Digital platforms to facilitate physical activities for people with physical or sensory disabilities: A scoping review.

BACKGROUND: People with disabilities (PWD) commonly experience difficulties in accessing their environments, which can lead to restricted participation in outdoor leisure-time physical activity. Participating in outdoor leisure-time physical activity (OLTPA) provides health and social benefits to PWD and benefits to the communities in which they live. OBJECTIVE: The aim of the study was to identify features existing in digital platforms that facilitate access to OLTPA for PWD. METHODS: A scoping review was conducted in four library databases and in Google advance search to identify relevant scientific and grey literature, and websites. Each step of the review was independently conducted by two co-authors who confirmed consensus of results. Descriptive data analyses were performed. RESULTS: Seven scientific studies and ten websites were included in the scoping review. Seven presented mobile apps, nine presented a website and one presented an online database. Sources reported five main obstacles to using digital platforms that support access to physical activities (e.g., lack of digital literacy, technical issues, unintuitive design), and 10 facilitators (e.g., possibility to personalize your online space, accessibility features of the navigation). Among these sources, a trend emerged in the most important factors and features to consider for the visuals and navigation of the platforms. CONCLUSION: The features of digital platforms that facilitate access to OLTPA include intuitive design compliant with accessibility guidelines and supported by navigation tools, personalization of the online space, and features for social interactions.

Automatic detection of skate strokes in short-track speed skating using one single IMU: validation of a new method.

Greater impulse is a key performance indicator of success in short track speed skating. The main objective of this study was to develop a method to measure skating strokes using a single IMU. Eight elite or world-class speed skaters had one IMU placed against their skin on the lower back, and a camera setup was positioned to capture the test. A maximal speed trial was then executed by each participant, and the data were analysed to estimate agreement between the camera and IMU estimates of skate stroke events. Inter-evaluator reliability was assessed on a dataset of 22 athletes performing speed trials as well. The algorithm detected 100% of the strokes identified on the video capture system with a root mean square error of 0.06s. Bland-Altman analysis showed a bias of 0.03s between the two methods, which corresponds to the frame rate of the camera. The inter-evaluator reliability yielded an intra-class correlation of 1.00 (ICC3,1) from a dataset of 7089 strokes. This study provides an example of on-ice evaluation of speed skating strokes using a single IMU. This equipment is less expensive than that employed by previous authors and can be implemented in training situations with low invasiveness.

The persistence of emamectin benzoate in marine sediments with different organic matter regimes, temperature conditions, and antibiotic presence.

The objectives of this 318-day study are to determine half-lives of the anti-sea lice medication emamectin benzoate (EMB) under conditions present in sediments at aquaculture sites and document the degradation of EMB into its main metabolite desmethyl emamectin benzoate (DES). Tested conditions include different matrix types (sand, mud), two temperatures (4, 10 degrees), organic matter presence (fish feed waste and feces), and the presence of oxytetracycline. We document a transformation ratio of EMB to DES of 0.16 to 4.4 % and show that the co-presence of oxytetracycline increases EMB calculated half-lives to values >6000 days for mud matrices. EMB incubated in high organic enrichment regimes was not observed to degrade at 4 degrees. Multivariate analyses show interactions between sediment conditions (matrix, temperature, organic matter [OM], oxytetracycline) influence EMB persistence and DES:EMB ratios. Ranges of EMB half-lives and information on metabolites can be used to anticipate potential effects on marine communities.

Bioaccumulation and metabolic impact of environmental PFAS residue on wild-caught urban wetland tiger snakes (Notechis scutatus).

