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Background: Low detection and nonadherence are major problems in current management approaches for patients with suspected atrial fibrillation (AF). Mobile health devices may enable earlier AF detection and improved AF management. Objectives: This study sought to investigate the effectiveness of AF screening in a large population-based cohort using smart device–based photoplethysmography (PPG) technology, combined with a clinical care AF management pathway using a mobile health approach. Methods: AF screening was performed with smart devices using PPG technology, which were made available for the population ≥18 years of age across China. Monitoring for at least 14 days with a wristband (Honor Band 4) or wristwatch (Huawei Watch GT, Honor Watch, Huawei Technologies Co., Ltd., Shenzhen, China) was allowed. The patients with “possible AF” episodes using the PPG algorithm were further confirmed by health providers among the MAFA (mobile AF app) Telecare center and network hospitals, with clinical evaluation, electrocardiogram, or 24-h Holter monitoring. Results: There were 246,541 individuals who downloaded the PPG screening app, and 187,912 individuals used smart devices to monitor their pulse rhythm between October 26, 2018, and May 20, 2019. Among those with PPG monitoring (mean age 35 years, 86.7% male), 424 (of 187,912, 0.23%) (mean age 54 years, 87.0% male) received a “suspected AF” notification. Of those effectively followed up, 227 individuals (of 262, 87.0%) were confirmed as having AF, with the positive predictive value of PPG signals being 91.6% (95% confidential interval [CI]: 91.5% to 91.8%). Both suspected AF and identified AF markedly increased with age (p for trend

One of the main challenges in clinical translation of polymeric micelles is retention of the drug in the nanocarrier system upon its systemic administration. Core crosslinking and coupling of the drug to the micellar backbone are common strategies to overcome these issues. In the present study, polymeric micelles were prepared for tumor cell targeting of the kinase inhibitor dactolisib which inhibits both the mammalian Target of Rapamycin (mTOR) kinase and phosphatidylinositol-3-kinase (PI3K). We employed platinum(II)-based linker chemistry to couple dactolisib to the core of poly(ethylene glycol)-b-poly(acrylic acid) (PEG-b-PAA) polymeric micelles. The formed dactolisib-PEG-PAA unimers are amphiphilic and self-assemble in an aqueous milieu into core–shell polymeric micelles. Folate was conjugated onto the surface of the micelles to yield folate-decorated polymeric micelles which can target folate receptor over-expressing tumor cells. Fluorescently labeled polymeric micelles were prepared using a lissamine-platinum complex linked in a similar manner as dactolisib. Dactolisib polymeric micelles showed good colloidal stability in water and released the coupled drug in buffers containing chloride or glutathione. Folate decorated micelles were avidly internalized by folate-receptor-positive KB cells and displayed targeted cellular cytotoxicity at 50–75 nM IC50. In conclusion, we have prepared a novel type of folate-receptor targeted polymeric micelles in which platinum(II) linker chemistry modulates drug retention and sustained release of the coupled inhibitor dactolisib.

