Loss-tailoring single-mode high-power supersymmetric lasers.

Diode lasers with high beam quality and high power have many promising applications. However, high beam quality is always in conflict with high power. In this Letter, we theoretically and experimentally confirm the mode instability property of supersymmetric structures at higher operating currents. Meanwhile, we propose a loss-tailoring diode laser based on a supersymmetric structure, which enables the higher-order lateral modes to obtain higher losses, raises the excitation threshold of the higher-order lateral modes, and achieves a stable fundamental-lateral-mode output at higher current operation. The device obtained a quasi-single-lobe lateral far-field distribution with the full width at half maximum (FWHM) of 7.58° at 350 mA under room temperature, which is a 65% reduction compared to the traditional Fabry-Perot (FP) diode lasers. Moreover, the M2 of 2.181@350 mA has an improvement of about 37% over traditional FP and supersymmetric structure lasers.

A dynamic model to predict early occurrence of acute kidney injury in ICU hospitalized cirrhotic patients: a MIMIC database analysis.

BACKGROUND: This study aimed to develop a tool for predicting the early occurrence of acute kidney injury (AKI) in ICU hospitalized cirrhotic patients. METHODS: Eligible patients with cirrhosis were identified from the Medical Information Mart for Intensive Care database. Demographic data, laboratory examinations, and interventions were obtained. After splitting the population into training and validation cohorts, the least absolute shrinkage and selection operator regression model was used to select factors and construct the dynamic online nomogram. Calibration and discrimination were used to assess nomogram performance, and clinical utility was evaluated by decision curve analysis (DCA). RESULTS: A total of 1254 patients were included in the analysis, and 745 developed AKI. The mean arterial pressure, white blood cell count, total bilirubin level, Glasgow Coma Score, creatinine, heart rate, platelet count and albumin level were identified as predictors of AKI. The developed model had a good ability to differentiate AKI from non-AKI, with AUCs of 0.797 and 0.750 in the training and validation cohorts, respectively. Moreover, the nomogram model showed good calibration. DCA showed that the nomogram had a superior overall net benefit within wide and practical ranges of threshold probabilities. CONCLUSIONS: The dynamic online nomogram can be an easy-to-use tool for predicting the early occurrence of AKI in critically ill patients with cirrhosis.

The burden and predictors of 30-day unplanned readmission in patients with acute liver failure: a national representative database study.

BACKGROUND: Liver diseases were significant source of early readmission burden. This study aimed to evaluate the 30-day unplanned readmission rates, causes of readmissions, readmission costs, and predictors of readmission in patients with acute liver failure (ALF). METHODS: Patients admitted for ALF from 2019 National Readmission Database were enrolled. Weighted multivariable logistic regression models were applied and based on Directed Acyclic Graphs. Incidence, causes, cost, and predictors of 30-day unplanned readmissions were identified. RESULTS: A total of 3,281 patients with ALF were enrolled, of whom 600 (18.3%) were readmitted within 30 days. The mean time from discharge to early readmission was 12.6 days. The average hospital cost and charge of readmission were $19,629 and $86,228, respectively. The readmissions were mainly due to liver-related events (26.6%), followed by infection (20.9%). The predictive factors independently associated with readmissions were age, male sex (OR 1.227, 95% CI 1.023-1.472; P = 0.028), renal failure (OR 1.401, 95% CI 1.139-1.723; P = 0.001), diabetes with chronic complications (OR 1.327, 95% CI 1.053-1.672; P = 0.017), complicated hypertension (OR 1.436, 95% CI 1.111-1.857; P = 0.006), peritoneal drainage (OR 1.600, 95% CI 1.092-2.345; P = 0.016), etc. CONCLUSIONS: Patients with ALF are at relatively high risk of early readmission, which imposes a heavy medical and economic burden on society. We need to increase the emphasis placed on early readmission of patients with ALF and establish clinical strategies for their management.

