response function, and subsequently used for guiding the formulation optimization. CTN-SRPs were prepared with the combinations of PVP, poloxamer 127 and EC as matrix using fluidized bed technology. An orthogonal design was employed to obtain the optimal formulation with its release profile similar with the desired one. Pharmacokinetic studies validated that the actual plasma concentration-time curve of these optimized CTN-SRPs was similar with the predicted one. In addition, the percent errors (%PE) of CTN plasma concentrations in 8-12 h were less than 10%. In conclusion, this deconvolution-based method could be applied to adjust the in vivo performance of drugs for angina chronotherapy.

Application of ethyl cellulose, microcrystalline cellulose and octadecanol for wax based floating solid dispersion pellets.

The present study aimed to develop and optimize the wax based floating sustained-release dispersion pellets for a weakly acidic hydrophilic drug protocatechuic acid to achieve prolonged gastric residence time and improved bioavailability. This low-density drug delivery system consisted of octadecanol/microcrystalline cellulose mixture matrix pellet cores prepared by extrusion-spheronization technique, coated with drug/ethyl cellulose 100cp solid dispersion using single-step fluid-bed coating method. The formulation-optimized pellets could maintain excellent floating state without lag time and sustain the drug release efficiently for 12h based on non-Fickian transport mechanism. Observed by SEM, the optimized pellet was the dispersion-layered spherical structure containing a compact inner core. DSC, XRD and FTIR analysis revealed drug was uniformly dispersed in the amorphous molecule form and had no significant physicochemical interactions with the polymer dispersion carrier. The stability study of the resultant pellets further proved the rationality and integrity of the developed formulation.

Development of protocatechualdehyde proliposomes-based sustained-release pellets with improved bioavailability and desired pharmacokinetic behavior for angina chronotherapy.

The present study was aimed to develope a proliposomal formulation to decrease the hepatic first-pass metabolism of protocatechualdehyde (PD), followed by pellet coating to modify the drug release for angina chronotherapy. PD proliposomes were prepared by depositing PD-phospholipid complex on mannitol powders to improve the drug encapsulation. Afterwards, the PD proliposomes were prepared into pellet cores via extrusion-spheronization using 10% κ-carrageenan as pelletization aid prior to the development of PD sustained-release pellets (PD-SRPs). Eudragit® NE 30D was chosen as coating material and the desired drug release profile of PD-SRPs was calculated for formulation optimization by deconvolution based on the circadian rhythm of variant angina. A high similarity factor (f2=85.72) was achieved when the coating weight was 30% and the sustained release behavior also prevented the destruction of liposomes by gastric fluids. Pharmacokinetic studies revealed a basically consistent trend between the actual and the predicted plasma concentration-time curve with absolute percent errors (%PE) of concentrations <10% in 2-12h. Meanwhile, a relative bioavailability of 200% was achieved compared with pure PD. Therefore, the development of proliposomes-based PD-SRPs was an effective strategy to provide both improved oral bioavailability and desired drug plasma concentration-time course for angina chronotherapy.

Tanshinone IIA - loaded pellets developed for angina chronotherapy: Deconvolution-based formulation design and optimization, pharmacokinetic and pharmacodynamic evaluation.

This paper put forward a deconvolution-based method for designing and optimizing tanshinone IIA sustained-release pellets (TA-SRPs) with improved efficacy in the treatment of variant angina. TA-SRPs were prepared by coating TA ternary solid dispersion immediate-release pellets (TA-tSD-IRPs) with the blends of polyvinyl acetate (PVAc) and polyvinyl alcohol-polyethylene glycol (PVA-PEG) using fluidized bed technology. The plasma concentration-time curve of TA-tSD-IRPs following oral administration as a weight function was investigated in New Zealand white rabbits. The predicted/expected plasma concentration-time curve of TA-SRPs as a response function was simulated according to the circadian rhythm of variant angina during 24h based on chronotherapy theory. The desired drug release profile of TA-SRPs was obtained via the point-area deconvolution procedure using the weight function and response function, and used for formulation optimization of TA-SRPs. The coating formulation of TA-SRPs was optimized as 70:30 (w/w) PVAc/PVA-PEG with 5% (w/w) coating weight due to in vitro drug release profile of these TA-SRPs was similar to the desired release profile (similarity factor f2=64.90). Pharmacokinetic studies of these optimized TA-SRPs validated that their actual plasma concentration-time curve possessed a basically consistent trend with the predicted plasma concentration-time curve and the absolute percent errors (%PE) of concentrations in 8-12h were less than 10%. Pharmacodynamic studies further demonstrated that these TA-SRPs had stable and improved efficacy with almost simultaneous drug concentration-efficacy. In conclusion, deconvolution could be employed in the development of TA-SRPs for angina chronotherapy with simultaneous drug efficacy and reduced design blindness and complexity.