BACKGROUND: Current management of patients with atrial fibrillation (AF) is limited by low detection of AF, non-adherence to guidelines, and lack of consideration of patients' preferences, thus highlighting the need for a more holistic and integrated approach to AF management.OBJECTIVE: The objective of this study was to determine whether a mobile health (mHealth) technology-supported AF integrated management strategy would reduce AF-related adverse events, compared with usual care.METHODS: This is a cluster randomized trial of patients with AF older than 18 years of age who were enrolled in 40 cities in China. Recruitment began on June 1, 2018 and follow-up ended on August 16, 2019. Patients with AF were randomized to receive usual care, or integrated care based on a mobile AF Application (mAFA) incorporating the ABC (Atrial Fibrillation Better Care) Pathway: A, Avoid stroke; B, Better symptom management; and C, Cardiovascular and other comorbidity risk reduction. The primary composite outcome was a composite of stroke/thromboembolism, all-cause death, and rehospitalization. Rehospitalization alone was a secondary outcome. Cardiovascular events were assessed using Cox proportional hazard modeling after adjusting for baseline risk.RESULTS: There were 1,646 patients allocated to mAFA intervention (mean age, 67.0 years; 38.0% female) with mean follow-up of 262 days, whereas 1,678 patients were allocated to usual care (mean age, 70.0 years; 38.0% female) with mean follow-up of 291 days. Rates of the composite outcome of 'ischemic stroke/systemic thromboembolism, death, and rehospitalization' were lower with the mAFA intervention compared with usual care (1.9% vs. 6.0%; hazard ratio [HR]: 0.39; 95% confidence interval [CI]: 0.22 to 0.67; p < 0.001). Rates of rehospitalization were lower with the mAFA intervention (1.2% vs. 4.5%; HR: 0.32; 95% CI: 0.17 to 0.60; p < 0.001). Subgroup analyses by sex, age, AF type, risk score, and comorbidities demonstrated consistently lower HRs for the composite outcome for patients receiving the mAFA intervention compared with usual care (all p < 0.05).CONCLUSIONS: An integrated care approach to holistic AF care, supported by mHealth technology, reduces the risks of rehospitalization and clinical adverse events. (Mobile Health [mHealth] technology integrating atrial fibrillation screening and ABC management approach trial; ChiCTR-OOC-17014138).

Rice husk gasification slag (RS) is a type of biochar that is one of the main by-products generated from the production of biomass power with rice husk as the feed. This study aimed to explore the short-term effect of the application of RS on the movement and transformation of fertilizer P in two different soil types through an incubation experiment. The results showed that the RS addition had a significant influence on the diffusive movement of P in soil microsites close to fertilizer placements both in latosolic red soil and fluvo-aquic soil. After 50 d of incubation, most of the WE-P (water-extractable P), AE-P (acid-extractable P), and Olsen-P (available P) were concentrated within 0&ndash, 5 mm from the fertilization site. WE-P, Olsen-P, and the movement amount of the P in the 0&ndash, 5 mm soil section were significantly increased at all levels of the RS application in the fertilizer P both in the two soil types. The application of the RS reduced the sorption and precipitation of the fertilizer P in the soil and improved the efficiency of the fertilizer P. The findings presented in this study may be used as references in developing RS applications that reduce losses of fertilizer P and reduce environmental risks.

A variety of diseases is associated with dysregulation of kinase signaling pathways and kinase inhibitors are hence being considered as potent drugs for the treatment of cancer and inherited diseases such as polycystic kidney disease. Although kinase inhibitors are considered as quite specific drugs that are molecularly targeted, side effects significantly limit their therapeutic applications. Moreover, their specific action also infers that the efficacy of kinase inhibitors is limited by drug resistance. In this thesis, we have explored the development of drug delivery systems such as small molecule-drug conjugates (SMDCs) and polymeric micelles for kinase inhibitors, which eventually can be used to overcome these problems. An SMDC typically is composed of a targeting ligand, a drug payload and a spacer which infers a cleavable linkage with the drug (see Figure 3, Chapter 1). SMDCs have attracted tremendous interest in the pharmaceutical field because they have several advantageous features. Firstly, the small size (as can be deduced from their low molecular weight) of SMDCs enables them to accumulate and penetrate in solid tumors very efficiently. Secondly, the synthesis strategy of SMDCs is versatile and controllable. Polymeric micelles are colloidal nanoparticles with a diameter size around 10 - 200 nm and have a core-shell structure that is formed by self-assembling of amphiphilic block copolymers in aqueous media. The hydrophilic block of the copolymers forms the shell of polymeric micelles to ensure their colloidal stability while the hydrophobic block forms the core of polymeric micelles. Hydrophobic drugs can be loaded in the core by physical entrapment or -preferably, in view of stable drug retention- by chemical crosslinking to the core. The physicochemical properties of polymeric micelles can be controlled by adjusting the components of polymers and drugs. The relatively small size of polymeric micelles -although much larger than SMDCs- enables them to passively accumulate and subsequently penetrate into tumours via the enhanced permeability and retention (EPR) effect. The loaded drug can subsequently be released in the tumor microenvironment. In addition to passive targeting, the surface of polymeric micelles can be decorated with targeting ligands which can facilitate active receptor mediated uptake by cancer cells. This thesis is focused on the development of novel SMDCs and polymeric micelles exploiting platinum coordination chemistry for conjugation of the drug to the delivery system. As discussed below, we have explored and optimized the reaction conditions to form drug conjugates and drug loaded micelles primarily with the kinase inhibitor dactolisib, which is a potent inhibitor of signaling pathways involved in cancer and polycystic kidney disease. In conclusion, small molecule-drug conjugates and polymeric micelles exploiting platinum coordination chemistry described in this thesis can target deliver kinase inhibitors to the diseased cells and, potentially, exert cellular kinase inhibitory effect. The promising results from this thesis encourage the further application of these novel drug delivery systems for preclinical and clinical studies.