PFAS contamination of urban waters is widespread but understanding the biological impact of its accumulation is limited to humans and common ecotoxicological model organisms. Here, we combine PFAS exposure and bioaccumulation patterns with whole organism responses and omics-based ecosurveillance methods to investigate the potential impacts of PFAS on a top predator of wetlands, the tiger snake (Notechis scutatus). Tiger snakes (18 male and 17 female) were collected from four wetlands with varying PFAS chemical profiles and concentrations in Perth, Western Australia. Tiger snake livers were tested for 28 known PFAS compounds, and Σ28PFAS in liver tissues ranged between 322 ± 193 µg/kg at the most contaminated site to 1.31 ± 0.86 µg/kg at the least contaminated site. The dominant PFAS compound detected in liver tissues was PFOS. Lower body condition was associated with higher liver PFAS, and male snakes showed signs of high bioaccumulation whereas females showed signs of maternal offloading. Biochemical profiles of snake muscle, fat (adipose tissue), and gonads were analysed using a combination of liquid chromatography triple quadrupole (QqQ) and quadrupole time-of-flight (QToF) mass spectrometry methodologies. Elevated PFAS was associated with enriched energy production and maintenance pathways in the muscle, and had weak associations with energy-related lipids in the fat tissue, and lipids associated with cellular genesis and spermatogenesis in the gonads. These findings demonstrate the bioavailability of urban wetland PFAS in higher-order reptilian predators and suggest a negative impact on snake health and metabolic processes. This research expands on omics-based ecosurveillance tools for informing mechanistic toxicology and contributes to our understanding of the impact of PFAS residue on wildlife health to improve risk management and regulation.

Toxicity and risk management of oil-spiked sediments by diluted bitumen for two freshwater benthic invertebrates.

Diluted bitumen (dilbit) is an unconventional oil produced by the oil sands industry in Canada. Despite the knowledge available on hydrocarbon toxicity, the effects of diluted bitumen on benthic organisms are still largely unknown. Moreover, in Quebec there are only provisional threshold values of 164 mg/kg C10-C50 for chronic effects and 832 mg/kg for acute effects. The protectiveness of these values for benthic invertebrates has not been tested for heavy unconventional oils such as dilbit. Two benthic organisms, the larvae of Chironomus riparius and Hyalella azteca, were exposed to these two concentrations and to an intermediate concentration (416 mg/kg) of two dilbits (DB1 and DB2) and a heavy conventional oil (CO). The aim of the study was to assess the sublethal and lethal effects of spiked sediment by dilbit. The oil was rapidly degraded in the sediment, especially in the presence of C. riparius. Amphipods were much more sensitive to oil than chironomids. LC50-14d values for H. azteca were 199 mg/kg C10-C50 for DB1, 299 mg/kg for DB2 and 8.42 mg/kg for CO compared to LC50-7d values for C. riparius of 492 mg/kg for DB1, 563 mg/kg for DB2 and 514 mg/kg for CO. The size of the organisms was reduced compared to controls for both species. The defense enzymes (GST, GPx, SOD and CAT) were not good biomarkers in these two organisms for this type of contamination. The current provisional sediment quality criteria seem too permissive for heavy oils and should be lowered.

Metabolization of emamectin benzoate into desmethyl emamectin benzoate in spiked marine sediments.

Emamectin benzoate (EMB) (4″deoxy- 4″-epi-methylaminoavermectin) is a pesticide developed to control pests on various crops, and in forestry. It is also used in salmon aquaculture to control sea lice infestations as an in-feed therapeutant. Little is known about EMB metabolites and potential associated toxicities in marine sediments. In this study, we used natural marine sediments (sand and mud) fortified at an EMB concentration of 60 ppb (wet weight). Results show an almost immediate transformation of EMB to Desmethyl EMB (DES) with no increased rates of metabolization when stored sediment samples were incubated for up to 16 h. The transformation ratio of EMB to DES represented between 0.16 and 0.39% of EMB; values are lower than what has been observed in fish tissue. Data suggest that DES is generated through both abiotic (tested after autoclaving marine sediments) and biological processes. Further work on freshly sampled marine sediments with EMB deposits, different organic regimes, and a detailed assessment of active bacterial communities are necessary to better evaluate the EMB to DES rate of transformation around aquaculture sites.

Barriers and facilitators of public transport use among people with disabilities: a scoping review.