Chemical Constituents from the Whole Plants of Limonium sinense and Their in†vitro Anti-inflammatory Activity.

The Yellow River Delta possesses lots of characteristic medicinal plants due to its high salinity and high alkaline environment and Limonium sinense is an iconic plant. However, there are very few studies on L. sinense and its chemical constituents have not been investigated in recent ten years. In the present study, the chemical constituents and bioactivities of L. sinense were fully studied for the first time. UPLC-MS/MS method combined with database comparison identified 109 compounds mainly including flavonoids, alkaloids and polyphenols. In addition, the potential bioactivities of L. sinense were considerated as anti-inflammatory, anti-oxidative, anti-tumor, hepatoprotective and hpyerglycemic activities based on these identified compounds and their related literature. Furthermore, four derivatives of 12-oxo-phytodienoic acid and butenolide including two new ones (1 and 2) were isolated from the whole plants of L. sinense. Their structures, including the absolute configurations, were determined by the analysis of comprehensive spectroscopic data. All isolates were evaluated for their anti-inflammatory activity. Compound 1 exhibited moderate anti-inflammatory activity with IC50 value of 37.5±1.2 µM on NO production level.

The current status of apathy in patients with dementia and its factors: A systematic review.

OBJECTIVE: To systematically evaluate the current status of apathy in dementia patients and its associated factors. METHODS: We searched Chinese and English databases to collect studies on the associated factors of apathy in patients with dementia from inception to March 14, 2023. Two researchers independently screened the literature, evaluated the quality, and extracted the data RESULTS: A total of 20 studies were included, and the incidence of apathy in patients with dementia ranged from 21 % to 90 %. According to the model of apathy proposed by Massimo in 2018, the associated factors were divided into individual factors for dementia patients, caregiver factors, and environmental factors. The individual factors of apathy in patients with dementia mainly include demographic characteristics, the severity of cognitive impairment, a combination of other behavioral and psychological symptoms of dementia, acute medical problems or adverse drug reactions, unmet needs, and malnutrition. Caregiver factors mainly include emotional expressions of hostility or criticism towards dementia patients and caregivers' expectations for a better life in the future. Environmental factors mainly include too high or too low stimulation and a lack of daytime activities CONCLUSIONS: Existing studies have shown that the incidence of apathy in dementia patients is high and is affected by multi-dimensional factors. There are more studies on individual factors in dementia patients and fewer studies on caregivers and environmental factors. In the future, a large number of high-quality studies are needed to demonstrate the mechanism of apathy in dementia patients and to find more related factors.

MicroRNA-26a-5p Restoration Ameliorates Unilateral Ureteral Obstruction-Induced Renal Fibrosis in Mice Through Modulating TGF-ß Signaling.

Renal fibrosis is a hallmark of chronic and progressive renal diseases characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and a loss of renal function, eventually leading to end-stage renal diseases. MicroRNA-26a-5p (miR-26a-5p) downregulation has been previously noted in the sera of unilateral ureteral occlusion (UUO)-injured mice, and exosome-mediated miR-26a-5p reportedly attenuated experimental pulmonary and cardiac fibrosis. This study evaluated the expression patterns of miR-26a in a human tissue microarray with kidney fibrosis and in tissues from a mouse model of UUO-induced renal fibrosis. Histologic analyses showed that miR-26a-5p was downregulated in human and mouse tissues with renal interstitial nephritis and fibrosis. Moreover, miR-26a-5p restoration by intravenous injection of a mimic agent prominently suppressed the expression of transforming growth factor ß1 (TGF-ß1) and its cognate receptors, the inflammatory transcription factor NF-κB, epithelial-mesenchymal transition, and inflammatory markers in UUO-injured kidney tissues. In vitro, miR-26a-5p mimic delivery significantly inhibited TGF-ß1-induced activation of cultured normal rat kidney NRK-49F cells, in terms of downregulation of TGF-ß1 receptors, restoration of the epithelial marker E-cadherin, and suppression of mesenchymal markers, including vimentin, fibronectin, and α-smooth muscle actin, as well as TGF-ß1/SMAD3 signaling activity. Our findings identified miR-26a-5p downregulation in kidney tissues with human interstitial nephritis and UUO-induced mouse kidney fibrosis. MiR-26a-5p restoration may exhibit an antifibrotic effect through the blockade of both TGF-ß and NF-κB signaling axes and is considered a novel therapeutic target for treating obstruction-induced renal fibrosis.

