In Vitro Models of Bacterial Biofilms: Innovative Tools to Improve Understanding and Treatment of Infections

Bacterial infections are a growing concern to the health care systems. Bacteria in the human body are often found embedded in a dense 3D structure, the biofilm, which makes their eradication even more challenging. Indeed, bacteria in biofilm are protected from external hazards and are more prone to develop antibiotic resistance. Moreover, biofilms are highly heterogeneous, with properties dependent on the bacteria species, the anatomic localization, and the nutrient/flow conditions. Therefore, antibiotic screening and testing would strongly benefit from reliable in vitro models of bacterial biofilms. This review article summarizes the main features of biofilms, with particular focus on parameters affecting biofilm composition and mechanical properties. Moreover, a thorough overview of the in vitro biofilm models recently developed is presented, focusing on both traditional and advanced approaches. Static, dynamic, and microcosm models are described, and their main features, advantages, and disadvantages are compared and discussed

Young people’s interaction with natural heritage through outdoor learning

Funded jointly by Scottish Natural Heritage and Learning and Teaching Scotland, this research forms part of a two-year research and development programme entitled Outdoor Connections. A key aim of the programme is to research the current state of outdoor education in Scotland for 3–18-year-olds. Outdoor Connections, in turn, is seeking to understand how outdoor learning can be harnessed to address the aims of the current national curriculum development initiative: A Curriculum for Excellence (hereafter ACfE). The research comes at a time when formal outdoor learning is broadening its scope beyond adventure and field studies activities to include a wider range of activities across the whole curriculum thereby potentially connecting learners with their environment, their community, their society and themselves. The report analyses two sets of data. The first comes from a survey of schools’ and pre-school centres’ provision of formal outdoor learning. The second set of data comes from interviews with young people themselves (ages 3–16) about their outdoor experiences more generally. The report analyses these data to show how different types, durations and locations for outdoor learning provide different kinds of opportunities for interaction with nature and different learning outcomes

Skilful sub-seasonal forecasts of aggregated temperature over Europe

Subseasonal-to-seasonal (S2S) forecasts span the prediction range of weeks to 2–3 months ahead, bridging the gap between medium-range and seasonal weather forecasts. There has been growing interest in S2S forecasts in recent years, largely because of the many potential uses of forecasts spanning these timescales. However, the skill of S2S forecasts beyond the first 2 weeks or so is poor, potentially limiting the usability of these forecasts. We show in this study that when considering accumulated temperatures, there is in fact good forecasting skill over Europe for accumulation periods up to 30 days ahead. Using a set of S2S hindcasts, we show using both a deterministic and a probabilistic measure of skill that the accumulated 2-metre temperature forecasts out to 30 days are skilful over most of Europe. In summer, South West Europe has highest skill, while in winter North East Europe has highest skill. As an exam�ple application of such forecasts, we also evaluate the skill for summer cooling degree-days (CDD) and winter heating degree-days (HDD). For 30-day winter HDD, there is good skill in all four European regions; for 30-day summer CDD, the skill is limited in North West Europe, but still good in other regions

Alternating block copolymer-based nanoparticles as tools to modulate the loading of multiple chemotherapeutics and imaging probes