Barriers to public transport use may be experienced differently by people with various types of disabilities (e.g., physical, intellectual, cognitive, sensory). Thus, it is important to identify the variable needs within each element of the travel chain. For example, the unavailability or low volume of auditory announcements in a stop or station or on the public transport vehicle may be a barrier to people with visual disability who rely on hearing the information. Consequently, this could provoke negative emotions and unpleasant experiences, which may not be the case for people with physical disabilities. The primary objective was to describe the barriers and facilitators to using public transport experienced by people with disabilities (PWD). The secondary aim was to explore experiences in terms of self-efficacy and satisfaction, when using public transport among people with disabilities. A scoping review was conducted. The search was performed in MEDLINE, TRANSPORT DATABASE, PsycINFO, EMBASE, and WEB OF SCIENCE from 1995 to 2023. Of 6,820 citations identified, 34 articles were included in the review for extraction. The main physical and social barriers included lack of ramp, long walking distance, long waiting time, unavailability of information at bus stop or station, and drivers' negative attitudes towards PWD. Personal factors that prevented the use of public transport included lack of confidence, and decreased satisfaction with public transport use. Strategies such as providing ramps on public transport vehicles, availability of kneeling buses and courtesy of bus drivers, and travel training were considered as enablers to the use of public transport that can lead the improved self-efficacy and satisfaction. In conclusion, this review identified the physical and social barriers and facilitators in travel chain, and highlighted issues related to lack of confidence or self-efficacy and decreased satisfaction when PWD and older adults are using public transport. Identifying and understanding the barriers and facilitators to the use of public transport by PWD is a milestone that may help policy makers and transport operators around the world to develop and implement interventions enabling access, use and inclusion of this mode of transport, as the experiences of PWD when using this mode of transport have an impact on their well-being.

Technology implementation in care practices for community-dwelling older adults with mild cognitive decline: Perspectives of professional caregivers in Quebec and Brussels.

Objective: As worldwide population aging is accelerating, innovative technologies are being developed to support independent living among community-dwelling older adults with mild cognitive decline. However, the successful implementation of these interventions is often challenging. Until now, literature on implementation issues related to the specific context of older adults with mild cognitive decline is lacking and the few studies available do not focus specifically on the perspective of professional caregivers. Yet the perspective of these caregivers is important as they can be considered a key facilitator for technology implementation among this population. Therefore, this study was the first to examine technology implementation among community-dwelling older adults with mild cognitive decline from the broader perspective of professional caregivers. Methods: In this qualitative study, two focus groups consisting of a heterogeneous pool of professional caregivers were conducted: one in Quebec (Canada, n = 6) and one in Brussels (Belgium, n = 8). Braun and Clarke' method for thematic analysis, guided by a qualitative descriptive approach was applied to inductively identify themes from the data. Results: We identified factors influencing technology implementation in older adults with mild cognitive decline on three levels: an individual level (e.g., characteristics of older adults with mild cognitive decline and professional caregivers' attitude), an organizational level (e.g., lack of training among professional caregivers) and a level referring to the broader context (e.g., ethical considerations). Conclusions: This study contributes to the research gap in knowledge on the needs of professional caregivers to facilitate technology implementation among the population of older adults with cognitive decline. Future directions for research, practice, and policy are given, more specifically to improve knowledge among caregivers and on the development of decision support to retrieve safe and effective technologies that suit patient-centered care.

Snake scales record environmental metal(loid) contamination.

Wetland snakes, as top predators, are becoming globally recognised as bioindicators of wetland contamination. Livers are the traditional test organ for contaminant exposure in organisms, but research is moving towards a preference for non-lethal tissue sampling. Snake scales can be used as an indicator of exposure, as many metals bind to the keratin. We used laser ablation with inductively coupled plasma-atomic emission spectroscopy and mass spectrometry (LA-ICP-MS) to quantify the concentrations of 19 metals and metalloids (collectively referred to 'metals' hereafter) in Western tiger snake (Notechis scutatus occidentalis) scales from four wetlands along an urban gradient, and compared them to concentrations measured in captive tiger snake scales. We conducted repeat measures to determine the concentration accuracy of each metal using LA-ICP-MS. Concentrations in wild Western tiger snake scales were significantly higher than in reference tiger snake scales for most metals analysed, suggesting accumulation from environmental exposure. We compared the scale concentrations to sediment concentrations of sampled wetlands, and found inter-site differences between mean concentrations of metals in scales parallel patterns recorded from sediment. Four metals (Mn, As, Se, Sb) had strong positive correlations with liver tissue contents suggesting scale concentrations can be used to infer internal concentrations. By screening for a larger suite of metals than we could using traditional digestive methods, we identified additional metals (Ti, V, Sr, Cs, Tl, Th, U) that may be accumulating to levels of concern in tiger snakes in Perth, Western Australia. This research has progressed the use of LA-ICP-MS for quantifying a suite of metals available in snake scales, and highlights the significance of using wetland snake scales as a non-lethal indicator of environmental contamination.