High-yield production of FK228 and new derivatives in a Burkholderia chassis.

FK228 (romidepsin) is the only natural histone deacetylases (HDACs) inhibitor approved by FDA to treat cutaneous and peripheral T-cell lymphoma. However, the limited supply and severe cardiotoxicity of FK228 underscore the importance to develop an effective synthetic biology platform for the manufacturing and fine-tuning of this drug lead. In this work, we constructed a Burkholderia chassis for the high-yield production of FK228-family (unnatural) natural products. By virtue of the optimized Burkholderia-specific recombineering system, the biosynthetic gene cluster (BGC) encoding the FK228-like skeleton thailandepsins (tdp) in Burkholderia thailandensis E264 was replaced with an attB integration site to afford the basal chassis KOGC1. The tdp BGC directly captured from E264 was hybridized with the FK228-encoding BGC (dep) using the versatile Red/ET technology. The hybrid BGC (tdp-dep) was integrated into the attB site of KOGC1, resulting in the heterologous expression of FK228. Remarkably, the titer reached 581 mg/L, which is 30-fold higher than that of native producer Chromobacterium violaceum No. 968. This success encouraged us to further engineer the NRPS modules 4 or 6 of hybrid tdp-dep BGC by domain units swapping strategy, and eight new FK228 derivatives (1-8) varying in the composition of amino acids were generated. Especially, the titers of 2 and 3 in KOGC1 were up to 985 mg/L and 453 mg/L, respectively. 2 and 3 displayed stronger cytotoxic activity than FK228. All in all, this work established a robust platform to produce FK228 and its new derivatives in sufficient quantities for anticancer drug development.

E-cadherin expression in the tumor microenvironment of advanced epidermal growth factor receptor-mutant lung adenocarcinoma and the association with prognosis.

BACKGROUND: The expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), E-cadherin, and vimentin in lung cancer tumor microenvironment is known to impact patient survival or response to therapy. The expression of these biomarkers may also differ between primary lung tumors and brain metastatic tumors. In this study, we investigated the interaction between these biomarkers in lung tumors with or without concomitant brain metastasis and the interaction with paired brain metastatic tumors. METHODS: The study included 48 patients with stage IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. Sixteen of the forty-eight patients were diagnosed with brain metastasis, while the remaining thirty-two were not. All sixteen patients with brain metastasis had brain tumors. The expression of PD-L1, TILs (CD8+ T lymphocytes and FOXP3+ regulatory T lymphocytes), E-cadherin, and vimentin were evaluated using immunohistochemical (IHC) staining. RESULTS: Patients with brain metastasis exhibited a higher frequency of exon 19 deletion and uncommon EGFR mutations, a higher lung tumor vimentin score, worse progression-free survival (PFS), and overall survival (OS) than patients without brain metastasis. IHC staining showed no difference between paired lung and brain tumors. Patients with low PD-L1 expression had better PFS and OS. After multivariate analysis, higher body mass index, the presence of brain metastasis, bone metastasis, and uncommon EGFR mutations were correlated with worse PFS, while the presence of brain metastasis and high lung tumor E-cadherin score was associated with worse OS. CONCLUSIONS: In patients with stage IV EGFR-mutant lung adenocarcinoma, high E-cadherin expression in the lung tumor might be associated with worse OS. Vimentin expression in the lung tumor was positively related to the risk of brain metastasis.

2D Heterolayer-Structured MoSe2-Carbon with Fast Kinetics for Sodium-Ion Capacitors.