Abstract Cancer therapy often relies on the combined action of different molecules to overcome drug resistance and enhance patient outcome. Combined strategies relying on molecules with different pharmacokinetics often fail due to the lack of concomitant tumor accumulation and, thus, to the loss of synergistic effect. Due to their ability to enhance treatment efficiency, improve drug pharmacokinetics, and reduce adverse effects, polymer nanoparticles (PNPs) have been widely investigated as co-delivery vehicles for cancer therapies. However, co-encapsulation of different drugs and probes in PNPs requires a flexible polymer platform and a tailored particle design, in which both the bulk and surface properties of the carriers are carefully controlled. In this work, we propose a core-shell PNP design based on a polyurethane (PUR) core and a phospholipid external surface. The modulation of the hydrophilic/hydrophobic balance of the PUR core enhanced the encapsulation of two chemotherapeutics with dramatically different water solubility (Doxorubicin hydrochloride, DOXO and Docetaxel, DCTXL) and of Iron Oxide Nanoparticles for MRI imaging. The outer shell remained unchanged among the platforms, resulting in un-modified cellular uptake and in vivo biodistribution. We demonstrate that the choice of PUR core allowed a high entrapment efficiency of all drugs, superior or comparable to previously reported results, and that higher core hydrophilicity enhances the loading efficiency of the hydrophilic DOXO and the MRI contrast effect. Moreover, we show that changing the PUR core did not alter the surface properties of the carriers, since all particles showed a similar behavior in terms of cell internalization and in vivo biodistribution. We also show that PUR PNPs have high passive tumor accumulation and that they can efficient co-deliver the two drugs to the tumor, reaching an 11-fold higher DOXO/DCTXL ratio in tumor as compared to free drugs. Statement of Significance Exploiting the synergistic action of multiple chemotherapeutics is a promising strategy to improve the outcome of cancer patients, as different agents can simultaneously engage different features of tumor cells and/or their microenvironment. Unfortunately, the choice is limited to drugs with similar pharmacokinetics that can concomitantly accumulate in tumors. To expand the spectrum of agents that can be delivered in combination, we propose a multi-compartmental core-shell nanoparticles approach, in which the core is made of biomaterials with high affinity for drugs of different physical properties. We successfully co-encapsulated Doxorubicin Hydrochloride, Docetaxel, and contrast agents and achieved a significantly higher concomitant accumulation in tumor versus free drugs, demonstrating that nanoparticles can improve synergistic cancer chemotherapy

MicroRNA delivery through nanoparticles

MicroRNAs (miRNAs) are attracting a growing interest in the scientific community due to their central role in the etiology of major diseases. On the other hand, nanoparticle carriers offer unprecedented opportunities for cell specific controlled delivery of miRNAs for therapeutic purposes. This review critically discusses the use of nanoparticles for the delivery of miRNA-based therapeutics in the treatment of cancer and neurodegenerative disorders and for tissue regeneration. A fresh perspective is presented on the design and characterization of nanocarriers to accelerate translation from basic research to clinical application of miRNA-nanoparticles. Main challenges in the engineering of miRNA-loaded nanoparticles are discussed, and key application examples are highlighted to underline their therapeutic potential for effective and personalized medicine

Intelligent policy making? Key actors' perspectives on the development and implementation of a national early years' initiative

Increased political enthusiasm for evidence-based policy and action has re-ignited interest in the use of evidence within political and practitioner networks. Theories of evidence-based policy making and practice are being re-considered in an attempt to better understand the processes through which knowledge translation occurs. Understanding how policy develops, and practice results, has the potential to facilitate effective evidence use. Further knowledge of the factors which shape healthcare delivery and their influence in different contexts is needed.<p></p> This paper explores the processes involved in the development of a complex intervention in Scotland's National Health Service (NHS). It uses a national oral health programme for children (Childsmile) as a case study, drawing upon key actors' perceptions of the influence of different drivers (research evidence, practitioner knowledge and values, policy, and political and local context) to programme development. Framework analysis is used to analyse stakeholder accounts from in-depth interviews. Documentary review is also undertaken.<p></p> Findings suggest that Childsmile can be described as an ‘evidence-informed’ intervention, blending available research evidence with knowledge from practitioner experience and continual learning through evaluation, to plan delivery. The importance of context was underscored, in terms of the need to align with prevailing political ideology and in the facilitative strength of networks within the relatively small public health community in Scotland. Respondents' perceptions support several existing theoretical models of translation, however no single theory offered a comprehensive framework covering all aspects of the complex processes reported. Childsmile's use of best available evidence and on-going contribution to knowledge suggest that the programme is an example of intelligent policy making with international relevance.<p></p&gt

The association of center volume with transplant outcomes in selected high-risk groups in kidney transplantation