The targeting of preschoolers, children, adolescents and adults by the Canadian food and beverage industry on television: a cross-sectional study.

Unhealthy food advertising can negatively impact children's food preferences and nutritional health. In Canada, only companies participating in the self-regulatory Children's Food and Beverage Advertising Initiative (CAI) commit to limiting unhealthy food advertising to children. We analyzed food advertising from 182 Canadian television stations in 2018. A principal component analysis explored patterns of advertising by 497 food companies and their targeting of preschoolers, children, adolescents, and adults. Chi-square analyses tested differences in the volume of advertising between target age groups by heavily advertising food companies and by CAI-participating and non-participating companies. In 2018, Maple Leaf Foods, Boulangerie St-Méthode, Exceldor Foods, Goodfood Market and Sobeys advertised most frequently during preschooler-programming. General Mills, Kellogg's, the Topps Company, Parmalat and Post Foods advertised most frequently during child-programming, while Burger King, McDonald's, General Mills, Kellogg's and Wendy's advertised most frequently during adolescent-programming. CAI-participating companies were responsible for over half of the food advertising broadcast during programs targeted to children (55%), while they accounted for less than half of the food advertising aired during programs targeting preschoolers (24%), adolescents (41%) and adults (42%). Statutory food advertising restrictions are needed to limit food companies' targeting of young people on television in Canada. Novelty: Advertising from fast food restaurant chains dominated television programming targeted to adolescents in 2018. Advertising from breakfast cereal, candy, and snack manufacturers dominated television programming targeted at children in 2018. Over 100 Canadian and transnational companies contravened broadcast restrictions on advertising to preschoolers in 2018.

[Beyond benefit evaluation: Considering the unintended consequences of telehealth]. / Au-delà de l'évaluation des bénéfices : réflexion sur les conséquences inattendues de la télésanté.

Telehealth is seen as a key lever in health policy choices. However, many challenges remain in terms of its successful integration into clinical practices. To date, many telehealth initiatives are struggling to move beyond the pilot project stage. This is partly due to a culture of innovation that is mainly focused on the expected benefits of the technology and less on the changes and transformations it can generate. Telehealth is used in health care organizations with complex social dynamics, to say the least. Its introduction has unintended consequences that can affect patients, communities, professionals, organizations, health systems and society as a whole. The aim of this article is to discuss some of the unintended consequences of using telehealth in health care organizations and systems.

The Broad-Scale Analysis of Metals, Trace Elements, Organochlorine Pesticides and Polycyclic Aromatic Hydrocarbons in Wetlands Along an Urban Gradient, and the Use of a High Trophic Snake as a Bioindicator.

Wetlands and their biodiversity are constantly threatened by contaminant pollution from urbanisation. Despite evidence suggesting that snakes are good bioindicators of environmental health, the bioaccumulation of contaminants in reptiles is poorly researched in Australia. We conducted the first broad-scale analysis of 17 metals and trace elements, 21 organochlorine pesticides, and 14 polycyclic aromatic hydrocarbons in the sediments (4 samples per site, December 2018) from four wetlands along an urban gradient in Perth, Western Australia, and from the livers (5 livers per site, February-April 2019) of western tiger snakes Notechis scutatus occidentalis captured at those sites. All 17 metals and trace elements were detected in the sediments of wetlands as well as 16 in the livers of tiger snakes. Arsenic, Cu, Hg, Pb, Se, and Zn were at concentrations exceeding government trigger values in at least one sediment sample. Two organochlorine pesticides and six of seven polycyclic aromatic hydrocarbons were detected in the sediments of a single wetland, all exceeding government trigger values, but were not detected in tiger snakes. Metals and trace elements were generally in higher concentration in sediments and snake livers from more heavily urbanised wetlands. The least urbanised site had some higher concentrations of metals and trace elements, possibly due to agriculture contaminated groundwater. Concentrations of nine metals and trace elements in snake livers were statistically different between sites. Arsenic, Cd, Co, Hg, Mo, Sb, and Se near paralleled the pattern of contamination measured in the wetland sediments; this supports the use of high trophic wetland snakes, such as tiger snakes, as bioindicators of wetland contamination. Contamination sources and impacts on these wetland ecosystems and tiger snakes are discussed herein.

