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Palliative care patients often present to the emergency department (ED) for various reasons e.g., acute illness, pain, altered mental status, and complications of therapy. Many visits involve less severe etiologies e.g., dyspnea, constipation, fear as patients approach the end of life, which may be more effectively and efficiently managed outside of the ED. The objective of this study is to identify and assess the frequency of presenting complaints, primary diagnosis, triage acuity, need for admission, in an Irish setting. A single-center retrospective, observational study of palliative care patients presenting to a tertiary-care university hospital emergency department in Dublin, Ireland. Study subjects were identified using the palliative care database and cross-referencing with the ED electronic patient record system database. The primary objective to identify potential areas to minimize ED visits and improve patient care and quality of life by elucidating reasons for visits. Outcome measures include presenting complaint, primary diagnosis, triage severity score, admission, discharge, death in hospital. Statistical analysis presented as descriptive statistics. Four-hundred-ninety-nine ED visits, 245 (49%) were male, and 254 (51%) were female with a mean age of 69.3 years-of-age. Most patients, 285 (57.1%) self-referred to the emergency department, with general practitioners and skilled nursing facility referrals 72 (14.4%) and 39 (7.8%), respectively. Primary diagnoses were various cancers, chronic obstructive pulmonary disease, congestive heart failure, and dementia. Major reasons for visits were dyspnea, pain, falls, trauma, fever, and altered mental status. Two-hundred-eighty-nine patients (58%) had an emergency severity index (ESI) score of 1 or 2 demonstrating a higher level of acuity. Three-hundred-fifty-eight (71.7%) were admitted, 141 (28.3%) discharged to home, 64 (12.8%) admitted patients died during their hospital admission. Palliative care patients utilize ED services not uncommonly. Though many of these patients presented with higher acuity triage scores, 42% had lower ESI scores and may be effectively managed outside of the ED. These data suggest developing mechanisms for these patients to be urgently evaluated in their homes or facilities obviating the need for an ED evaluation. [ABSTRACT FROM AUTHOR]

Since the recent observation that immune cells undergo metabolic reprogramming upon activation, there has been immense research in this area to not only understand the basis of such changes, but also to exploit metabolic rewiring for therapeutic benefit. In a resting state, macrophages preferentially utilise oxidative phosphorylation to generate energy; however, in the presence of immune cell activators, glycolytic genes are upregulated, and energy is generated through glycolysis. This facilitates the rapid production of biosynthetic intermediates and a pro-inflammatory macrophage phenotype. While this is essential to mount responses to infectious agents, more evidence is accumulating linking dysregulated metabolism to inappropriate immune responses. Given that certain biomaterials are known to promote an inflammatory macrophage phenotype, this prompted us to investigate if biomaterial particulates can impact on macrophage metabolism. Using micron and nano sized hydroxyapatite (HA), we demonstrate for the first time that these biomaterials can indeed drive changes in metabolism, and that this occurs in a size-dependent manner. We show that micronHA, but not nanoHA, particles upregulate surrogate markets of glycolysis including the glucose transporter (GLUT1), hexokinase 2 (HK2), GAPDH, and PKM2. Furthermore, we demonstrate that micronHA alters mitochondrial morphology and promotes a bioenergetic shift to favour glycolysis. Finally, we demonstrate that glycolytic gene expression is dependent on particle uptake and that targeting glycolysis attenuates the pro-inflammatory profile of micronHA-treated macrophages. These results not only further our understanding of biomaterial-based macrophage activation, but also implicate immunometabolism as a new area for consideration in intelligent biomaterial design and therapeutic targeting. Several recent studies have reported that immune cell activation occurs concurrently with metabolic reprogramming. Furthermore, metabolic reprogramming of innate immune cells plays a prominent role in determining cellular phenotype and function. In this study we demonstrate that hydroxyapatite particle size alters macrophage metabolism, in turn driving their functional phenotype. Specifically, the pro-inflammatory phenotype promoted by micron-sized HA-particles is accompanied by changes in mitochondrial dynamics and a bioenergetic shift favouring glycolysis. This effect is not seen with nano-HA particles and can be attenuated upon inhibition of glycolysis. This study therefore not only identifies immunometabolism as a useful tool for characterising the immune response to biomaterials, but also highlights immunometabolism as a targetable aspect of the host response for therapeutic benefit. [Display omitted] [ABSTRACT FROM AUTHOR]

The meniscus is characterised by an anisotropic collagen fibre network which is integral to its biomechanical functionality. The engineering of structurally organized meniscal grafts that mimic the anisotropy of the native tissue remains a significant challenge. In this study, inkjet bioprinting was used to deposit a cell-laden bioink into additively manufactured scaffolds of differing architectures to engineer fibrocartilage grafts with user defined collagen architectures. Polymeric scaffolds consisting of guiding fibre networks with varying aspect ratios (1:1; 1:4; 1:16) were produced using either fused deposition modelling (FDM) or melt electrowriting (MEW), resulting in scaffolds with different internal architectures and fibre diameters. Scaffold architecture was found to influence the spatial organization of the collagen network laid down by the jetted cells, with higher aspect ratios (1:4 and 1:16) supporting the formation of structurally anisotropic tissues. The MEW scaffolds supported the development of a fibrocartilaginous tissue with compressive mechanical properties similar to that of native meniscus, while the anisotropic tensile properties of these constructs could be tuned by altering the fibre network aspect ratio. This MEW framework was then used to generate scaffolds with spatially distinct fibre patterns, which in turn supported the development of heterogenous tissues consisting of isotropic and anisotropic collagen networks. Such bioprinted tissues could potentially form the basis of new treatment options for damaged and diseased meniscal tissue. This study describes a multiple tool biofabrication strategy which enables the engineering of spatially organized fibrocartilage tissues. The architecture of MEW scaffolds can be tailored to not only modulate the directionality of the collagen fibres laid down by cells, but also to tune the anisotropic tensile mechanical properties of the resulting constructs, thereby enabling the engineering of biomimetic meniscal-like tissues. Furthermore, the inherent flexibility of MEW enables the development of zonally defined and potentially patient-specific implants. [Display omitted] [ABSTRACT FROM AUTHOR]

Damaged or diseased bone can be treated using autografts or a range of different bone grafting biomaterials, however limitations with such approaches has motivated increased interest in developmentally inspired bone tissue engineering (BTE) strategies that seek to recapitulate the process of endochondral ossification (EO) as a means of regenerating critically sized defects. The clinical translation of such strategies will require the engineering of scaled-up, geometrically defined hypertrophic cartilage grafts that can be rapidly vascularised and remodelled into bone in mechanically challenging defect environments. The goal of this study was to 3D bioprint mechanically reinforced cartilaginous templates and to assess their capacity to regenerate critically sized femoral bone defects. Human mesenchymal stem/stromal cells (hMSCs) were incorporated into fibrin based bioinks and bioprinted into polycaprolactone (PCL) frameworks to produce mechanically reinforced constructs. Chondrogenic priming of such hMSC laden constructs was required to support robust vascularisation and graft mineralisation in vivo following their subcutaneous implantation into nude mice. With a view towards maximising their potential to support endochondral bone regeneration, we next explored different in vitro culture regimes to produce chondrogenic and early hypertrophic engineered grafts. Following their implantation into femoral bone defects within transiently immunosuppressed rats, such bioprinted constructs were rapidly remodelled into bone in vivo , with early hypertrophic constructs supporting higher levels of vascularisation and bone formation compared to the chondrogenic constructs. Such early hypertrophic bioprinted constructs also supported higher levels of vascularisation and spatially distinct patterns of new formation compared to BMP-2 loaded collagen scaffolds (here used as a positive control). In conclusion, this study demonstrates that fibrin based bioinks support chondrogenesis of hMSCs in vitro , which enables the bioprinting of mechanically reinforced hypertrophic cartilaginous templates capable of supporting large bone defect regeneration. These results support the use of 3D bioprinting as a strategy to scale-up the engineering of developmentally inspired templates for BTE. Despite the promise of developmentally inspired tissue engineering strategies for bone regeneration, there are still challenges that need to be addressed to enable clinical translation. This work reports the development and assessment (in vitro and in vivo) of a 3D bioprinting strategy to engineer mechanically-reinforced cartilaginous templates for large bone defect regeneration using human MSCs. Using distinct in vitro priming protocols, it was possible to generate cartilage grafts with altered phenotypes. More hypertrophic grafts, engineered in vitro using TGF-β3 and BMP-2, supported higher levels of blood vessel infiltration and accelerated bone regeneration in vivo. This study also identifies some of the advantages and disadvantages of such endochondral bone TE strategies over the direct delivery of BMP-2 from collagen-based scaffolds. [Display omitted] [ABSTRACT FROM AUTHOR]

