233 research outputs found

    A study on the preparation of alkyne functional nanoparticles via RAFT emulsion polymerisation

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    The multivalent presentation of functional groups on nanoparticle surfaces has long been exploited to attach biologically active moieties. The conventional chemistries typically used (amide, ester, disulfide) however, are non-selective and inefficient. The Huisgen azide alkyne [1,4] cycloaddition (CuAAC) ‘click’ reaction has paved the way for atom economic, and orthogonal conjugation chemistries, and is now widely used in nanoparticle science. In this work, alkyne functionalised nanoparticles were prepared, without lengthy post-nanoparticle synthesis modification procedures, exploiting RAFT emulsion polymerisations stabilised by functional macro-RAFT agents. Our results indicated that ester derived RAFT agents and addition of pendant charged groups are vital to retain colloidal stability and narrow molecular weight distributions. Finally the nanoparticles and model polymers were functionalised with an azido functional polymer and fluorescent dye, showing the surfaces were easily accessible for rapid and efficient post-polymerisation functionalisation

    Violence against female sex workers in Karnataka state, south India: impact on health, and reductions in violence following an intervention program.

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    ABSTRACT: BACKGROUND: Violence against female sex workers (FSWs) can impede HIV prevention efforts and contravenes their human rights. We developed a multi-layered violence intervention targeting policy makers, secondary stakeholders (police, lawyers, media), and primary stakeholders (FSWs), as part of wider HIV prevention programming involving >60,000 FSWs in Karnataka state. This study examined if violence against FSWs is associated with reduced condom use and increased STI/HIV risk, and if addressing violence against FSWs within a large-scale HIV prevention program can reduce levels of violence against them. METHODS: FSWs were randomly selected to participate in polling booth surveys (PBS 2006-2008; short behavioural questionnaires administered anonymously) and integrated behavioural-biological assessments (IBBAs 2005-2009; administered face-to-face). RESULTS: 3,852 FSWs participated in the IBBAs and 7,638 FSWs participated in the PBS. Overall, 11.0% of FSWs in the IBBAs and 26.4% of FSWs in the PBS reported being beaten or raped in the past year. FSWs who reported violence in the past year were significantly less likely to report condom use with clients (zero unprotected sex acts in previous month, 55.4% vs. 75.5%, adjusted odds ratio (AOR) 0.4, 95% confidence interval (CI) 0.3 to 0.5, p < 0.001); to have accessed the HIV intervention program (ever contacted by peer educator, 84.9% vs. 89.6%, AOR 0.7, 95% CI 0.4 to 1.0, p = 0.04); or to have ever visited the project sexual health clinic (59.0% vs. 68.1%, AOR 0.7, 95% CI 0.6 to 1.0, p = 0.02); and were significantly more likely to be infected with gonorrhea (5.0% vs. 2.6%, AOR 1.9, 95% CI 1.1 to 3.3, p = 0.02). By the follow-up surveys, significant reductions were seen in the proportions of FSWs reporting violence compared with baseline (IBBA 13.0% vs. 9.0%, AOR 0.7, 95% CI 0.5 to 0.9 p = 0.01; PBS 27.3% vs. 18.9%, crude OR 0.5, 95% CI 0.4 to 0.5, p < 0.001). CONCLUSIONS: This program demonstrates that a structural approach to addressing violence can be effectively delivered at scale. Addressing violence against FSWs is important for the success of HIV prevention programs, and for protecting their basic human rights

    PHarmacist Avoidance or Reductions in Medical Costs in CRITically Ill Adults: PHARM-CRIT Study