Two-dimensional (2D) layered MoSe2 has been demonstrated to be a promising electrode material for new energy storage systems. However, its nature of poor conductivity and the undesirable interlayer spacing hinder its further application. In this paper, a general and simple plasma-enhanced chemical vapor deposition method is proposed to produce 2D heterolayer-structured MoSe2-carbon (MoSe2/C) with carbon atoms inserted in the MoSe2 layers. After morphology optimization, when applying flat-type MoSe2/C-200 nanosheets with an enlarged interlayer spacing of 0.79 nm as the anode and activated carbon as the cathode, the assembled sodium-ion hybrid capacitors can reach a maximum energy/power density of 116.5 W h kg-1/107.5 W kg-1 and exhibit superior cycling durability (91.3% capacitance retention after 4000 cycles at 1 A g-1). The good electrochemical property can be ascribed to the enlarged interlayer spacing that can offer fast diffusion channels for Na ions, and the carbon layer sandwiched in the MoSe2 layer can not only enhance the electron transfer, accelerating the reaction kinetics, but also alleviate the volume change of MoSe2, ensuring the good stability of the electrode. The proposed approach can also be extended to other 2D transition metal chalcogenide (TMC) materials for constructing the TMC/C heterostructures for the application in energy storage systems.

Genetic Interference of FGFR3 Impedes Invasion of Upper Tract Urothelial Carcinoma Cells by Alleviating RAS/MAPK Signal Activity.

Upper tract urothelial cancer (UTUC) is a less common disease in Western countries but has a high level of prevalence in Asian populations. Compared to bladder cancer, unique etiologic and genomic factors are involved in UTUC. Fibroblast growth factor receptor 3 (FGFR3) up-regulation has been proposed as a promising target for bladder cancer therapy. In this study, we aimed to profile the expression of FGFR3 in Asian and Caucasian UTUC tissues and to evaluate the in vitro therapeutic efficacy of small interference RNA (siRNA)-mediated FGFR3 silencing in UTUC treatment. The FGFR3 expression levels in renal pelvis tissues and microarray sections from Asian and Caucasian patients with UTUC, respectively, were measured via immunohistochemistry. The BFTC-909 and UM-UC-14 UTUC cell lines were used to examine the effects of FGFR3 silencing on proliferation, migration, epithelial-mesenchymal transition (EMT) marker expression, and signaling machinery. FGFR3 expression increased as the TNM stage increased in both Asian and Caucasian UTUC tumors, and no statistical difference was identified between the two groups. In vitro studies demonstrated that FGFR3 siRNA delivery significantly inhibited proliferation and migration and suppressed the expression of EMT markers and transcription factors in UTUC cells. Mechanistically, FGFR3 silencing alleviated the constitutive expression of RAS and the phosphorylation of MAPK signaling mediators, including ERK1/2 and JNK1/2. FGFR3 silencing elicited an apoptosis-inducing effect similar to that of FGFR inhibition. Conclusion: siRNA-targeted FGFR3 expression may impede the expansion and invasion of UTUC cells by alleviating the RAS/MAPK signaling pathway. The genetic interference of FGFR3 expression via siRNA in UTUC cells may constitute a useful therapeutic strategy.

Modeling the power system resilience in China under different natural disasters.

A good understanding of the power system resilience is necessary for optimizing the investment strategies and supporting the emergency rescue, but the existing quantitative estimation results based on real outage events are still lacked due to the data limitations. Therefore, this study first establishes a unified framework to measure the power system resilience under different natural disasters, by integrating the electricity performance curve with the dynamic inoperability input-output model. Then, a database of 285 Chinese historical big power outage events caused by natural disasters is established, and the city-level power system resilience values are estimated. Finally, a benefit analysis is conducted for improving the power system resilience. Our major findings are that: (1) Electricity system recoveries quickest from hail (23.05 h), while restores slowest from snowstorm (117.31 h). (2) China's city electricity system is the most resilient to the thunderstorm, while is the least resilient to the earthquake. (3) Enhancing the power system resilience will significantly reduce the requirements for rescue resources, and the saved emergency rescue cost ranges from 0.57 million yuan to 12.08 million yuan with 1% reduction of initial inoperability.

