Challenges in applying human factors approaches to health service design

A participatory systems approach is a fundamental characteristic of the human factors and ergonomics discipline. However, the appropriate application of relevant methods is challenging in healthcare, since there is very limited time for staff to participate and their knowledge on design methods is usually very limited. An action research was carried out in a health service design project commissioned by a local health service commissioner. The aim of this paper is to examine and discuss challenges in applying the participatory systems approach

A pH-responsive, endosomolytic liposome functionalized with membrane-anchoring, comb-like pseudopeptides for enhanced intracellular delivery and cancer treatment

Low intracellular delivery efficiency and multidrug resistance are among major barriers to effective cancer therapy. Herein, we report a novel, virus-mimicking, endosomolytic liposomal drug-delivery platform to address these two key challenges. The pH-responsive, comb-like pseudopeptides were prepared by grafting relatively long alkyl side chains onto a polyamide, poly(L-lysine isophthalamide), to mimic fusogenic peptides in viral spikes. The cholesterol-containing liposome, which mimics the viral envelope, was readily coated with these pseudopeptides due to their hydrophobic side chains acting as membrane anchors. These endosomolytic pseudopeptides displayed high adsorption onto the liposomal membrane and enabled the significantly higher cellular uptake. The virus-mimicking system showed a pH-triggered content-release profile which could be manipulated by varying the structure and concentration of the adsorbed polymers. The endosomolytic ability of the multifunctional liposome and its use for efficient intracellular delivery of the widely used anticancer drug doxorubicin (DOX) were demonstrated. The virus-mimicking liposomal system with DOX encapsulation exhibited considerably higher potency against HeLa cervical cancer cells, A549 lung cancer cells, MES-SA uterus cancer cells, and MES-SA/DX5 multidrug-resistant cancer cells than DOX-loaded bare liposomes and free DOX. These results suggest its potential applications for enhanced cytoplasmic delivery and cancer treatment

Comparison of 2D and 3D gamma evaluation method in patient specific intensity-modulated radiotherapy quality assurance

Background: In this study we have compared 2D and 3D gamma pass percentage for a variety of acceptance criteria for 40 step-and-shoot IMRT (intensity-modulated radiotherapy) plans. Methods: Treatment planning was done for 40 patient including head and neck, abdomen and pelvis simulated on the Siemens Healthcare GmBH CT simulator with images of 3 mm slice thickness using treatment planning system (TPS) (Monaco Version 5.11.03, Elekta medical system) using Monte Carlo algorithm. The gamma evaluation was done using PTW VeriSoft 8.1 which allowed us to perform 2D and 3D gamma index calculation, slice-by-slice comparison of measured and calculated dose distributions, measured dose was compared against the calculated DICOMRT dose on the OCTAVIUS 3D phantom from TPS. Results: The average 3D and 2D gamma passing in coronal planes were 96.61±0.45% and 96.27±0.78% for 5 mm/5% criteria, 93.74±4.17% and 91.9±4.88% for 3 mm/3% criteria, 85.83±7.58% and 82.41±8.06% for 2 mm/2% criteria and 62.8±9.42% and 59.18±9.52% for 1 mm/1% criteria respectively for all cases. The average gamma passing rate for 3D gamma analysis was 0.35%, 1.97 %, 3.97% and 5.78% higher when compared with 2D coronal planar analyses for 5 mm/5%, 3 mm/3%, 2 mm/2% and 1 mm/1% DTA criteria respectively. Conclusions: It is concluded in the study that 3 D gamma passing rate is higher compared to 2D gamma passing for head and neck, abdomen and pelvis cases

Prion propagation is dependent on key amino acids in Charge cluster 2 within the prion protein

To dissect the N-terminal residues within the cellular prion protein (PrPC) that are critical for efficient prion propagation, we generated a library of point, double, or triple alanine replacements within residues 23-111 of PrP, stably expressed them in cells silenced for endogenous mouse PrPC and challenged the reconstituted cells with four common but biologically diverse mouse prion strains. Amino acids (aa) 105-111 of Charge Cluster 2 (CC2), which is disordered in PrPC, were found to be required for propagation of all four prion strains; other residues had no effect or exhibited strain-specific effects. Replacements in CC2, including aa105-111, dominantly inhibited prion propagation in the presence of endogenous wild type PrPC whilst other changes were not inhibitory. Single alanine replacements within aa105-111 identified leucine 108 and valine 111 or the cluster of lysine 105, threonine 106 and asparagine 107 as critical for prion propagation. These residues mediate specific ordering of unstructured CC2 into β-sheets in the infectious prion fibrils from Rocky Mountain Laboratory (RML) and ME7 mouse prion strains

Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib.

Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance, respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.Significance Pazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy

The enpp4 ectonucleotidase regulates kidney patterning signalling networks in Xenopus embryos

Abstract The enpp ectonucleotidases regulate lipidic and purinergic signalling pathways by controlling the extracellular concentrations of purines and bioactive lipids. Although both pathways are key regulators of kidney physiology and linked to human renal pathologies, their roles during nephrogenesis remain poorly understood. We previously showed that the pronephros was a major site of enpp expression and now demonstrate an unsuspected role for the conserved vertebrate enpp4 protein during kidney formation in Xenopus . Enpp4 over-expression results in ectopic renal tissues and, on rare occasion, complete mini-duplication of the entire kidney. Enpp4 is required and sufficient for pronephric markers expression and regulates the expression of RA, Notch and Wnt pathway members. Enpp4 is a membrane protein that binds, without hydrolyzing, phosphatidylserine and its effects are mediated by the receptor s1pr5, although not via the generation of S1P. Finally, we propose a novel and non-catalytic mechanism by which lipidic signalling regulates nephrogenesis

The Use of the S-Quattro Dynamic External Fixator for the Treatment of Intra-Articular Phalangeal Fractures: A Review of the Literature

Intra-articular phalangeal fractures are a common injury. If left untreated, these injuries can lead to poor functional outcome with severe dehabilitating consequences, especially in younger patients

Atomic-scale insights into the tribochemical wear of diamond on quartz surfaces

A detailed understanding of diamond wear is crucial due to its use in high-performance cutting tools. Despite being a much harder material, diamond shows appreciable wear when cutting silicon dioxides due to a tribochemical mechanism. Here, we use nonequilibrium molecular dynamics simulations with a reactive force field to investigate the wear of single-crystal diamond tips sliding on α-quartz surfaces. Atom-by-atom attrition of carbon atoms is initiated by the formation of C-O interfacial bonds, followed by C-C cleavage, and either diffusion into the substrate or further oxidation to form CO2 molecules. Water molecules dissociate to form hydroxyl groups, which passivates the surfaces and reduces interfacial bonding and wear. At low loads, the initial wear rate increases exponentially with temperature and normal stress, consistent with stress-augmented thermally activated wear models. At higher loads, the initial wear rate becomes less sensitive to the normal stress, eventually plateauing towards a constant value. This behaviour can be described using the multibond wear model. After long sliding distances, wear also occurs through cluster detachment via tail fracture. Here, wear becomes approximately proportional to the sliding distance and normal load, consistent with the Archard model. The normalised wear rates from the simulations are within the experimentally-measured range