Successfully replacing damaged cartilage with tissue-engineered constructs requires integration with the host tissue and could benefit from leveraging the native tissue's intrinsic healing capacity; however, efforts are limited by a poor understanding of how cartilage repairs minor defects. Here, we investigated the conditions that foster natural cartilage tissue repair to identify strategies that might be exploited to enhance the integration of engineered/grafted cartilage with host tissue. We damaged porcine articular cartilage explants and using a combination of pulsed SILAC-based proteomics, ultrastructural imaging, and catabolic enzyme blocking strategies reveal that integration of damaged cartilage surfaces is not driven by neo-matrix synthesis, but rather local depletion of proteoglycans. ADAMTS4 expression and activity are upregulated in injured cartilage explants, but integration could be reduced by inhibiting metalloproteinase activity with TIMP3. These observations suggest that catabolic enzyme-mediated proteoglycan depletion likely allows existing collagen fibrils to undergo cross-linking, fibrillogenesis, or entanglement, driving integration. Catabolic enzymes are often considered pathophysiological markers of osteoarthritis. Our findings suggest that damage-induced upregulation of metalloproteinase activity may be a part of a healing response that tips towards tissue destruction under pathological conditions and in osteoarthritis, but could also be harnessed in tissue engineering strategies to mediate repair. Cartilage tissue engineering strategies require graft integration with the surrounding tissue; however, how the native tissue repairs minor injuries is poorly understood. We applied pulsed SILAC-based proteomics, ultrastructural imaging, and catabolic enzyme blocking strategies to a porcine cartilage explant model and found that integration of damaged cartilage surfaces is driven by catabolic enzyme-mediated local depletion of proteoglycans. Although catabolic enzymes have been implicated in cartilage destruction in osteoarthritis, our findings suggest that damage-induced upregulation of metalloproteinase activity may be a part of a healing response that tips towards tissue destruction under pathological conditions. They also suggest that this natural cartilage tissue repair process could be harnessed in tissue engineering strategies to enhance the integration of engineered cartilage with host tissue. [Display omitted] [ABSTRACT FROM AUTHOR]

While some clinical advances in cartilage repair have occurred, osteochondral (OC) defect repair remains a significant challenge, with current scaffold-based approaches failing to recapitulate the complex, hierarchical structure of native articular cartilage (AC). To address this need, we fabricated bilayered extracellular matrix (ECM)-derived scaffolds with aligned pore architectures. By modifying the freeze-drying kinetics and controlling the direction of heat transfer during freezing, it was possible to produce anisotropic scaffolds with larger pores which supported homogenous cellular infiltration and improved sulfated glycosaminoglycan deposition. Neo-tissue organization in vitro could also be controlled by altering scaffold pore architecture, with collagen fibres aligning parallel to the long-axis of the pores within scaffolds containing aligned pore networks. Furthermore, we used in vitro and in vivo assays to demonstrate that AC and bone ECM derived scaffolds could preferentially direct the differentiation of mesenchymal stromal cells (MSCs) towards either a chondrogenic or osteogenic lineage respectively, enabling the development of bilayered ECM scaffolds capable of spatially supporting unique tissue phenotypes. Finally, we implanted these scaffolds into a large animal model of OC defect repair. After 6 months in vivo , scaffold implantation was found to improve cartilage matrix deposition, with collagen fibres preferentially aligning parallel to the long axis of the scaffold pores, resulting in a repair tissue that structurally and compositionally was more hyaline-like in nature. These results demonstrate how scaffold architecture and composition can be spatially modulated to direct the regeneration of complex interfaces such as the osteochondral unit, enabling their use as cell-free, off-the-shelf implants for joint regeneration. The architecture of the extracellular matrix, while integral to tissue function, is often neglected in the design and evaluation of regenerative biomaterials. In this study we developed a bilayered scaffold for osteochondral defect repair consisting of tissue-specific extracellular matrix (ECM)-derived biomaterials to spatially direct stem/progenitor cell differentiation, with a tailored pore microarchitecture to promote the development of a repair tissue that recapitulates the hierarchical structure of native AC. The use of this bilayered scaffold resulted in improved tissue repair outcomes in a large animal model, specifically the ability to guide neo-tissue organization and therefore recapitulate key aspects of the zonal structure of native articular cartilage. These bilayer scaffolds have the potential to become a new therapeutic option for osteochondral defect repair. [Display omitted] [ABSTRACT FROM AUTHOR]

Tissue healing and regeneration is a complex, choreographed, spatiotemporal process involving a plethora of cell types, the activity of which is stringently regulated in order for effective tissue repair to ensue post injury. A number of globally prevalent conditions such as heart disease, organ failure, and severe musculoskeletal disorders require new therapeutic strategies to repair damaged or diseased tissue, particularly given an ageing population in which obesity, diabetes, and consequent tissue defects have reached epidemic proportions. This is further compounded by the lack of intrinsic healing and poor regenerative capacity of certain adult tissues. While vast progress has been made in the last decade regarding tissue regenerative strategies to direct self-healing, for example, through implantation of tissue engineered scaffolds, several challenges have hampered the clinical application of these technologies. Control of the immune response is growing as an attractive approach in regenerative medicine and it is becoming increasingly apparent that an in depth understanding of the interplay between cells of the immune system and tissue specific progenitor cells is of paramount importance. Furthermore, the integration of immunology and bioengineering promises to elevate the efficacy of biomaterial-based tissue repair and regeneration. In this review, we highlight the role played by individual immune cell subsets in tissue repair processes and describe new approaches that are being taken to direct appropriate healing outcomes via biomaterial mediated targeting of immune cell activity. It is becoming increasingly apparent that controlling the immune response is as an attractive approach in regenerative medicine. Here, we propose that an in-depth understanding of immune system and tissue specific progenitor cell interactions may reveal mechanisms by which tissue healing and regeneration takes place, in addition to identifying novel therapeutic targets that could be used to enhance the tissue repair process. To date, most reviews have focused solely on macrophage subsets. This manuscript details the role of other innate and adaptive immune cells such as innate lymphoid cells (ILCs), natural killer (NK) cells and γδT cells (in addition to macrophages) in tissue healing. We also describe new approaches that are being taken to direct appropriate healing outcomes via biomaterial mediated cytokine and drug delivery. [Display omitted] [ABSTRACT FROM AUTHOR]

3D bioprinting has emerged as a promising technology in the field of tissue engineering and regenerative medicine due to its ability to create anatomically complex tissue substitutes. However, it still remains challenging to develop bioactive bioinks that provide appropriate and permissive environments to instruct and guide the regenerative process in vitro and in vivo. In this study alginate sulfate, a sulfated glycosaminoglycan (sGAG) mimic, was used to functionalize an alginate-gelatin methacryloyl (GelMA) interpenetrating network (IPN) bioink to enable the bioprinting of cartilaginous tissues. The inclusion of alginate sulfate had a limited influence on the viscosity, shear-thinning and thixotropic properties of the IPN bioink, enabling high-fidelity bioprinting and supporting mesenchymal stem cell (MSC) viability post-printing. The stiffness of printed IPN constructs greatly exceeded that achieved by printing alginate or GelMA alone, while maintaining resilience and toughness. Furthermore, given the high affinity of alginate sulfate to heparin-binding growth factors, the sulfated IPN bioink supported the sustained release of transforming growth factor-β3 (TGF-β3), providing an environment that supported robust chondrogenesis in vitro, with little evidence of hypertrophy or mineralization over extended culture periods. Such bioprinted constructs also supported chondrogenesis in vivo , with the controlled release of TGF-β3 promoting significantly higher levels of cartilage-specific extracellular matrix deposition. Altogether, these results demonstrate the potential of bioprinting sulfated bioinks as part of a 'single-stage' or 'point-of-care' strategy for regenerating cartilaginous tissues. This study highlights the potential of using sulfated interpenetrating network (IPN) bioink to support the regeneration of phenotypically stable articular cartilage. Construction of interpenetrating networks in the bioink enables unique high-fidelity bioprinting and provides synergistic increases in mechanical properties. The presence of alginate sulfate enables the capacity of high affinity-binding of TGF-β3, which promoted robust chondrogenesis in vitro and in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