Diterpenoids from Streptomyces: Structures, Biosyntheses and Bioactivities.

Bacteria, especially Streptomyces spp., have emerged as a rich source for natural diterpenoids with diverse structures and broad bioactivities. Here, we review diterpenoids biosynthesized by Streptomyces, with an emphasis on their structures, biosyntheses, and bioactivities. Although diterpenoids from Streptomyces are relatively rare compared to those from plants and fungi, their novel skeletons, biosyntheses and bioactivities present opportunities for discovering new drugs, enzyme mechanisms, and applications in biocatalysis and metabolic pathway engineering.

Isolation, complete genome sequencing and in silico genome mining of Burkholderia for secondary metabolites.

Recent years, Burkholderia species have emerged as a new source of natural products (NPs) with increasing attractions. Genome mining suggests the Burkholderia genomes include many natural product biosynthetic gene clusters (BGCs) which are new targets for drug discovery. In order to collect more Burkholderia, here, a strain S-53 was isolated from the soil samples on a mountain area in Changde, P.R. China and verified by comparative genetic analysis to belong to Burkholderia. The complete genome of Burkholderia strain S-53 is 8.2 Mbps in size with an average G + C content of 66.35%. Its taxonomy was both characterized by 16S rRNA- and whole genome-based phylogenetic trees. Bioinformatic prediction in silico revealed it has a total of 15 NP BGCs, some of which may encode unknown products. It is expectable that availability of these BGCs will speed up the identification of new secondary metabolites from Burkholderia and help us understand how sophisticated BGC regulation works.

LncRNA SUMO1P3 regulates the invasion, migration and cell cycle of gastric cancer cells through Wnt/ß-catenin signaling pathway.

OBJECTIVE: To investigate the regulatory effect of long non-coding RNA (lncRNA) SUMO1P3 on invasion, migration and cell cycle of gastric cancer (GC) cells through Wnt/ß-catenin signaling pathway. METHODS: Tumor tissues and adjacent normal tissues from the GC patients were collected, and human normal gastric epithelial cells GES1 and GC cells SGC-7901, MKN45, HGC-27 and AGS were selected for study. The expression of SUMO1P3 in GC tissues and cells were detected by RT-qPCR. The effects of SUMO1P3 on the proliferation, invasion and migration of SGC-7901 and MKN45 cells were detected by CCK-8, transwell and wound healing assay respectively, and the effects of SUMO1P3 on apoptosis and cycle progression of SGC-7901 and MKN45 cells were detected by flow cytometry. The expressions of Wnt/ß-catenin pathway-related and cell cycle-related proteins were detected by Western blot. RESULTS: The expression of SUMO1P3 was significantly upregulated in GC tissues and cell lines. Downregulation of SUMO1P3 significantly inhibited the SGC-7901 and MKN45 cell proliferation, invasion, migration, and cycle progression and promoted the cell apoptosis, while overexpression of SUMO1P3 showed the opposite effect. Further study showed that downregulation of SUMO1P3 significantly reduced the expressions of Wnt1, ß-catenin, c-myc, and Cyclin D1 in SGC-7901 and MKN45 cells. CONCLUSION: SUMO1P3 may promote invasion, migration, and cycle progression of SGC-7901 and MKN45 cells by enhancing the Wnt/ß-catenin pathway.

Internet Hospitals Help Prevent and Control the Epidemic of COVID-19 in China: Multicenter User Profiling Study.