Sociocultural determinants of nomadic women's utilization of assisted childbirth in Gossi, Mali: a qualitative study.

BACKGROUND: In sub-Saharan Africa (SSA), nomads account for 30 to 60 million people. Their mobility, due to a constant search for pastures and water points, makes health services less accessible to them. Few nomadic women use assisted delivery, which increases the risk of maternal mortality. The reasons behind this limited use have been poorly documented. The objective of this study was to understand the sociocultural determinants of assisted childbirth by nomadic women. METHODS: We conducted a qualitative research in the health area of Gossi (Mali), mainly populated by nomads. Data were collected through a literature review, 26 semi-structured interviews, a non-participant observation, and a logbook. Nomadic women who gave birth in the past three months were included in the study, whether they used assisted delivery or not. A thematic content analysis was performed with QDA Miner software. RESULTS: The study identified a complex combination of determinants resulting in the use or non-use of assisted childbirth by the nomads of Gossi. Several participants recognized the value of assisted delivery but gave birth at home. They identified sociocultural determinants related to their representations and bodily experiences; the risks and emotions (fear, stress, anxiety) associated with pregnancy; the onset of labor and delivery; and their weak autonomy in terms of movement, decision-making, and economic agency. Nomadic women are not free in their movements, and in order to seek care, they require the permission and support of a man (husband, brother, or father). Furthermore, the participants are housewives, and men control family resources and make decisions regarding all financial matters. Assisted delivery is often only considered when there are complications. CONCLUSION: This research has made it possible to understand the sociocultural determinants of the use of assisted childbirth among nomadic women, which should be taken into account when organizing health services for these populations.

Exploring factors associated with the uneven utilization of telemedicine in Norway: a mixed methods study.

BACKGROUND: Norway has a long history of using telemedicine, especially for geographical reasons. Despite the availability of promising telemedicine applications and the implementation of national initiatives and policies, the sustainability and scaling-up of telemedicine in the health system is still far from accomplished. The main objective of this study was to explore and identify the multi-level (micro, meso and macro) factors affecting telemedicine utilization in Norway. METHODS: We used a mixed methods approach. Data from a national registry were collected to analyze the use of outpatient visits and telemedicine contacts in Norway from 2009 to 2015. Interviews with key stakeholders at national, regional and local level helped complete and contextualize the data analysis and explore the main issues affecting the use of telemedicine by health authorities and hospitals. Relevant national documents were also used to support, contradict, contextualize or clarify information and data. RESULTS: Telemedicine use in Norway from 2009 to 2015 remained very low, not exceeding 0.5% of total outpatient activity at regional level and 0.1% at national level. All four regions used telemedicine. Of the 29 hospitals, 24 used it at least once over the 7-year period. Telemedicine was not used regularly everywhere, with some hospitals using it sporadically. Telemedicine was mostly used in selected specialties, including rehabilitation, neurosurgery, skin and venereal diseases. Three major themes affecting implementation and utilization of telemedicine in Norway emerged: (i) governance and strategy; (ii) organizational and professional dimensions; (iii) economic and financial dimensions. For each theme, a number of factors and challenges faced at different health care levels were identified. CONCLUSIONS: This study allowed shedding light on multi-level and interdependent factors affecting utilization of telemedicine in Norway. The identification of the main implementation and utilization challenges might support decision makers and practitioners in the successful scaling-up of telemedicine. This work provides a knowledge base useful to other countries which intend to implement telemedicine or other digital health services into their healthcare systems.

In vitro characterization and in vivo ultrasound molecular imaging of nucleolin-targeted microbubbles.