BACKGROUND: In context of increasing complexity and risk of deceased kidney donors and transplant recipients, the impact of center volume (CV) on the outcomes of high-risk kidney transplants(KT) has not been well determined. METHODS: We examined the association of CV and outcomes among 285 U.S. transplant centers from 2000-2016. High-risk KT were defined as recipient age ≥ 70 years, body mass index (BMI) ≥ 35 kg/m RESULTS: Two hundred fifty thousand five hundred seventy-four KT were analyzed. Compared to high CV, recipients with BMI ≥ 35 kg/m CONCLUSIONS: Recipients of high-risk KT with BMI ≥ 35 kg/

in vitro microfluidic modelling of the human blood brain barrier microvasculature and testing of nanocarrier transport

The blood-brain barrier (BBB) protects the brain from pathogens but also hinders drug delivery to the central nervous system. Most of the BBB models developed up to date failed to reproduce the human anatomical complexity of brain barriers, contributing to less predictive experimental platforms and poor patient outcomes. To overcome those limitations, the development of reliable in vitro models represents a crucial step towards more effective therapies. This contribution was focused on the development of an in vitro microfluidic model of the BBB able to replicate the human neurovascular organization. The microfluidic model included human induced pluripotent stem cell-derived endothelial cells, brain pericytes, and astrocytes as self-assembled microvascular networks in a 3-dimensional fibrin gel. As previously demonstrated, the BBB model exhibited perfusable and selective microvasculature, with permeability lower than conventional in vitro models and comparable with in vivo rat brain. Permeability of polystyrene nanoparticles (NPs) and synthesized polyurethane NP was measured across the BBB model as compared to conventional Transwell assays. This physiologically relevant BBB model offers an innovative and valuable platform to preclinically predict transport efficacy of drugs and carriers

Strategies to reduce clinical inertia in hypertensive kidney transplant recipients

<p>Abstract</p> <p>Background</p> <p>Many kidney transplant recipients have hypertension. Elevated systolic blood pressures are associated with lower patient and kidney allograft survival.</p> <p>Methods</p> <p>This retrospective analysis examined the prevalence of clinical inertia (failure to initiate or increase therapy) in the treatment of hypertension before and after the introduction of an automated device (BpTRU) in the kidney transplant clinic.</p> <p>Results</p> <p>Historically only 36% (49/134) of patients were prescribed a change in therapy despite a systolic blood pressure ≥ 130 mmHg. After the introduction of BpTRU, 56% (62/110) of the patients had a change in therapy. In a multivariate logistic regression analysis of the entire cohort (n = 244) therapeutic changes were associated with higher blood pressures (OR 1.08 per mmHg, 95% CI 1.04–1.12) and use of the BpTRU (OR 2.12, 95% CI 1.72–3.83). In addition patients on more medications were also more likely to have a change in therapy.</p> <p>Conclusion</p> <p>Blood pressure measurement with automated devices may help reduce clinical inertia in the kidney transplant clinic.</p

Dipping-Induced Azimuthal Helix Orientation in Langmuir-Blodgett Monolayers of α-Helical Amphiphilic Diblock Copolypeptides

The azimuthal helix orientation of the rigid-rod amphiphilic diblock copolypeptides (PLGA-b-PMLGSLGs) of poly(α-L-glutamic acid) (PLGA) and poly(γ-methyl-L-glutamate-ran-γ-stearyl-L-glutamate) with 30 mol % of stearyl substituents (PMLGSLG) in Langmuir-Blodgett (LB) monolayers was investigated using polarized transmission Fourier transform infrared spectroscopy. The relative position of dipping with respect to the previous transfer position can be used to manipulate the azimuthal orientation of the helices parallel to or tilted by an angle of 45° with respect to the dipping direction in the transferred films. The study of the azimuthal order for the LB monolayers of PLGA-b-PMLGSLGs of various block lengths revealed that the observed effect arises mainly from the deformation of the PMLGSLG top brush layer, induced by the flow orientation around the transfer region. In those cases where the PMLGSLG block is tilted by a sufficiently large angle with respect to the surface normal, high azimuthal order parameters of 0.5-0.75 were obtained.