BACKGROUND: During the spread of the novel coronavirus disease (COVID-19), internet hospitals in China were engaged with epidemic prevention and control, offering epidemic-related online services and medical support to the public. OBJECTIVE: The aim of this study is to explore the role of internet hospitals during the prevention and control of the COVID-19 outbreak in China. METHODS: Online epidemic-related consultations from multicenter internet hospitals in China during the COVID-19 epidemic were collected. The counselees were described and classified into seven type groups. Symptoms were recorded and compared with reported patients with COVID-19. Hypochondriacal suspicion and offline visit motivation were detected within each counselees' group to evaluate the social panic of the epidemic along with the consequent medical-seeking behaviors. The counselees' motivation and the doctors' recommendation for an offline visit were compared. Risk factors affecting the counselees' tendency of hypochondriacal suspicion and offline visit motivation were explored by logistic regression models. The epidemic prevention and control measures based on internet hospitals were listed, and the corresponding effects were discussed. RESULTS: A total of 4913 consultations were enrolled for analysis with the median age of the counselees at 28 years (IQR 22-33 years). There were 104 (2.12%) healthy counselees, 147 (2.99%) hypochondriacal counselees, 34 (0.69%) exposed counselees, 853 (17.36%) mildly suspicious counselees, 42 (0.85%) moderately suspicious counselees, 3550 (72.26%) highly suspicious counselees, and 183 (3.72%) severely suspicious counselees. A total of 94.20% (n=4628) of counselees had epidemic-related symptoms with a distribution similar to those of COVID-19. The hypochondriacal suspicion (n=2167, 44.11%) was common. The counselees' motivation and the doctors' recommendation for offline visits were inconsistent (P<.001) with a Cohen kappa score of 0.039, indicating improper medical-seeking behaviors. Adult counselees (odds ratio [OR]=1.816, P<.001) with epidemiological exposure (OR 7.568, P<.001), shortness of breath (OR 1.440, P=.001), diarrhea (OR 1.272, P=.04), and unrelated symptoms (OR 1.509, P<.001) were more likely to have hypochondriacal suspicion. Counselees with severe illnesses (OR 2.303, P<.001), fever (OR 1.660, P<.001), epidemiological exposure history (OR 1.440, P=.01), and hypochondriacal suspicion (OR 4.826, P<.001) were more likely to attempt an offline visit. Reattending counselees (OR 0.545, P=.002) were less motivated to go to the offline clinic. CONCLUSIONS: Internet hospitals can serve different types of epidemic counselees, offer essential medical supports to the public during the COVID-19 outbreak, reduce the social panic, promote social distancing, enhance the public's ability of self-protection, correct improper medical-seeking behaviors, reduce the chance of nosocomial cross-infection, and facilitate epidemiological screening, thus, playing an important role on preventing and controlling COVID-19.

Effects of heterogeneous self-protection awareness on resource-epidemic coevolution dynamics.

Recent studies have demonstrated that the allocation of individual resources has a significant influence on the dynamics of epidemic spreading. In the real scenario, individuals have a different level of awareness for self-protection when facing the outbreak of an epidemic. To investigate the effects of the heterogeneous self-awareness distribution on the epidemic dynamics, we propose a resource-epidemic coevolution model in this paper. We first study the effects of the heterogeneous distributions of node degree and self-awareness on the epidemic dynamics on artificial networks. Through extensive simulations, we find that the heterogeneity of self-awareness distribution suppresses the outbreak of an epidemic, and the heterogeneity of degree distribution enhances the epidemic spreading. Next, we study how the correlation between node degree and self-awareness affects the epidemic dynamics. The results reveal that when the correlation is positive, the heterogeneity of self-awareness restrains the epidemic spreading. While, when there is a significant negative correlation, strong heterogeneous or strong homogeneous distribution of the self-awareness is not conducive for disease suppression. We find an optimal heterogeneity of self-awareness, at which the disease can be suppressed to the most extent. Further research shows that the epidemic threshold increases monotonously when the correlation changes from most negative to most positive, and a critical value of the correlation coefficient is found. When the coefficient is below the critical value, an optimal heterogeneity of self-awareness exists; otherwise, the epidemic threshold decreases monotonously with the decline of the self-awareness heterogeneity. At last, we verify the results on four typical real-world networks and find that the results on the real-world networks are consistent with those on the artificial network.

