A retrospective cohort study of Paxlovid efficacy depending on treatment time in hospitalized COVID-19 patients.

Paxlovid, a SARS-CoV-2 antiviral, not only prevents severe illness but also curtails viral shedding, lowering transmission risks from treated patients. By fitting a mathematical model of within-host Omicron viral dynamics to electronic health records data from 208 hospitalized patients in Hong Kong, we estimate that Paxlovid can inhibit over 90% of viral replication. However, its effectiveness critically depends on the timing of treatment. If treatment is initiated three days after symptoms first appear, we estimate a 17% chance of a post-treatment viral rebound and a 12% (95% CI: 0-16%) reduction in overall infectiousness for non-rebound cases. Earlier treatment significantly elevates the risk of rebound without further reducing infectiousness, whereas starting beyond five days reduces its efficacy in curbing peak viral shedding. Among the 104 patients who received Paxlovid, 62% began treatment within an optimal three-to-five-day day window after symptoms appeared. Our findings indicate that broader global access to Paxlovid, coupled with appropriately timed treatment, can mitigate the severity and transmission of SARS-Cov-2.

CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia.

Clinically, arsenic trioxide (ATO) was applied to the treatment of acute promyelocytic leukemia (APL) as a reliable and effective frontline drug. However, the administration regimen of AsⅢ was limited due to its fast clearance, short therapeutic window and toxicity as well. Based on CD71 overexpressed on APL cells, in present study, a transferrin (Tf)-modified liposome (LP) was established firstly to encapsulate AsⅢ in arsenic-nickel complex by nickel acetate gradient method. The AsⅢ-loaded liposomes (AsLP) exhibited the feature of acid-sensitive release in vitro. Tf-modified AsLP (Tf-AsLP) were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢ which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of AsⅢ in blood circulation, lowered systemic toxicity, and promoted apoptosis and induced cell differentiation at lesion site in vivo. Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect, accordingly, a Tf-modified RA liposome (Tf-RALP) was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy. As expected, the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model. Furthermore, APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection. The effect of co-administration (Tf-AsLP + Tf-RALP) was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells' apoptosis and differentiation in peripheral blood and bone marrow. Collectively, Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug. Moreover, Tf-AsLP combined with Tf-RALP could achieve better efficacy. Thus, transferrin-modified AsⅢ liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects.

Recent Advances in Perfluorocarbon-Based Delivery Systems for Cancer Theranostics.

Hypoxia is a key impediment encountered in the treatment of most solid tumors, leading to immune escape and therapeutic resistance. Perfluorocarbons (PFCs) have a unique electrical structure and are characterized by a high solubility for gases. PFC-based oxygen carriers have been evaluated for their ability to deliver oxygen effectively to hypoxic tissues, and significant clinical translation has been demonstrated. And due to the unique acoustic activity, PFCs have been employed to stabilize the injection of gas microbubbles (MBs) as clinical ultrasonography contrast agents. In contrast, the ultrasound and photothermally activatable PFC phase-shift nanodroplets (P-SNDs) represent a novel alternative to ultrasound imaging and hypoxia improvement. The PFC-based oxygen carriers may be utilized to improve the efficacy of cancer treatments based on synergistic radiotherapy (RT), chemotherapy (CMT), and photodynamic therapy (PDT) to reshape the tumor microenvironment through synergistic immunotherapy (IMT) and to achieve precise tumor diagnosis using acoustic imaging. This review described the characteristics of PFCs to provide an update on the design of PFC delivery systems used for oxygen delivery and ultrasound imaging to facilitate the treatment and diagnosis of tumors. The objective was to contribute to overcoming the obstacles encountered during PFC research and provide the developing prospects.

Tumor-permeable smart liposomes by modulating the tumor microenvironment to improve the chemotherapy.

Low levels of accumulation and permeability in tumors are two primary reasons for the limited efficacy of conventional antineoplastic nanodrugs. In the present study, based on an original corosolic acid liposome (CALP) carrier with the functions of cell penetration, tumor permeability and anti-inflammation developed by our previous work, a versatile PTX/CALP was achieved by CALP loading paclitaxel (PTX). Compared to conventional PTX liposomes (PTX/LP) prepared by cholesterol and phospholipid, PTX/CALP exhibited extremely increasing cellular uptake and cytotoxicity in vitro, and in vivo enhancing the accumulation and permeability of tumor, thus significantly improving the antitumor efficacy. Further evidence indicated that PTX/CALP conspicuously promoted the recruitment of CD8+ T cells as well as reduced the infiltration of regulatory T cells and M2 macrophages into tumor by inducing enhanced immunogenic cell death (ICD) and down-regulating the inflammation level. Therefore, the improvement of efficacy was also attributed to the superiorities of PTX/CALP in modulating the inflammatory and immunosuppressive tumor microenvironment. Overall, the smart PTX liposomes based on the multi-functional CALP carrier without any modification could overcome the harsh tumor biological barriers, enhance the induction of ICD and then achieve satisfactory efficacy, suggesting its promising potentials in industrial transfer and clinical application.

Graphdiyne-supported single-cluster electrocatalysts for highly efficient carbon dioxide reduction reaction.