For 3D bioprinted tissues to be scaled-up to clinically relevant sizes, effective prevascularisation strategies are required to provide the necessary nutrients for normal metabolism and to remove associated waste by-products. The aim of this study was to develop a bioprinting strategy to engineer prevascularised tissues in vitro and to investigate the capacity of such constructs to enhance the vascularisation and regeneration of large bone defects in vivo. From a screen of different bioinks, a fibrin-based hydrogel was found to best support human umbilical vein endothelial cell (HUVEC) sprouting and the establishment of a microvessel network. When this bioink was combined with HUVECs and supporting human bone marrow stem/stromal cells (hBMSCs), these microvessel networks persisted in vitro. Furthermore, only bioprinted tissues containing both HUVECs and hBMSCs, that were first allowed to mature in vitro , supported robust blood vessel development in vivo. To assess the therapeutic utility of this bioprinting strategy, these bioinks were used to prevascularise 3D printed polycaprolactone (PCL) scaffolds, which were subsequently implanted into critically-sized femoral bone defects in rats. Micro-computed tomography (µCT) angiography revealed increased levels of vascularisation in vivo , which correlated with higher levels of new bone formation. Such prevascularised constructs could be used to enhance the vascularisation of a range of large tissue defects, forming the basis of multiple new bioprinted therapeutics. This paper demonstrates a versatile 3D bioprinting technique to improve the vascularisation of tissue engineered constructs and further demonstrates how this method can be incorporated into a bone tissue engineering strategy to improve vascularisation in a rat femoral defect model. [Display omitted] [ABSTRACT FROM AUTHOR]

The modest clinical impact of musculoskeletal tissue engineering (TE) can be attributed, at least in part, to a failure to recapitulate the structure, composition and functional properties of the target tissue. This has motivated increased interest in developmentally inspired TE strategies, which seek to recapitulate key events that occur during embryonic and post-natal development, as a means of generating truly biomimetic grafts to replace or regenerate damaged tissues and organs. Such TE strategies can be substantially enabled by emerging biofabrication and bioprinting strategies, and in particular the use of cellular aggregates, microtissues and organoids as 'building blocks' for the development of larger tissues and/or organ precursors. Here, the application of such biological building blocks for the engineering of musculoskeletal tissues, from vascularised bone to zonally organised articular cartilage, will be reviewed. The importance of first scaling-down to later scale-up will be discussed, as this is viewed as a key component of engineering functional grafts using cellular aggregates or microtissues. In the context of engineering anatomically accurate tissues of scale suitable for tissue engineering and regenerative medicine applications, novel bioprinting modalities and their application in controlling the process by which cellular aggregates or microtissues fuse and self-organise will be reviewed. Throughout the paper, we will highlight some of the key challenges facing this emerging field. The field of bioprinting has grown substantially in recent years, but despite the hype and excitement it has generated, there are relatively few examples of bioprinting strategies producing implants with superior regenerative potential to that achievable with more traditional tissue engineering approaches. This paper provides an up-to-date review of emerging biofabrication and bioprinting strategies which use cellular aggregates and microtissues as 'building blocks' for the development of larger musculoskeletal tissues and/or organ precursors – a field of research that can potentially enable functional regeneration of damaged and diseased tissues. The application of cellular aggregates and microtissues for the engineering of musculoskeletal tissues, from vascularised bone to zonally organised articular cartilage, will be reviewed. In the context of engineering anatomically accurate tissues of scale, novel bioprinting modalities and their application in controlling the process by which cellular aggregates or microtissues self-organise is addressed, as well as key challenges facing this emerging field. [Display omitted] [ABSTRACT FROM AUTHOR]

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Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage that is resistant to vascularization and endochondral ossification. During skeletal development articular cartilage also functions as a surface growth plate, which postnatally is replaced by a more spatially complex bone-cartilage interface. Motivated by this developmental process, the hypothesis of this study is that bi-phasic, fibre-reinforced cartilaginous templates can regenerate both the articular cartilage and subchondral bone within osteochondral defects created in caprine joints. To engineer mechanically competent implants, we first compared a range of 3D printed fibre networks (PCL, PLA and PLGA) for their capacity to mechanically reinforce alginate hydrogels whilst simultaneously supporting mesenchymal stem cell (MSC) chondrogenesis in vitro. These mechanically reinforced, MSC-laden alginate hydrogels were then used to engineer the endochondral bone forming phase of bi-phasic osteochondral constructs, with the overlying chondral phase consisting of cartilage tissue engineered using a co-culture of infrapatellar fat pad derived stem/stromal cells (FPSCs) and chondrocytes. Following chondrogenic priming and subcutaneous implantation in nude mice, these bi-phasic cartilaginous constructs were found to support the development of vascularised endochondral bone overlaid by phenotypically stable cartilage. These fibre-reinforced, bi-phasic cartilaginous templates were then evaluated in clinically relevant, large animal (caprine) model of osteochondral defect repair. Although the quality of repair was variable from animal-to-animal, in general more hyaline-like cartilage repair was observed after 6 months in animals treated with bi-phasic constructs compared to animals treated with commercial control scaffolds. This variability in the quality of repair points to the need for further improvements in the design of 3D bioprinted implants for joint regeneration. Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage. In this study, we hypothesised that bi-phasic, fibre-reinforced cartilaginous templates could be leveraged to regenerate both the articular cartilage and subchondral bone within osteochondral defects. To this end we used 3D printed fibre networks to mechanically reinforce engineered transient cartilage, which also contained an overlying layer of phenotypically stable cartilage engineered using a co-culture of chondrocytes and stem cells. When chondrogenically primed and implanted into caprine osteochondral defects, these fibre-reinforced bi-phasic cartilaginous grafts were shown to spatially direct tissue development during joint repair. Such developmentally inspired tissue engineering strategies, enabled by advances in biofabrication and 3D printing, could form the basis of new classes of regenerative implants in orthopaedic medicine. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. Notably, we found that the ketolytic enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with BDH1 deficiency in striated muscles, we discover that this enzyme optimizes FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues, and muscle BDH1 flux does indeed play an essential role in conferring the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone flux enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart. [Display omitted] • iTRF-induced muscle remodeling coincides with systemic adaptations in ketone flux • Muscle ketone flux depends on fiber-type-specific mitochondrial BDH1 abundance • BDH1 flux in striated muscles fine-tunes fat oxidation and pyruvate partitioning • BDH1 flux in striated muscles optimizes the metabolic benefits of iTRF Researchers found that ketone flux in cardiac and skeletal muscles promotes exercise tolerance and contributes to the full adaptive benefits of an intermittent time-restricted feeding (iTRF) regimen, both attributable to an unexpected interplay between ketolysis and fat burning efficiency that occurs selectively in mitochondria residing within highly oxidative myofibers. [ABSTRACT FROM AUTHOR]

The recent approval of first-line tyrosine kinase inhibitor plus immuno-oncology agent combination therapy for the treatment of advanced renal cell carcinoma offers substantially improved response rates and survival compared with the previous standard of care. This expansion of treatment options has also led to a greater range and complexity of potential treatment-related adverse events related to overlapping toxicities. The aim of this article is to discuss the management of common treatment-emergent adverse events (AEs) associated with axitinib plus immuno-oncology therapy, highlight the specific roles of oncology nurses in managing these events, and provide AE management resources to aid oncology nurses in their care of patients with advanced renal cell carcinoma. Author experience, journal articles, and treatment guidelines were used. The use of oncology nurses and nurse-led innovations to monitor and assess treatments can have a positive impact on the management of AEs in cancer patients by identifying those who are most at risk, providing regular assessment, appropriate patient education, and supporting the monitoring of patient safety. Skilled oncology nurses should be a key part of a team that addresses the supportive care needs and management of AEs that are associated with novel cancer treatments. Early and ongoing communication between the patient and oncology nurses regarding the development of adverse events is a critical component of maximizing treatment outcomes and quality of life. [Display omitted] [ABSTRACT FROM AUTHOR]

All human tissues present with unique mechanical properties critical to their function. This is achieved in part through the specific architecture of the extracellular matrix (ECM) fibres within each tissue. An example of this is seen in the walls of the vasculature where each layer presents with a unique ECM orientation critical to its functions. Current adopted vascular grafts to bypass a stenosed/damaged vessel fail to recapitulate this unique mechanical behaviour, particularly in the case of small diameter vessels (<6 mm), leading to failure. Therefore, in this study, melt-electrowriting (MEW) was adopted to produce a range of fibrous scaffolds to mimic the extracellular matrix (ECM) architecture of the tunica media of the vasculature, in an attempt to match the mechanical and biological behaviour of the native porcine tissue. Initially, the range of collagen architectures within the native vessel was determined, and subsequently replicated using MEW (winding angles (WA) 45°, 26.5°, 18.4°, 11.3°). These scaffolds recapitulated the anisotropic, non-linear mechanical behaviour of native carotid blood vessels. Moreover, these grafts facilitated human mesenchymal stem cell (hMSC) infiltration, differentiation, and ECM deposition that was independent of WA. The bioinspired MEW fibre architecture promoted cell alignment and preferential neo-tissue orientation in a manner similar to that seen in native tissue, particularly for WA 18.4° and 11.3°, which is a mandatory requirement for long-term survival of the regenerated tissue post-scaffold degradation. Lastly, the WA 18.4° was translated to a tubular graft and was shown to mirror the mechanical behaviour of small diameter vessels within physiological strain. Taken together, this study demonstrates the capacity to use MEW to fabricate bioinspired scaffolds to mimic the tunica media of vessels and recapitulate vascular mechanics which could act as a framework for small diameter graft development to guide tissue regeneration and orientation. [ABSTRACT FROM AUTHOR]