[Effect of density and directional cultivation on yield, quality and benefit of Nuomi yam].

A split-plot experiment was conducted to study the optimum planting density of Nuomi yam in directional groove shallow cultivation. Nuomi yam was the main local cultivar of Dioscorea. The study of this paper may help to give valuable instructions of local production. Three different planting densities and shallow groove diameter were designed in the experiment. The results showed that the fresh weight of aerial part per plant, yield and planting benefit of Nuomi yam tuber were the highest when the planting density was 12 000 plants/hm~2 and the diameter of shallow growth groove was 11.0 cm, while they were the lowest when the planting density was 22 500 plants/hm~2 and the diameter of shallow growth groove was 7.5 cm. Along with the increase of planting density, the fresh weight of aerial part, tuber, fresh yield, benefit and commercial tuber rate of Nuomi yam also decreased. The commercial tuber rate of Nuomi yam of 11.0 cm diameter in shallow growing pot was the highest, while it was the lowest with no shallow growing pot. On the contrary, the content of amylopectin and mucin was the highest when there was no shallow groove, and was the lowest when the diameter of shallow groove was 7.5 cm, although there was no significant difference between the two treatments. Therefore, Nuomi yam with the directional cultivation combination of planting density of 12 000 plants/hm~2 and shallow groove diameter of 11.0 cm showed high yield, good appearance quality, high planting benefit and no obvious adverse effect on internal quality.

Spray drying OZ439 nanoparticles to form stable, water-dispersible powders for oral malaria therapy.

BACKGROUND: OZ439 is a new chemical entity which is active against drug-resistant malaria and shows potential as a single-dose cure. However, development of an oral formulation with desired exposure has proved problematic, as OZ439 is poorly soluble (BCS Class II drug). In order to be feasible for low and middle income countries (LMICs), any process to create or formulate such a therapeutic must be inexpensive at scale, and the resulting formulation must survive without refrigeration even in hot, humid climates. We here demonstrate the scalability and stability of a nanoparticle (NP) formulation of OZ439. Previously, we applied a combination of hydrophobic ion pairing and Flash NanoPrecipitation (FNP) to formulate OZ439 NPs 150 nm in diameter using the inexpensive stabilizer hydroxypropyl methylcellulose acetate succinate (HPMCAS). Lyophilization was used to process the NPs into a dry form, and the powder's in vitro solubilization was over tenfold higher than unprocessed OZ439. METHODS: In this study, we optimize our previous formulation using a large-scale multi-inlet vortex mixer (MIVM). Spray drying is a more scalable and less expensive operation than lyophilization and is, therefore, optimized to produce dry powders. The spray dried powders are then subjected to a series of accelerated aging stability trials at high temperature and humidity conditions. RESULTS: The spray dried OZ439 powder's dissolution kinetics are superior to those of lyophilized NPs. The powder's OZ439 solubilization profile remains constant after 1 month in uncapped vials in an oven at 50 °C and 75% RH, and for 6 months in capped vials at 40 °C and 75% RH. In fasted-state intestinal fluid, spray dried NPs achieved 80-85% OZ439 dissolution, to a concentration of 430 µg/mL, within 3 h. In fed-state intestinal fluid, 95-100% OZ439 dissolution is achieved within 1 h, to a concentration of 535 µg/mL. X-ray powder diffraction and differential scanning calorimetry profiles similarly remain constant over these periods. CONCLUSIONS: The combined nanofabrication and drying process described herein, which utilizes two continuous unit operations that can be operated at scale, is an important step toward an industrially-relevant method of formulating the antimalarial OZ439 into a single-dose oral form with good stability against humidity and temperature.

Amorphous nanoparticles by self-assembly: processing for controlled release of hydrophobic molecules.