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    OBJECTIVES: To comprehensively classify interventions performed by ICU clinical pharmacists and quantify cost avoidance generated through their accepted interventions. DESIGN: A multicenter, prospective, observational study was performed between August 2018 and January 2019. SETTING: Community hospitals and academic medical centers in the United States. PARTICIPANTS: ICU clinical pharmacists. INTERVENTIONS: Recommendations classified into one of 38 intervention categories (divided into six unique sections) associated with cost avoidance. MEASUREMENTS AND MAIN RESULTS: Two-hundred fifteen ICU pharmacists at 85 centers performed 55,926 interventions during 3,148 shifts that were accepted on 27,681 adult patient days and generated 23,404,089ofcostavoidance.Thequantityofacceptedinterventionsandcostavoidancegeneratedinsixestablishedsectionswasadversedrugeventprevention(5,777interventions;23,404,089 of cost avoidance. The quantity of accepted interventions and cost avoidance generated in six established sections was adverse drug event prevention (5,777 interventions; 5,822,539 CA), resource utilization (12,630 interventions; 4,491,318),individualizationofpatientcare(29,284interventions;4,491,318), individualization of patient care (29,284 interventions; 9,680,036 cost avoidance), prophylaxis (1,639 interventions; 1,414,465costavoidance),handsoncare(1,828interventions;1,414,465 cost avoidance), hands-on care (1,828 interventions; 1,339,621 cost avoidance), and administrative/supportive tasks (4,768 interventions; 656,110costavoidance).Meancostavoidancewas656,110 cost avoidance). Mean cost avoidance was 418 per intervention, 845perpatientday,and845 per patient day, and 7,435 per ICU pharmacist shift. The annualized cost avoidance from an ICU pharmacist is 1,784,302.Thepotentialmonetarycostavoidancetopharmacistsalaryratiowasbetween1,784,302. The potential monetary cost avoidance to pharmacist salary ratio was between 3.3:1 and 9.6:1.CONCLUSIONS:Pharmacistinvolvementinthecareofcriticallyillpatientsresultsinsignificantavoidanceofhealthcarecosts,particularlyintheareasofindividualizationofpatientcare,adversedrugeventprevention,andresourceutilization.ThepotentialmonetarycostavoidancetopharmacistsalaryratioemployinganICUclinicalpharmacistisbetween9.6:1. CONCLUSIONS: Pharmacist involvement in the care of critically ill patients results in significant avoidance of healthcare costs, particularly in the areas of individualization of patient care, adverse drug event prevention, and resource utilization. The potential monetary cost avoidance to pharmacist salary ratio employing an ICU clinical pharmacist is between 3.3:1 and $9.6:1

    Asymmetric triplex metallohelices with high and selective activity against cancer cells

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    Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and ​p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 ​p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. At a glanc

    Dopaminergic and prefrontal basis of learning from sensory confidence and reward value

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    Deciding between stimuli requires combining their learned value with one’s sensory confidence. We trained mice in a visual task that probes this combination. Mouse choices reflected not only present confidence and past rewards but also past confidence. Their behavior conformed to a model that combines signal detection with reinforcement learning. In the model, the predicted value of the chosen option is the product of sensory confidence and learned value. We found precise correlates of this variable in the pre-outcome activity of midbrain dopamine neurons and of medial prefrontal cortical neurons. However, only the latter played a causal role: inactivating medial prefrontal cortex before outcome strengthened learning from the outcome. Dopamine neurons played a causal role only after outcome, when they encoded reward prediction errors graded by confidence, influencing subsequent choices. These results reveal neural signals that combine reward value with sensory confidence and guide subsequent learning

    PHarmacist Avoidance or Reductions in Medical Costs in Patients Presenting the EMergency Department: PHARM-EM Study