With smart-devices becoming increasingly more commonplace, methods of capturing an individual's activities are becoming feasible. This is more generally performed through questionnaires or within unnatural environments bringing drawbacks in accuracy or requiring impractical conditions. This paper presents a simpler method of data collection which reduces the complications of typical activity data collection by collecting labels directly from a user. Instead of capturing activity beginning and end times, user requests are made at time intervals and labels are populated to feature vectors. These methods can provide a simpler method of data collection and could provide a solution to the annotation problem within activity recognition [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Biomaterial implantation is followed by an inflammatory cascade dominated by macrophages, which determine implant acceptance or rejection through pro- and anti-inflammatory polarization states (Anderson et al., 2008; Brown and Badylak, 2013). It is known that chemical signals such as bacterial endotoxins and cytokines (IL4) can direct macrophage polarization (Mantovani et al., 2004); however, recent evidence implicates biophysical cues in this process (McWhorter et al., 2015; Patel et al., 2012). Here we report that THP-1 derived macrophages cultured on collagen-coated polyacrylamide gels of varying stiffness adapt their polarization state, functional roles and migration mode according to the stiffness of the underlying substrate. Through gene expression and protein secretion analysis, we show that stiff polyacrylamide gels (323 kPa) prime macrophages towards a pro-inflammatory phenotype with impaired phagocytosis in macrophages, while soft (11 kPa) and medium (88 kPa) stiffness gels prime cells towards an anti-inflammatory, highly phagocytic phenotype. Furthermore, we show that stiffness dictates the migration mode of macrophages; on soft and medium stiffness gels, cells display Rho-A kinase (ROCK)-dependent, podosome-independent fast amoeboid migration and on stiff gels they adopt a ROCK-independent, podosome-dependent slow mesenchymal migration mode. We also provide a mechanistic insight into this process by showing that the anti-inflammatory property of macrophages on soft and medium gels is ROCK-dependent and independent of the ligand presented to them. Together, our results demonstrate that macrophages adapt their polarization, function and migration mode in response to the stiffness of the underlying substrate and suggest that biomaterial stiffness is capable of directing macrophage behaviour independent of the biochemical cues being presented to them. The results from this study establish an important role for substrate stiffness in directing macrophage behaviour, and will lead to the design of immuno-informed biomaterials that are capable of modulating the macrophage response after implantation. Statement of significance Biomaterial implantation is followed by an inflammatory cascade dominated by macrophages, which determine implant acceptance or rejection through pro- and anti-inflammatory polarization states. It is known that chemical signals can direct macrophage polarization; however, recent evidence implicates biophysical cues in this process. Here we report that macrophages cultured on gels of varying stiffness adapt their polarization state, functional roles and migration mode according to the stiffness of the underlying substrate. The results from this study establish an important role for substrate stiffness in directing macrophage behaviour, and will lead to the design of immuno-informed biomaterials that are capable of modulating the macrophage response after implantation. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Controlling the phenotype of transplanted stem cells is integral to ensuring their therapeutic efficacy. Hypoxia is a known regulator of stem cell fate, the effects of which can be mimicked using hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors such as dimethyloxalylglycine (DMOG). By releasing DMOG from mesenchymal stem cell (MSC) laden alginate hydrogels, it is possible to stabilize HIF-1α and enhance its nuclear localization. This correlated with enhanced chondrogenesis and a reduction in the expression of markers associated with chondrocyte hypertrophy, as well as increased SMAD 2/3 nuclear localization in the encapsulated MSCs. In vivo , DMOG delivery significantly reduced mineralisation of the proteoglycan-rich cartilaginous tissue generated by MSCs within alginate hydrogels loaded with TGF-β3 and BMP-2. Together these findings point to the potential of hypoxia mimicking hydrogels to control the fate of stem cells following their implantation into the body. Statement of Significance There are relatively few examples where in vivo delivery of adult stem cells has demonstrated a true therapeutic benefit. This may be attributed, at least in part, to a failure to control the fate of transplanted stem cells in vivo. In this paper we describe the development of hydrogels that mimic the effects of hypoxia on encapsulated stem cells. In vitro , these hydrogels enhance chondrogenesis of MSCs and suppress markers associated with chondrocyte hypertrophy. In an in vivo environment that otherwise supports progression along an endochondral pathway, we show that these hydrogels will instead direct mesenchymal stem cells (MSCs) to produce a more stable, cartilage-like tissue. In addition, we explore potential molecular mechanisms responsible for these phenotypic changes in MSCs. [ABSTRACT FROM AUTHOR]

Purpose This paper presents findings from an in-depth study exploring agency in decision making when young people experience cancer. Methods Exploratory case studies were utilised to examine all aspects of decision making, beginning with the onset of symptoms followed by diagnosis and treatment. Interviews, observations and documentary analysis were used to generate data. Multiple sources were selected to generate further insights and these included family, partners, friends and healthcare professionals who were close to the young people during their experience. Results Three overarching themes were identified during analysis of the data: 'life then', 'life interrupted' and 'life reclaimed'. Key elements of these themes included a number of complex and interrelating factors which were interwoven within the everyday lives of the young people. In the 'life then' phase, 'holding on' to agency prior to diagnosis and the importance of close and intimate relationships was illuminated. In 'life interrupted', agentic power during treatment, in terms of the range of decision making and the complexity of the parental role, were prominent. In 'life reclaimed' the 'different but determined' nature of young people's behaviour and re-aligned agency was transparent as they were near to completing treatment. Conclusions This study has culminated in the development of a model of individual cancer trajectories relating to the fluctuation of agency during young people's cancer experiences. These trajectories could be applied in future healthcare practice. Highlights • During the young person's cancer experience agency fluctuates over time. • Personal, proxy and collective agency are evident the context of the experience. • Three phases are identified, 'life then', 'life interrupted' and life reclaimed. • Agency is important in decisions made in everyday life and not just in treatment. [ABSTRACT FROM AUTHOR]

Summary The major objective of this study was to understand the molecular basis of how sarcolipin uncoupling of SERCA regulates muscle oxidative metabolism. Using genetically engineered sarcolipin (SLN) mouse models and primary muscle cells, we demonstrate that SLN plays a crucial role in mitochondrial biogenesis and oxidative metabolism in muscle. Loss of SLN severely compromised muscle oxidative capacity without affecting fiber-type composition. Mice overexpressing SLN in fast-twitch glycolytic muscle reprogrammed mitochondrial phenotype, increasing fat utilization and protecting against high-fat diet-induced lipotoxicity. We show that SLN affects cytosolic Ca2+ transients and activates the Ca2+/calmodulin-dependent protein kinase II (CamKII) and PGC1α axis to increase mitochondrial biogenesis and oxidative metabolism. These studies provide a fundamental framework for understanding the role of sarcoplasmic reticulum (SR)-Ca2+ cycling as an important factor in mitochondrial health and muscle metabolism. We propose that SLN can be targeted to enhance energy expenditure in muscle and prevent metabolic disease. Graphical Abstract Highlights • Sarcolipin (SLN) regulates thermogenesis and energy metabolism in skeletal muscle • Loss of SLN leads to obesity, whereas overexpression of SLN resists against obesity • SLN promotes mitochondrial biogenesis and oxidative phenotype in glycolytic muscle • SLN activates the CamKII-PGC1α signaling pathway to promote mitochondrial biogenesis Maurya et al. report that sarcolipin, a regulator of the SERCA pump, promotes mitochondrial biogenesis and oxidative phenotype in muscle. Loss of SLN decreases fat oxidation, whereas overexpression of SLN in muscle provides resistance against diet-induced lipotoxicity. By increasing cytosolic Ca2+ transients, SLN activates the CamKII-PGC1α signaling pathway to promote mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]