More than 40% of newly developed drug molecules are highly hydrophobic and, thus, suffer from low bioavailability. Kinetically trapping the drug as a nanoparticle in an amorphous state enhances solubility. However, enhanced solubility can be compromised by subsequent recrystallization from the amorphous state during drying processes. We combine Flash NanoPrecipitation (FNP) to generate nanoparticles with spray-drying to produce stable solid powders. We demonstrate that the continuous nanofabrication platform for nanoparticle synthesis and recovery does not compromise the dissolution kinetics of the drug. Lumefantrine, an anti-malaria drug, is highly hydrophobic with low bioavailability. Increasing the bioavailability of lumefantrine has the potential to reduce the dose and number of required administrations per treatment, thus reducing cost and increasing patient compliance. The low melting temperature of lumefantrine (Tm = 130 °C) makes the drying of amorphous nanoparticles at elevated temperatures potentially problematic. Via FNP, we produced 200-400 nm nanoparticles using hydroxypropyl methylcellulose acetate succinate (HPMCAS), lecithin phospholipid, and zein protein stabilizers. Zein nanoparticles were spray-dried at 100 °C and 120 °C to study the effect of the drying temperature. For zein powders, at two hours the dissolution kinetics under fasted conditions reached 85% release for the 100 °C sample, but only 60% release for the 120 °C sample. Powder X-ray diffraction, differential scanning calorimetry, and solid state nuclear magnetic resonance indicate that the lumefantrine in the nanoparticle core is amorphous for samples spray-dried at 100 °C. Dissolution under fed state conditions showed similar release kinetics for both temperatures, with 90-95% release at two hours. Zein and HPMCAS nanoparticles spray-dried at 100 °C showed release profiles in fasted and fed state media that are identical to those of lyophilized samples, i.e. those dried at cryogenic conditions where no transformation to the crystalline state can occur. Thus, spray drying 30 °C below the melting transition of lumefantrine is sufficient to maintain the amorphous state. These inexpensive formulations have potential to be developed into future therapies for malaria, and the results also highlight the potential of combining FNP and spray-drying as a versatile platform to assemble and rapidly recover amorphous nanoparticles in a solid dosage form.

In situ quasi-elastic neutron scattering study on the water dynamics and reaction mechanisms in alkali-activated slags.

In this study, in situ quasi-elastic neutron scattering (QENS) has been employed to probe the water dynamics and reaction mechanisms occurring during the formation of NaOH- and Na2SiO3-activated slags, an important class of low-CO2 cements, in conjunction with isothermal conduction calorimetry (ICC), Fourier transform infrared spectroscopy (FTIR) analysis and N2 sorption measurements. We show that the single ICC reaction peak in the NaOH-activated slag is accompanied with a transformation of free water to bound water (from QENS analysis), which directly signals formation of a sodium-containing aluminum-substituted calcium-silicate-hydrate (C-(N)-A-S-H) gel, as confirmed by FTIR. In contrast, the Na2SiO3-activated slag sample exhibits two distinct reaction peaks in the ICC data, where the first reaction peak is associated with conversion of constrained water to bound and free water, and the second peak is accompanied by conversion of free water to bound and constrained water (from QENS analysis). The second conversion is attributed to formation of the main reaction product (i.e., C-(N)-A-S-H gel) as confirmed by FTIR and N2 sorption data. Analysis of the QENS, FTIR and N2 sorption data together with thermodynamic information from the literature explicitly shows that the first reaction peak is associated with the formation of an initial gel (similar to C-(N)-A-S-H gel) that is governed by the Na+ ions and silicate species in Na2SiO3 solution and the dissolved Ca/Al species from slag. Hence, this study exemplifies the power of in situ QENS, when combined with laboratory-based characterization techniques, in elucidating the water dynamics and associated chemical mechanisms occurring in complex materials, and has provided important mechanistic insight on the early-age reactions occurring during formation of two alkali-activated slags.