Polymeric micelles are attractive nanocarriers for hydrophobic drug molecules such as the kinase inhibitor dactolisib. Two different poly(ethylene glycol)–poly(acrylic acid) (PEG-b-PAA) block-copolymers are synthesized, PEG(5400)-b-PAA(2000) and PEG(10000)-b-PAA(3700), respectively. Polymeric micelles are formed by self-assembly once dactolisib is conjugated via the ethylenediamine platinum(II) linker (Lx) to the PAA block of the block copolymers. Dactolisib micelles with dactolisib loading content of 17% w/w show good colloidal stability and display sustained release of Lx-dactolisib over 96 h in PBS at 37 °C, while media containing reagents that compete for platinum coordination (e.g., glutathione (GSH) or dithiothreitol (DTT)) effectuate release of the parent inhibitor dactolisib at similar release rates. Dactolisib/lissamine-loaded micelles are internalized by human breast adenocarcinoma cells (MCF-7) in a dose and time-dependent manner as demonstrated by confocal microscopy. Dactolisib-loaded micelles inhibit the PI3K/mTOR signaling pathway at low concentrations (400 × 10−9 m) and exhibit potent cytotoxicity against MCF-7 cells with IC50 values of 462 ± 46 and 755 ± 75 × 10−9 m for micelles with either short or longer PEG-b-PAA block lengths. In conclusion, dactolisib loaded PEG-b-PAA micelles are successfully prepared and hold potential for nanomedicine-based tumor delivery of dactolisib.

The aim of the present study was to develop folic acid (FA) conjugates which can deliver the kinase inhibitor dactolisib to the kidneys via folate receptor-mediated uptake in tubular epithelial cells. Dactolisib is a dual inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) and is considered an attractive agent for treatment of polycystic kidney disease. The ethylenediamine platinum(II) linker, herein called Lx, was employed to couple dactolisib via coordination chemistry to thiol-containing FA-spacer adducts to yield FA-Lx-dactolisib conjugates. The dye lissamine was coupled via similar linker chemistry to folate to yield fluorescent FA-Lx-lissamine conjugates. Three different spacers (PEG(5)-Cys, PEG(27)-Cys or an Asp-Arg-Asp-Asp-Cys peptide spacer) were used to compare the influence of hydrophilicity and charged groups in the spacer on interaction with target cells and in vivo organ distribution of the final conjugates. The purity and identity of the final products were confirmed by UPLC and LC-MS analysis, respectively. FA-Lx-dactolisib conjugates were stable in serum and culture medium, while dactolisib was released from the conjugates in the presence of glutathione. All three type of conjugates were internalized efficiently by HK-2 cells and uptake could be blocked by an excess of folic acid in the medium, demonstrating FR mediated uptake. FA-Lx-dactolisib conjugates showed nanomolar inhibition of the PI3K pathway (Akt phosphorylation) and mTOR pathway (S6 phosphorylation) in cultured kidney epithelial cells (HK-2 cells). After intraperitoneal administration, all three types conjugates accumulated extensively in kidneys of iKsp-Pkd1(del) mice with polycystic kidney disease. In conclusion, folate conjugates were successfully prepared by platinum(II) coordination chemistry and accumulated in a target-specific manner in kidney cells and polycystic kidneys. The folate conjugate of dactolisib thus may have potential for targeted therapy of polycystic kidney disease.