Total joint replacements (TJR) are costly procedures required to relieve pain and restore function in patients suffering from end-stage arthritis. Despite great progress in the development and durability of TJRs, the generation of prosthesis-associated wear particles over time leads to an inflammatory cascade which culminates in periprosthetic osteolysis. Studies suggest that wear particles drive the polarization/differentiation of immature macrophages towards a pro-inflammatory M1 phenotype rather than an anti-inflammatory M2 phenotype associated with normal bone and wound healing. This, in turn, contributes to the initiation of peri-implant inflammation. As a result, modulating M1 macrophage cytokine production has been recognised as a viable therapeutic option. The aim of this study was to examine the impact of hydroxyapatite (HA) and poly(methyl methacrylate) (PMMA) particles on human macrophage polarization by comparing their effect on M1/M2-associated gene expression using real-time PCR. Furthermore, using immunoblotting to assess kinase activation, we sought to identify the intracellular signalling molecules activated by PMMA/HA particles and to determine whether pharmacological blockade of these molecules impacts on macrophage phenotype and cytokine production as measured by ELISA. We report that wear particles preferentially polarize macrophages towards an M1 phenotype, an effect that is dependent on activation of the membrane proximal kinase, Syk and members of the mitogen-activated protein kinase (MAPK) family of signalling molecules. Pre-treatment of macrophages with Syk inhibitors (R788/piceatannol) or MAPK inhibitors (SB203580 and PD98059), not only prevents M1 polarization, but also attenuates production of key pro-inflammatory mediators that have been specifically implicated in periprosthetic osteolysis and osteoclast differentiation. Statement of Significance It is now well established that wear-debris particles from implanted materials drive deleterious inflammatory responses which can eventually lead to implant loosening. In this study, we provide further insight into the specific cellular pathways activated by wear particles in primary human immune cells. We demonstrate that PMMA bone cement and hydroxyapatite, a commonly used biomaterial, drive the polarization of macrophages towards an inflammatory phenotype and identify the specific signalling molecules that are activated in this process. Pre-treatment of macrophages with pharmacological inhibitors of these molecules in turn prevents macrophage polarization and dampens inflammatory cytokine production. Hence these signalling molecules represent potential therapeutic targets to treat or possibly prevent particulate induced osteolysis. [ABSTRACT FROM AUTHOR]

The ideal tissue engineering (TE) strategy for ligament regeneration should recapitulate the bone – calcified cartilage – fibrocartilage – soft tissue interface. Aligned electrospun-fibers have been shown to guide the deposition of a highly organized extracellular matrix (ECM) necessary for ligament TE. However, recapitulating the different tissues observed in the bone-ligament interface using such constructs remains a challenge. This study aimed to explore how fiber alignment and growth factor stimulation interact to regulate the chondrogenic and ligamentous differentiation of mesenchymal stem cells (MSCs). To this end aligned and randomly-aligned electrospun microfibrillar scaffolds were seeded with bone marrow derived MSCs and stimulated with transforming growth factor β3 (TGFβ3) or connective tissue growth factor (CTGF), either individually or sequentially. Without growth factor stimulation, MSCs on aligned-microfibers showed higher levels of tenomodulin ( TNMD ) and aggrecan gene expression compared to MSCs on randomly-oriented fibers. MSCs on aligned-microfibers stimulated with TGFβ3 formed cellular aggregates and underwent robust chondrogenesis, evidenced by increased type II collagen expression and sulphated glycosaminoglycans (sGAG) synthesis compared to MSCs on randomly-oriented scaffolds. Bone morphogenetic protein 2 ( BMP2 ) and type I collagen gene expression were higher on randomly-oriented scaffolds stimulated with TGFβ3, suggesting this substrate was more supportive of an endochondral phenotype. In the presence of CTGF, MSCs underwent ligamentous differentiation, with increased TNMD expression on aligned compared to randomly aligned scaffolds. Upon sequential growth factor stimulation, MSCs expressed types I and II collagen and deposited higher overall levels of collagen compared to scaffolds stimulated with either growth factor in isolation. These findings demonstrate that modulating the alignment of microfibrillar scaffolds can be used to promote either an endochondral, chondrogenic, fibrochondrogenic or ligamentous MSC phenotype upon presentation of appropriate biochemical cues. Statement of Significance Polymeric electrospun fibers can be tuned to match the fibrillar size and anisotropy of collagen fibers in ligaments, and can be mechanically competent. Therefore, their use is attractive when attempting to tissue engineer the bone-ligament interface. A central challenge in this field is recapitulating the cellular phenotypes observed across the bone-ligament interface. Here we demonstrated that it is possible to direct MSCs seeded onto aligned electrospun fibres towards either a ligamentogenic, chondrogenic or fibrochondrogenic phenotype upon presentation of appropriate biochemical cues. This opens the possibility of using aligned microfibrillar scaffolds that are spatially functionalized with specific growth factors to direct MSC differentiation for engineering the bone-ligament interface. [ABSTRACT FROM AUTHOR]

There is little research to help health care professionals understand what patient outcomes are considered a priority in advanced liver or kidney cancer. Knowing what is important to patients can help promote person-centered approaches to treatment and disease management. The aim of this study was to identify those patient-reported outcomes (PROs) that patients, carers, and health care professionals consider as "core" when providing care to those with advanced liver or kidney cancer. A three-round Delphi study was undertaken to ask experts by profession or experience to rank PROs identified from a previous literature review. Fifty-four experts, including people living with advanced liver or kidney cancer (44.4%), family members and caregivers (9.3%), and health care professionals (46.8%), reached consensus on 49 PROs including 12 new items (eg, palpitations, hopefulness, or social isolation). Items with the highest rate of consensus included quality of life, pain, mental health, and capacity to do daily activities. People living with advanced liver or kidney cancer experience complex health care needs. Some important outcomes were not actually captured in practice in this population and were suggested as part of this study. There are discrepancies between the views of health care professionals, patients, and family in what is important, highlighting the need of using measures to facilitate communication. Identification of priority PROs reported here will be key to facilitate more focused patient assessments. The actual use of measures in cancer nursing practice to allow monitoring of PROs must be tested for feasibility and usability. [ABSTRACT FROM AUTHOR]

Exercise elicits coordinated multi-organ responses including skeletal muscle, vasculature, heart, and lung. In the short term, the output of the heart increases to meet the demand of strenuous exercise. Long-term exercise instigates remodeling of the heart including growth and adaptive molecular and cellular re-programming. Signaling pathways such as the insulin-like growth factor 1/PI3K/Akt pathway mediate many of these responses. Exercise-induced, or physiologic, cardiac growth contrasts with growth elicited by pathological stimuli such as hypertension. Comparing the molecular and cellular underpinnings of physiologic and pathologic cardiac growth has unveiled phenotype-specific signaling pathways and transcriptional regulatory programs. Studies suggest that exercise pathways likely antagonize pathological pathways, and exercise training is often recommended for patients with chronic stable heart failure or following myocardial infarction. Herein, we summarize the current understanding of the structural and functional cardiac responses to exercise as well as signaling pathways and downstream effector molecules responsible for these adaptations. [ABSTRACT FROM AUTHOR]

Patient-reported outcomes (PROs) are key indicators of health status and functioning, coming directly from the patient. Comprehensive monitoring of PROs enables implementation of person-centred care. Currently, the PROs that patients with advanced renal cell carcinoma (RCC) or hepatocellular carcinoma (HCC) consider of greatest importance remains unknown. A rapid literature review was carried out to identify PROs commonly reported in clinical studies of patients with advanced RCC/HCC. We searched MEDLINE, CINAHL & PsycInfo for relevant peer-reviewed publications in the period from 2000 to 2021. Pre-specified selection criteria were applied to all retrieved records. Findings were integrated into a narrative synthesis. Eighty-one studies met our selection criteria and were retained. Most research was on advanced RCC (n = 64, 79%); 46 studies (57%) were drug trials. Only twenty-six studies (32%) employed PROs as their primary endpoint. Most PROs concerned physical symptoms (45% RCC, 54% HCC) and emotional wellbeing (19% RCC, 16% HCC). The most common outcome measured was quality of life (65% of the total), followed by fatigue (62%) and pain (54%). Whether selection of these PROs was patient-driven was not reported. A wide range of PROs were assessed. Deficits in PROs often cause patients to seek out help; however, which PROs matter the most to people with advanced RCC/HCC must be further clarified. Targeting, monitoring, and responding to the 'right' PROs can enhance provision of person-centred care in advanced RCC/HCC and augment the clinical efficacy of established and emerging targeted therapies. • We explored what PROs are commonly reported in advanced renal or liver cancer. • Quality of life and physical symptoms were the most frequently assessed PROs. • Whether selection of these PROs was patient-driven was not reported. • Clinicians must address the 'right' PROs for person-centred care to be enhanced. [ABSTRACT FROM AUTHOR]

Highlights from the article: The path leading to a new drug becoming commercially available is long and expensive, involving an average of 13 years [1] and estimated costs from US$618 million to US$2.6 billion [1], [2], [3]. Drug repurposing, the use of an existing drug for a new indication, has emerged as a viable alternative to traditional de novo drug discovery. Drug repurposing allows investigators to bypass or streamline toxicity studies and should make these drugs more acceptable than early-phase drugs to providers, patients and families [4].