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    Objectives: To comprehensively classify interventions performed by emergency medicine clinical pharmacists and quantify cost avoidance generated through their accepted interventions. Design: A multicenter, prospective, observational study was performed between August 2018 and January 2019. Setting: Community and academic hospitals in the United States. Participants: Emergency medicine clinical pharmacists. Interventions: Recommendations classified into one of 38 intervention categories associated with cost avoidance. Measurements and Main Results: Eighty-eight emergency medicine pharmacists at 49 centers performed 13,984 interventions during 917 shifts that were accepted on 8,602 patients and generated 7,531,862ofcostavoidance.Thequantityofacceptedinterventionsandcostavoidancegeneratedinsixestablishedcategorieswereasfollows:adversedrugeventprevention(1,631interventions;7,531,862 of cost avoidance. The quantity of accepted interventions and cost avoidance generated in six established categories were as follows: adverse drug event prevention (1,631 interventions; 2,225,049 cost avoidance), resource utilization (628; 310,582),individualizationofpatientcare(6,122;310,582), individualization of patient care (6,122; 1,787,170), prophylaxis (24; 22,804),handsoncare(3,533;22,804), hands-on care (3,533; 2,836,811), and administrative/supportive tasks (2,046; 342,881).Meancostavoidancewas342,881). Mean cost avoidance was 538.61 per intervention, 875.60perpatient,and875.60 per patient, and 8,213.59 per emergency medicine pharmacist shift. The annualized cost avoidance from an emergency medicine pharmacist was 1,971,262.Themonetarycostavoidancetopharmacistsalaryratiowasbetween1,971,262. The monetary cost avoidance to pharmacist salary ratio was between 1.4:1 and 10.6:1.Conclusions:Pharmacistinvolvementinthecareofpatientspresentingtotheemergencydepartmentresultsinsignificantavoidanceofhealthcarecosts,particularlyintheareasofhandsoncareandadversedrugeventprevention.Thepotentialmonetarybenefittocostratioforemergencymedicinepharmacistsisbetween10.6:1. Conclusions: Pharmacist involvement in the care of patients presenting to the emergency department results in significant avoidance of healthcare costs, particularly in the areas of hands-on care and adverse drug event prevention. The potential monetary benefit-to-cost ratio for emergency medicine pharmacists is between 1.4:1 and $10.6:1

    Liposome-Coupled Antigens Are Internalized by Antigen-Presenting Cells via Pinocytosis and Cross-Presented to CD8+ T Cells

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    We have previously demonstrated that antigens chemically coupled to the surface of liposomes consisting of unsaturated fatty acids were cross-presented by antigen-presenting cells (APCs) to CD8+ T cells, and that this process resulted in the induction of antigen-specific cytotoxic T lymphocytes. In the present study, the mechanism by which the liposome-coupled antigens were cross-presented to CD8+ T cells by APCs was investigated. Confocal laser scanning microscopic analysis demonstrated that antigens coupled to the surface of unsaturated-fatty-acid-based liposomes received processing at both MHC class I and class II compartments, while most of the antigens coupled to the surface of saturated-fatty-acid-based liposomes received processing at the class II compartment. In addition, flow cytometric analysis demonstrated that antigens coupled to the surface of unsaturated-fatty-acid-liposomes were taken up by APCs even in a 4°C environment; this was not true of saturated-fatty-acid-liposomes. When two kinds of inhibitors, dimethylamiloride (DMA) and cytochalasin B, which inhibit pinocytosis and phagocytosis by APCs, respectively, were added to the culture of APCs prior to the antigen pulse, DMA but not cytochalasin B significantly reduced uptake of liposome-coupled antigens. Further analysis of intracellular trafficking of liposomal antigens using confocal laser scanning microscopy revealed that a portion of liposome-coupled antigens taken up by APCs were delivered to the lysosome compartment. In agreement with the reduction of antigen uptake by APCs, antigen presentation by APCs was significantly inhibited by DMA, and resulted in the reduction of IFN-γ production by antigen-specific CD8+ T cells. These results suggest that antigens coupled to the surface of liposomes consisting of unsaturated fatty acids might be pinocytosed by APCs, loaded onto the class I MHC processing pathway, and presented to CD8+ T cells. Thus, these liposome-coupled antigens are expected to be applicable for the development of vaccines that induce cellular immunity
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