Nucleolin (NCL) plays an important role in tumor vascular development. An increased endothelial expression level of NCL has been related to cancer aggressiveness and prognosis and has been detected clinically in advanced tumors. Here, with a peptide targeted to NCL (F3 peptide), we created an NCL-targeted microbubble (MB) and compared the performance of F3-conjugated MBs with non-targeted (NT) MBs both in vitro and in vivo. In an in vitro study, F3-conjugated MBs bound 433 times more than NT MBs to an NCL-expressing cell line, while pretreating cells with 0.5 mM free F3 peptide reduced the binding of F3-conjugated MBs by 84%, n = 4, p < 0.001. We then set out to create a method to extract both the tumor wash-in and wash-out kinetics and tumor accumulation following a single injection of targeted MBs. In order to accomplish this, a series of ultrasound frames (a clip) was recorded at the time of injection and subsequent time points. Each pixel within this clip was analyzed for the minimum intensity projection (MinIP) and average intensity projection (AvgIP). We found that the MinIP robustly demonstrates enhanced accumulation of F3-conjugated MBs over the range of tumor diameters evaluated here (2-8 mm), and the difference between the AvgIP and the MinIP quantifies inflow and kinetics. The inflow and clearance were similar for unbound F3-conjugated MBs, control (non-targeted) and scrambled control agents. Targeted agent accumulation was confirmed by a high amplitude pulse and by a two-dimensional Fourier Transform technique. In summary, F3-conjugated MBs provide a new imaging agent for ultrasound molecular imaging of cancer vasculature, and we have validated metrics to assess performance using low mechanical index strategies that have potential for use in human molecular imaging studies.

Design and structure-activity relationships of novel inhibitors of human rhinovirus 3C protease.

Human rhinovirus (HRV) is a primary cause of common cold and is linked to exacerbation of underlying respiratory diseases such as asthma and COPD. HRV 3C protease, which is responsible for cleavage of viral polyprotein in to proteins essential for viral life-cycle, represents an important target. We have designed proline- and azetidine-based analogues of Rupintrivir that target the P2 pocket of the binding site. Potency optimization, aided with X-ray crystallography and quantum mechanical calculations, led to compounds with activity against a broad spectrum of HRV serotypes. Altogether, these compounds represent alternative starting points to identify promising leads in our continual efforts to treat HRV infections.

Integrating Multiple Biomarkers of Fish Health: A Case Study of Fish Health in Ports.

Biomarkers of fish health are recognised as valuable biomonitoring tools that inform on the impact of pollution on biota. The integration of a suite of biomarkers in a statistical analysis that better illustrates the effects of exposure to xenobiotics on living organisms is most informative; however, most published ecotoxicological studies base the interpretation of results on individual biomarkers rather than on the information they carry as a set. To compare the interpretation of results from individual biomarkers with an interpretation based on multivariate analysis, a case study was selected where fish health was examined in two species of fish captured in two ports located in Western Australia. The suite of variables selected included chemical analysis of white muscle, body condition index, liver somatic index (LSI), hepatic ethoxyresorufin-O-deethylase activity, serum sorbitol dehydrogenase activity, biliary polycyclic aromatic hydrocarbon metabolites, oxidative DNA damage as measured by serum 8-oxo-dG, and stress protein HSP70 measured on gill tissue. Statistical analysis of individual biomarkers suggested little consistent evidence of the effects of contaminants on fish health. However, when biomarkers were integrated as a set by principal component analysis, there was evidence that the health status of fish in Fremantle port was compromised mainly due to increased LSI and greater oxidative DNA damage in fish captured within the port area relative to fish captured at a remote site. The conclusions achieved using the integrated set of biomarkers show the importance of viewing biomarkers of fish health as a set of variables rather than as isolated biomarkers of fish health.

Determinants of Physicians' Intention to Collect Data Exhaustively in Registries: an Exploratory Study in Bamako's Community Health Centres.

BACKGROUND: The incomplete collection of health data is a prevalent problem in healthcare systems around the world, especially in developing countries. Missing data hinders progress in population health and perpetuates inefficiencies in healthcare systems. OBJECTIVE: This study aims to identify the factors that predict the intention of physicians practicing in community health centres of Bamako, Mali, to collect data exhaustively in medical registries. DESIGN: A cross sectional study. METHOD: In January and February 2011, we conducted a study with a random sample of thirty two physicians practicing in community health centres of Bamako, using a questionnaire. Data was analyzed by using descriptive statistics, correlations and linear regression. MAIN OUTCOMES MEASURES: Trained investigators administered a questionnaire measuring physicians' sociodemographic and professional characteristics as well as constructs from the Theory of Planned Behaviour. RESULTS: Our results showed that physicians' intention to collect data exhaustively is influenced by subjective norms and by the physician's number of years in practice. CONCLUSIONS: the results of this study could be used as a guide for health workers and decision makers to improve the quality of health information collected in community health centers.

Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE(-/-) Mice.

The current study presents an effective and selective multifunctional nanoparticle used to deliver antiatherogenic therapeutics to inflamed pro-atherogenic regions without off-target changes in gene expression or particle-induced toxicities. MicroRNAs (miRNAs) regulate gene expression, playing a critical role in biology and disease including atherosclerosis. While anti-miRNA are emerging as therapeutics, numerous challenges remain due to their potential off-target effects, and therefore the development of carriers for selective delivery to diseased sites is important. Yet, co-optimization of multifunctional nanoparticles with high loading efficiency, a hidden cationic domain to facilitate lysosomal escape and a dense, stable incorporation of targeting moieties is challenging. Here, we create coated, cationic lipoparticles (CCLs), containing anti-miR-712 (∼1400 molecules, >95% loading efficiency) within the core and with a neutral coating, decorated with 5 mol % of peptide (VHPK) to target vascular cell adhesion molecule 1 (VCAM1). Optical imaging validated disease-specific accumulation as anti-miR-712 was efficiently delivered to inflamed mouse aortic endothelial cells in vitro and in vivo. As with the naked anti-miR-712, the delivery of VHPK-CCL-anti-miR-712 effectively downregulated the d-flow induced expression of miR-712 and also rescued the expression of its target genes tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) in the endothelium, resulting in inhibition of metalloproteinase activity. Moreover, an 80% lower dose of VHPK-CCL-anti-miR-712 (1 mg/kg dose given twice a week), as compared with naked anti-miR-712, prevented atheroma formation in a mouse model of atherosclerosis. While delivery of naked anti-miR-712 alters expression in multiple organs, miR-712 expression in nontargeted organs was unchanged following VHPK-CCL-anti-miR-712 delivery.

Accumulation, internalization and therapeutic efficacy of neuropilin-1-targeted liposomes.

Advancements in liposomal drug delivery have produced long circulating and very stable drug formulations. These formulations minimize systemic exposure; however, unfortunately, therapeutic efficacy has remained limited due to the slow diffusion of liposomal particles within the tumor and limited release or uptake of the encapsulated drug. Here, the carboxyl-terminated CRPPR peptide, with affinity for the receptor neuropilin-1 (NRP), which is expressed on both endothelial and cancer cells, was conjugated to liposomes to enhance the tumor accumulation. Using a pH sensitive probe, liposomes were optimized for specific NRP binding and subsequent cellular internalization using in vitro cellular assays. Liposomes conjugated with the carboxyl-terminated CRPPR peptide (termed C-LPP liposomes) bound to the NRP-positive primary prostatic carcinoma cell line (PPC-1) but did not bind to the NRP-negative PC-3 cell line, and binding was observed with liposomal peptide concentrations as low as 0.16mol%. Binding of the C-LPP liposomes was receptor-limited, with saturation observed at high liposome concentrations. The identical peptide sequence bearing an amide terminus did not bind specifically, accumulating only with a high (2.5mol%) peptide concentration and adhering equally to NRP positive and negative cell lines. The binding of C-LPP liposomes conjugated with 0.63mol% of the peptide was 83-fold greater than liposomes conjugated with the amide version of the peptide. Cellular internalization was also enhanced with C-LPP liposomes, with 80% internalized following 3h incubation. Additionally, fluorescence in the blood pool (~40% of the injected dose) was similar for liposomes conjugated with 0.63mol% of carboxyl-terminated peptide and non-targeted liposomes at 24h after injection, indicating stable circulation. Prior to doxorubicin treatment, in vivo tumor accumulation and vascular targeting were increased for peptide-conjugated liposomes compared to non-targeted liposomes based on confocal imaging of a fluorescent cargo, and the availability of the vascular receptor was confirmed with ultrasound molecular imaging. Finally, over a 4-week course of therapy, tumor knockdown resulting from doxorubicin-loaded, C-LPP liposomes was similar to non-targeted liposomes in syngeneic tumor-bearing FVB mice and C-LPP liposomes reduced doxorubicin accumulation in the skin and heart and eliminated skin toxicity. Taken together, our results demonstrate that a carboxyl-terminated RXXR peptide sequence, conjugated to liposomes at a concentration of 0.63mol%, retains long circulation but enhances binding and internalization, and reduces toxicity.