Electrospun nanofibers are a promising material for ligamentous tissue engineering, however weak mechanical properties of fibers to date have limited their clinical usage. The goal of this work was to modify electrospun nanofibers to create a robust structure that mimics the complex hierarchy of native tendons and ligaments. The scaffolds that were fabricated in this study consisted of either random or aligned nanofibers in flat sheets or rolled nanofiber bundles that mimic the size scale of fascicle units in primarily tensile load bearing soft musculoskeletal tissues. Altering nanofiber orientation and geometry significantly affected mechanical properties; most notably aligned nanofiber sheets had the greatest modulus; 125% higher than that of random nanofiber sheets; and 45% higher than aligned nanofiber bundles. Modifying aligned nanofiber sheets to form aligned nanofiber bundles also resulted in approximately 107% higher yield stresses and 140% higher yield strains. The mechanical properties of aligned nanofiber bundles were in the range of the mechanical properties of the native ACL: modulus=158±32 MPa, yield stress=57±23 MPa and yield strain=0.38±0.08. Adipose derived stem cells cultured on all surfaces remained viable and proliferated extensively over a 7 day culture period and cells elongated on nanofiber bundles. The results of the study suggest that aligned nanofiber bundles may be useful for ligament and tendon tissue engineering based on their mechanical properties and ability to support cell adhesion, proliferation, and elongation. [ABSTRACT FROM AUTHOR]

Purpose This was an evaluation of an innovation in curriculum content and delivery within undergraduate nursing education in the UK. Its purpose was to investigate the effect on knowledge, attitudes and confidence in delivering cancer care. Methods The study design was a pre-test post-test survey design with a comparison group. Participants were two cohorts of undergraduate nursing students (n intervention = 84, n comparison = 91). The intervention cohort were exposed to a new 3.5 day programme of cancer education, coproduced with patients, carers and health professionals, which focused on cancer as a life changing long-term condition. The comparison cohort had been exposed to a 2 day programme produced by a lecturer. Results Following exposure to the new model for the delivery of undergraduate nurse cancer education, the intervention cohort demonstrated good overall knowledge of the impact of cancer, more positive attitudes towards cancer treatment and more confidence in their ability to deliver cancer care. Attitudes were more positive and confidence in ability to support cancer patients at all stages of the cancer journey were greater than in the comparison group. Insights gained into the cancer patient and carer perspectives were highly valued. Conclusions This study has found that a new model for the delivery of cancer education focusing on survivorship and delivered in partnership with patients, carers and clinicians, may improve knowledge, attitudes and confidence in the delivery of cancer care. Further work is now needed, using a more robust experimental design, to investigate the generalisability of the results to other education programs. [ABSTRACT FROM AUTHOR]

Engineering tissues with comparable structure, composition and mechanical functionality to native articular cartilage remains a challenge. One possible solution would be to decellularize xenogeneic articular cartilage in such a way that the structure of the tissue is maintained, and to then repopulate this decellularized matrix with human chondroprogenitor cells that will facilitate the reconstitution, maintenance and eventual turnover of the construct following implantation. The overall objective of this study was to develop a protocol to efficiently decellularize porcine articular cartilage grafts and to identify a methodology to subsequently repopulate such explants with human chondroprogenitor cells. To this end, channels were first introduced into cylindrical articular cartilage explants, which were then decellularized with a combination of various chemical reagents including sodium dodecyl sulfate (SDS) and nucleases. The decellularization protocol resulted in a ~90% reduction in porcine DNA content, with little observed effect on the collagen content and the collagen architecture of the tissue, although a near-complete removal of sulfated glycosaminoglycans (sGAG) and a related reduction in tissue compressive properties was observed. The introduction of channels did not have any detrimental effect on the biochemical or the mechanical properties of the decellularized tissue. Next, decellularized cartilage explants with or without channels were seeded with human infrapatellar fat pad derived stem cells (FPSCs) and cultured chondrogenically under either static or rotational conditions for 10 days. Both channeled and non-channeled explants supported the viability, proliferation and chondrogenic differentiation of FPSCs. The addition of channels facilitated cell migration and subsequent deposition of cartilage-specific matrix into more central regions of these explants. The application of rotational culture appeared to promote a less proliferative cellular phenotype and led to an increase in sGAG synthesis within the explants. Rotational culture also appeared to promote higher cell viability and led to a more even distribution of cells within the channels of decellularized explants. To conclude, this study describes an effective protocol for the decellularization of porcine articular cartilage grafts and a novel methodology for the partial recellularization of such explants with human stem cells. Decellularized soft tissue explants that maintain their native collagen architecture may represent promising scaffolds for musculoskeletal tissue engineering applications. [ABSTRACT FROM AUTHOR]

Clinical translation of tissue engineered therapeutics is hampered by the significant logistical and regulatory challenges associated with such products, prompting increased interest in the use of decellularized extracellular matrix (ECM) to enhance endogenous regeneration. Most bones develop and heal by endochondral ossification, the replacement of a hypertrophic cartilaginous intermediary with bone. The hypothesis of this study is that a porous scaffold derived from decellularized tissue engineered hypertrophic cartilage will retain the necessary signals to instruct host cells to accelerate endogenous bone regeneration. Cartilage tissue (CT) and hypertrophic cartilage tissue (HT) were engineered using human bone marrow derived mesenchymal stem cells, decellularized and the remaining ECM was freeze-dried to generate porous scaffolds. When implanted subcutaneously in nude mice, only the decellularized HT-derived scaffolds were found to induce vascularization and de novo mineral accumulation. Furthermore, when implanted into critically-sized femoral defects, full bridging was observed in half of the defects treated with HT scaffolds, while no evidence of such bridging was found in empty controls. Host cells which had migrated throughout the scaffold were capable of producing new bone tissue, in contrast to fibrous tissue formation within empty controls. These results demonstrate the capacity of decellularized engineered tissues as ‘off-the-shelf’ implants to promote tissue regeneration. [ABSTRACT FROM AUTHOR]

Cartilaginous tissues engineered using mesenchymal stem cells (MSCs) have been shown to generate bone in vivo by executing an endochondral programme. This may hinder the use of MSCs for articular cartilage regeneration, but opens the possibility of using engineered cartilaginous tissues for large bone defect repair. Hydrogels may be an attractive tool in the scaling-up of such tissue engineered grafts for endochondral bone regeneration. In this study, we compared the capacity of different naturally derived hydrogels (alginate, chitosan and fibrin) to support chondrogenesis and hypertrophy of MSCs in vitro and endochondral ossification in vivo. In vitro, alginate and chitosan constructs accumulated the highest levels of sulfated glycosaminoglycan (sGAG), with chitosan constructs synthesizing the highest levels of collagen. Alginate and fibrin constructs supported the greatest degree of calcium accumulation, though only fibrin constructs calcified homogeneously. In vivo , chitosan constructs facilitated neither vascularization nor endochondral ossification, and also retained the greatest amount of sGAG, suggesting it to be a more suitable material for the engineering of articular cartilage. Both alginate and fibrin constructs facilitated vascularization and endochondral bone formation as well as the development of a bone marrow environment. Alginate constructs accumulated significantly more mineral and supported greater bone formation in central regions of the engineered tissue. In conclusion, this study demonstrates the capacity of chitosan hydrogels to promote and better maintain a chondrogenic phenotype in MSCs and highlights the potential of utilizing alginate hydrogels for MSC-based endochondral bone tissue engineering applications. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop a scaffold derived from cartilaginous extracellular matrix (ECM) that could be used as a growth factor delivery system to promote chondrogenesis of stem cells. Dehydrothermal crosslinked scaffolds were fabricated using a slurry of homogenized porcine articular cartilage, which was then seeded with human infrapatellar-fat-pad-derived stem cells (FPSCs). It was found that these ECM-derived scaffolds promoted superior chondrogenesis of FPSCs when the constructs were additionally stimulated with transforming growth factor (TGF)-β3. Cell-mediated contraction of the scaffold was observed, which could be limited by the additional use of 1-ethyl-3-3dimethyl aminopropyl carbodiimide (EDAC) crosslinking without suppressing cartilage-specific matrix accumulation within the construct. To further validate the utility of the ECM-derived scaffold, we next compared its chondro-permissive properties to a biomimetic collagen–hyaluronic acid (HA) scaffold optimized for cartilage tissue engineering (TE) applications. The cartilage-ECM-derived scaffold supported at least comparable chondrogenesis to the collagen–HA scaffold, underwent less contraction and retained a greater proportion of synthesized sulfated glycosaminoglycans. Having developed a promising scaffold for TE, with superior chondrogenesis observed in the presence of exogenously supplied TGF-β3, the final phase of the study explored whether this scaffold could be used as a TGF-β3 delivery system to promote chondrogenesis of FPSCs. It was found that the majority of TGF-β3 that was loaded onto the scaffold was released in a controlled manner over the first 10 days of culture, with comparable long-term chondrogenesis observed in these TGF-β3-loaded constructs compared to scaffolds where the TGF-β3 was continuously added to the media. The results of this study support the use of cartilage-ECM-derived scaffolds as a growth factor delivery system for use in articular cartilage regeneration. [ABSTRACT FROM AUTHOR]