The electrochemical CO2 reduction reaction (CO2RR) has become a promising technology to resolve globally accelerating CO2 emissions and produce chemical fuels. In this work, the electrocatalytic performance of transition metal (TM = Cu, Cr, Mn, Co, Ni, Mo, Pt, Rh, Ru and V) triatomic clusters embedded in a graphdiyne (GDY) monolayer (TM3@GDY) for CO2RR is investigated by density functional theory (DFT) calculations. The results indicate that Cr3@GDY possesses the best catalytic performance with a remarkably low rate-limiting step of 0.39 eV toward the CO2 product, and it can also effectively suppress the hydrogen evolution reaction (HER) during the entire CO2RR process. Studies on the rate-limiting steps (CHO* + H+ + e- → CHOH) of Crn@GDY (n = 1-4) structures demonstrate that the high catalytic performance is attributed to the strong synergistic reaction of three Cr atoms interacting with the C atom for the Cr3@GDY structure. The strong synergistic reaction gives rise to the weakest interaction between O-Cr atoms, which leads to the strongest interaction between O-H atoms and makes the hydrogenation process easier for the Cr3@GDY structure. Furthermore, ab initio molecular dynamics simulations (AIMD) at 500 K reveal the high thermodynamic stability of the Cr3@GDY structure. These studies may provide a new approach for designing highly efficient electrocatalysts for the CO2RR under ambient conditions.

A practical strategy to subcutaneous administered in-situ gelling co-delivery system of arsenic and retinoic acid for the treatment of acute promyelocytic leukemia.

Arsenic trioxide (ATO) combined with all trans retinoic acid (ATRA) is the first choice for the treatment of low and medium risk acute promyelocytic leukemia (APL). Clinical studies reported that the combination of ATO and ATRA could achieve a significant curative effect. However, the retinoic acid syndrome, serious drug resistance and the short half-life in vivo which lead to frequent and large dose administration limit the application of ATRA. In addition, the preparations of arsenic are conventional injections and tablets in clinic, which has poor patients' compliance caused by frequent long-term administration and serious side effects. In order to overcome the above limitations, a phospholipid phase separation gel (PPSG) loaded with ATO and ATRA was developed. ATO+ATRA-PPSG (AAP), as a biodegradable sustained-release delivery system, was the first achievement of co-delivery of hydrophilic ATO and lipophilic ATRA with high drug loading which is the main problem in the application of nano preparation. The prepared PPSG displayed high safety and biocompatibility. The drug in PPSG was released slowly and continuously in vivo and in vitro for up to 10 d, which could reduce the side effects caused by the fluctuation of blood drug concentration and solve the problem of the long treatment cycle and frequent administration. In vivo pharmacokinetics depicted that PPSG could improve the bioavailability, decrease the peak concentration, and prolong the t1/2 of ATO and ATRA. Particularly, AAP significantly inhibited the tumor volume, extended the survival period of tumor-bearing mice, and promoted the differentiation of APL cells into normal cells. Therefore, ATO+ATRA-PPSG not only could co-load hydrophilic ATO and lipophilic ATRA according to the clinical dosage, but also possessed the sustained-release and long-acting treatment effect which was expected to reduce administration time and ameliorate compliance of patients. Thus, it had great potential for clinical transformation and application.

Giant magnetic moment of the core-shell Co13@Mn20 clusters: first-principles calculations.

The core-shell clusters Co(13)@TM(20) with TM = Mn, Fe, Co, and Ni are investigated within first-principles simulations in the framework of density-functional theory. Huge magnetic moments have been found in the Co(13)@TM(20) clusters especially for the Co(13)@Mn(20) cluster with a giant magnetic moment of 113 µ(B). The large magnetic moments are mainly due to the special core-shell structure and the weak interaction between the TM and other atoms.

Characteristics associated with falls among the elderly within aged care wards in a tertiary hospital: a retrospective.

BACKGROUND: Falls are the most frequently reported adverse events in inpatient settings. We conducted a retrospective case-control study of inpatient falls within aged care wards in a tertiary hospital to investigate the associated characteristics of elderly patients suffering from falls and fall-related characteristics. METHODS: Consecutive retrospective cross-sectional design spanned July 2006 to December 2008. PATIENT GROUP: Information on all aged care inpatients who suffered from 1 or more falls was extracted from Incident Information Management System (IIMS). Further details about the particular admission(s) were obtained from patients' medical records, e.g., patients' characteristics and circumstances surrounding the falls. Randomly selected aged care patients who did not suffer from a fall and who were discharged from the hospital in the same period served control group. Characteristics among patients with single fall and recurrent falls, as well as non-fallers were compared. RESULTS: Of the 438 falls evaluated, 71.9% occurred in patients' room and 18.9% in patients' bathroom/toilet. The common activities were moving/transferring and taking shower/toileting, respectively, 70.3%, 12.1% while occurring falls; and time of falls had a high peak during 9:00-11:00 a.m. Many were unassisted while falling. The common contributing factors for fall were intrinsic factors. Patients with recurrent falls were more likely to have lower Mini-Mental State Examination (MMSE) score. Logistic regression analysis showed length of stay longer than five weeks, dementia and stroke were independent risk factors for recurrent falls; and living in hostel/nursing home preadmission, needing assistance with mobility, cognitive impairment, stroke, incontinence and arthritis/osteoporosis were independent risk factors for fall. CONCLUSIONS: In an aged care ward, falls are independently associated with recurrent factors. Cognitive impairment/dementia was a strong risk factor for falls, and main causes leading to fall were intrinsic factors. For patients with cognitive impairment/dementia and behavioral disorder providing special and effective interventions is of paramount importance for reducing the incidence of fall in an aged care ward in hospital settings.