Summary: Background: Online learning is frequently used in continuing professional development for qualified nurses and midwives. It is frequently assumed that the same package is appropriate for different groups of learners and that by reducing the need for tutorial input, tutorial time is saved. Objectives: We evaluated the suitability of an online learning resource for suitability in continuing professional development for midwives. Originally developed for use as part of a work-based package for a specific audience, there had always been plans for more general use of the resource with other groups of health workers. Design: Sequential mixed methods study. Setting: English universities. Participants: Seventy university tutors. Methods: Online questionnaire and in-depth interviews. Findings: Tutors did not consider that the online learning materials would be suitable for a wider audience without significant adaptation. They thought that uptake would increase need for tutorial input. Conclusion: Our findings demonstrate the pitfalls of removing learning from the context of practice. Technology customised to meet the needs of one group of learners probably does not have the potential for transfer to another group without significant adaptation. Those responsible for designing e-learning should take into account the needs of all the different audiences for whom the resource is intended from the outset, with consideration for the context in which learning will be applied to practice and how students will be supported. If the same package is to be used by different audiences and in different settings, tutors and students will require explicit instructions of how they should use the resource and depth of knowledge and level of competency that should be attained at the conclusion of the programme. [Copyright &y& Elsevier]

Abstract: Purpose: To determine the incidence of catheter-associated venous thromboembolic events (VTE) in long gap esophageal atresia (LGEA) patients treated at Boston Children's Hospital (BCH) and to identify possible risk factors associated with their development. Methods: We performed a retrospective analysis of LGEA patients from 2005 to 2012. Symptomatic VTEs with radiographic confirmation were defined as events. Potential risk factors were assessed by univariate analysis and multivariate logistic regression. Covariates included age, weight, initial gap length, cumulative days of pharmacologic paralysis and paralytic episodes, number and type of central venous catheters (CVCs), and number of operations. Results: Forty-four LGEA patients were identified. The incidence of CVC associated VTE was 34%. Univariate analysis identified age at Foker 1 (P =.03), paralysis duration (P =.01), episodes of paralysis (P =.001), cumulative number of CVC (P =.007) and length of stay (P =.03) as significant. Multivariate logistic regression identified the number of paralytic episodes as the only significant independent risk factor for VTE (P <.0001). Conclusions: The incidence of symptomatic VTE was 34%, significantly higher than the VTE incidence of 4.5% reported for our other hospitalized children. These data have led to multidisciplinary discussions regarding thromboprophylaxis and development of a consensus-driven protocol. Since the initiation of this protocol, no VTEs have been identified. [Copyright &y& Elsevier]

Abstract: Agricultural intensification has caused significant declines in biodiversity. Agri-environmental schemes (AES), including organic farming, are thought to benefit biodiversity. However, under similar production conditions and in comparable locations and schemes, farms are not managed in the same way, with variable consequences for production and the environment. Understanding farmer attitude, behaviour and knowledge of the environment and their impacts on biodiversity may help us understand the variable impacts of AES on biodiversity. We combined a sociological survey of nine organic and eight conventional dairy farmers (measuring environmental and achievement attitudes; environmental and production-orientated behaviours and environmental knowledge), in Ireland, with a biodiversity (using plant richness as an indicator) assessment of their farms. We found higher plant richness on organic farms than conventional. Organic and conventional farmers had similar attitudes to farming achievement and the environment but organic farmers were better informed about environmental issues and carried out more environmentally orientated behaviours. Biodiversity was positively related to the amount of environmentally orientated behaviours and negatively related to production-orientated behaviours carried out on farms. Organic farmers who had more positive attitudes to the environment and were better informed about it had higher biodiversity on their farms compared to less positively inclined, less informed organic farmers. We show disparities between attitude and actual behaviour in relation to the environment, with organic farmers sharing similar attitudes to conventional farmers, but more prepared to inform themselves about and carry out environmentally friendly farming. Results indicate that organic farming and environmentally orientated behaviours benefit biodiversity and that there is an important link between farmer environmental attitudes and knowledge and the beneficial effects of organic farming on biodiversity. We encourage conservation orientated thinking and better environmental education among farmers, including those who already participate in an AES. This way, the benefits of the AES for the environment may be maximised. [Copyright &y& Elsevier]

Abstract: Prestress in the collagen network has a significant impact on the material properties of cartilaginous tissues. It is closely related to the recruitment configuration of the collagen network which defines the transition from lax collagen fibres to uncrimped, load-bearing collagen fibres. This recruitment configuration can change in response to alterations in the external environmental conditions. In this study, the influence of changes in external salt concentration or sequential proteoglycan digestion on the configuration of the collagen network of tissue engineered cartilage is investigated using a previously developed computational model. Collagen synthesis and network assembly are assumed to occur in the tissue configuration present during in vitro culture. The model assumes that if this configuration is more compact due to changes in tissue swelling, the collagen network will adapt by lowering its recruitment stretch. When returned to normal physiological conditions, these tissues will then have a higher prestress in the collagen network. Based on these assumptions, the model demonstrates that proteoglycan digestion at discrete time points during culture as well as culture in a hypertonic medium can improve the functionality of tissue engineered cartilage, while culture in hypotonic solution is detrimental to the apparent mechanical properties of the graft. [Copyright &y& Elsevier]

Abstract: Chondrogenically primed bone marrow-derived mesenchymal stem cells (MSCs) have been shown to become hypertrophic and undergo endochondral ossification when implanted in vivo. Modulating this endochondral phenotype may be an attractive approach to engineering the osseous phase of an osteochondral implant. The objective of this study was to engineer an osteochondral tissue by promoting endochondral ossification in one layer of a bilayered construct and stable cartilage in the other. The top half of bilayered agarose hydrogels were seeded with culture expanded chondrocytes (termed the chondral layer) and the bottom half of the bilayered agarose hydrogels with MSCs (termed the osseous layer). Constructs were cultured in chondrogenic medium for 21days and thereafter were either maintained in chondrogenic medium, transferred to hypertrophic medium, or implanted subcutaneously into nude mice. This structured chondrogenic bilayered co-culture was found to enhance chondrogenesis in the chondral layer, appearing to help re-establish the chondrogenic phenotype that is lost in chondrocytes during monolayer expansion. Furthermore, the bilayered co-culture appeared to suppress hypertrophy and mineralization in the osseous layer. The addition of hypertrophic factors to the media was found to induce mineralization of the osseous layer in vitro. A similar result was observed in vivo where endochondral ossification was restricted to the osseous layer of the construct, leading to the development of an osteochondral tissue. This novel approach represents a potential new treatment strategy for the repair of osteochondral defects. [Copyright &y& Elsevier]

Abstract: The inherent biocompatibility of fibrin hydrogels makes them an attractive material for use in a wide range of tissue engineering applications. Despite this, their relatively low stiffness and high compliance limits their potential for certain orthopaedic applications. Enhanced mechanical properties are desirable so as to withstand surgical handling and in vivo loading after implantation and additionally, can provide important cues to cells seeded within the hydrogel. Standard methods used to enhance the mechanical properties of biological scaffolds such as chemical or thermal crosslinking cannot be used with fibrin hydrogels as cell seeding and gel formation occurs simultaneously. The objective of this study was to investigate the use of plastic compression as a means to improve the mechanical properties of chondrocyte-seeded fibrin hydrogels and to determine the influence of such compression on cell viability within these constructs. It was found that the application of 80% strain to fibrin hydrogels for 30min (which resulted in a permanent strain of 47.4%) produced a 2.1-fold increase in the subsequent compressive modulus. Additionally, chondrocyte viability was maintained in the plastically compressed gels with significant cellular proliferation and extracellular matrix accumulation observed over 28 days of culture. In conclusion, plastic compression can be used to modulate the density and mechanical properties of cell-seeded fibrin hydrogels and represents a useful tool for both in theatre and in vitro tissue engineering applications. [Copyright &y& Elsevier]

Abstract: Inelastic phenomena such as softening and unrecoverable inelastic strains induced by loading have been observed experimentally in soft tissues such as arteries. These phenomena need to be accounted for in constitutive models of arterial tissue so that computational models can accurately predict the outcomes of interventional procedures such as balloon angioplasty and stenting that involve non-physiological loading of the tissue. In this study, a novel constitutive model is described that accounts for inelastic effects such as Mullins-type softening and permanent set in a fibre reinforced tissue. The evolution of inelasticity is governed by a set of internal variables. Softening is introduced through a typical continuum damage mechanics approach, while the inelastic residual strains are introduced through an additive split in the stress tensor. Numerical simulations of aorta and carotid arterial tissue subjected to uniaxial testing in the longitudinal, circumferential and axial directions are used to demonstrate the model’s ability to reproduce the anisotropic inelastic behaviour of the tissue. Material parameters derived from best-fits to experimental data are provided to describe these inelastic effects for both aortic and carotid tissue. [Copyright &y& Elsevier]

Abstract: Continuous fibre distribution models can be applied to a variety of biological tissues with both charged and neutral extracellular matrices. In particular, ellipsoidal models have been used to describe the complex material behaviour of tissues such as articular cartilage and their engineered tissue equivalents. The choice of material parameters is more difficult than in classical anisotropic models and the impact that changes to these parameters can have on the predictions of such models are poorly understood. The objective of this study is to demonstrate the apparent behaviour of this class of materials over a range of material parameters. We further introduce a scaling approach to overcome certain counter-intuitive aspects related to the choice of anisotropy parameters and outline the integration method used in our implementations. User material codes for the commercial FE software packages Abaqus and MSC Marc are provided for use by other investigators. Cross-validation of our code against similar implementations in FEBio is also presented. [Copyright &y& Elsevier]

Abstract: Changes in ground flora were monitored over a 32-year period in deer exclosures in a yew-wood and a neighbouring oakwood in Killarney National Park, southwest Ireland; both woods are Annex I habitats under the European Habitats Directive. Comparison was made with unfenced plots adjacent to each of the exclosures. During the period of the study, both woods were heavily grazed by introduced sika deer (Cervus nippon). In the yew-wood exclosures, total ground flora cover increased markedly during the period of deer exclusion, the main species to increase in abundance being Rubus fruticosus agg. and Hedera helix. Herbaceous species increased initially in frequency but subsequently declined; herbaceous species had higher total cover in unfenced plots than in fenced plots at the end of the study. In the oakwood, Luzula sylvatica and Vaccinium myrtillus expanded their cover in one exclosure with cover in ferns declining, but in other exclosures where dense holly thickets developed, it was instead R. fruticosus and H. helix that became more abundant within the fences than outside. Overall, long-term fencing has caused a shift from vegetation characterised by woodland specialist to woodland generalist species and there are indications of a long-term decline in diversity. We conclude that chronic heavy grazing in these woodlands has strongly influenced the overall abundance and composition of the ground flora, but that complete exclusion of grazing is also undesirable due to potential declines in diversity of woodland specialists. [Copyright &y& Elsevier]

Abstract: Purpose: Using a transnasal, transfacial, anterior skull base approach, we have removed olfactory neuroblastomas (OFN) obviating the need for a frontal craniotomy. The objectives were to present our surgical approach in achieving clear margins, to assess patient survival, and to recommend eligibility criteria. Materials and methods: A retrospective chart review was done to identify patients diagnosed with OFN who underwent this surgical approach. Thirteen patients were identified who underwent our pictorially described approach. Postoperative assessment of pathologic margins, patient survival, and limitations of surgical approach was determined. Results: Of the 13 patients, 12 (92%) had clear postsurgical margins. One patient had residual intracranial disease due to coagulopathy preventing further resection. Twelve patients remain alive with 10 patients remaining disease-free (follow-up ranging from 11 to 64 months). Three patients presented with recurrent disease initially, with 2 having had subsequent repeat local and regional recurrences, respectively; one of whom died recently of the rerecurrent disease. One patient had a postoperative cerebrospinal fluid leak repaired via the original surgical approach. Conclusions: Although craniofacial resection remains an accepted approach for surgical treatment of OFN, we have adopted a transnasal, transfacial approach eliminating the need for a frontal craniotomy. This approach allows for adequate exposure of the cribriform plate, dura, and anterior skull base. Our technique minimizes dural defects and prevents many craniotomy-associated complications, including frontal lobe retraction. Long-term follow-up is needed to compare survival using this approach; however, our results to date are quite promising. [Copyright &y& Elsevier]

Summary: Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α− /− β f/f/MLC-Cre mice) were generated and characterized. PGC-1α − /− βf/f/MLC-Cre mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α − /− βf/f/MLC-Cre mice was associated with a marked diminution in muscle oxidative capacity, together with rapid depletion of muscle glycogen stores. In addition, the PGC-1α/β-deficient muscle exhibited mitochondrial structural derangements consistent with fusion/fission and biogenic defects. Surprisingly, the proportion of oxidative muscle fiber types (I, IIa) was not reduced in the PGC-1α − /− βf/f/MLC-Cre mice. Moreover, insulin sensitivity and glucose tolerance were not altered in the PGC-1α − /− βf/f/MLC-Cre mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity. [ABSTRACT FROM AUTHOR]

Abstract: Agarose hydrogels are commonly used for cartilage tissue engineering studies and to provide a three dimensional environment to investigate cellular mechanobiology. Interpreting the results of such studies requires accurate quantification of the mechanical properties of the hydrogel. There is significant variation in the reported mechanical properties of agarose hydrogels, and little is reported on the influence of factors associated with mixing these hydrogels with cell suspensions on their initial mechanical properties. The objective of this study was to determine the influence of agarose concentration, the cooling rate during gelation, the thermal history following gelation and the cell seeding density on the initial mechanical properties of agarose hydrogels. The average ramp modulus of 2% agarose gel in tension was 24.9 kPa (±1.7, ), compared with 55.6 kPa (±0.5, ) in compression. The average tensile equilibrium modulus was 39.7 kPa (±5.7, ), significantly higher than the compressive equilibrium modulus of 14.2 kPa (±1.6, ). The equilibrium and dynamic compressive modulus of agarose hydrogels were observed to reduce if maintained at 37  ∘C following gelation compared with samples maintained at room temperature. Depending on the methodology used to encapsulate chondrocytes within agarose hydrogels, the equilibrium compressive modulus was found to be significantly higher for acellular 2% agarose gels compared with 2% agarose gels seeded at approximately 40×106 cells/mL. These results have important implications for interpreting the results of chondrocyte mechanobiology studies in agarose hydrogels. [Copyright &y& Elsevier]

To detail social knowledge of prostate cancer risk amongst cultural groups. Prostate cancer is the most common cancer in men, and black men are at the highest risk. Despite this, black men are the least likely to be diagnosed early with prostate cancer. It is important to understand why this is so that these men can receive early access to effective treatment and support. A constructivist grounded theory methodology was used. Data were collected between December 2015 and October 2017; seventeen men were interviewed, and eighteen men took part in focus groups. There were differences in the way the men constructed their understanding of risks for prostate cancer. The social construction of prostate cancer risk knowledge was mediated by the way the men were socialised to understand and accept this risk. The Somali and African Caribbean men placed social importance on the healthy body, whereas the white working class men seemed to find social value through the unwell body. This research proposes the theory that social constructions of knowledge mediate the way men perceive and accept their risk for prostate cancer. Understanding socially-derived knowledge of risk may mediate the acceptance of factors relating to prostate cancer. This knowledge may help health providers and third sector organisations produce targeted health-related information. Health practitioners may also benefit from understanding how socially constructed ideas of the body could influence the way men respond to conversations about prostate cancer so that tailored and culturally appropriate support can be offered. • This paper presents data from research conducted with men without prostate cancer, to offer insights into how these men understand their risk for this particular cancer. • This research is distinctive in focusing on the differences in social understanding of prostate cancer between cultural groups. • This paper suggested ways healthcare professionals may consider their approach to education of prostate cancer risk, based on socially constructed cultural knowledge. [ABSTRACT FROM AUTHOR]

This systematic literature review identified publications evaluating the role and benefits of nurse-led care in the management of patients with a diagnosis of renal cell carcinoma (RCC) or hepatocellular carcinoma (HCC). The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. Structured searches of the PubMed database and the EMCare nursing and allied health database were conducted (August 11, 2021). Eligible publications were English-language, full-text, peer-reviewed journal articles featuring HCC and/or RCC populations, interventions involving nurses, any/no comparators, and reporting any related healthcare outcomes. Data on study design and size, patient characteristics and impact of nursing care were extracted. Fifty-six relevant articles were identified (43 on HCC; 10 on RCC; 3 on HCC and RCC). The literature described the role and impact of oncology nurses across a variety of care functions, including in health promotion and screening, care coordination, holistic oversight, symptom and adverse event monitoring and management, and emotional support. Twenty-nine empirical studies/case reports were identified demonstrating benefit of nurse-led interventions in HCC/liver cancer (n = 28) and RCC (n = 1). Benefits were achieved through: improved patient participation in screening programs; reduced time to diagnosis; improved treatment adherence, reduced treatment complications, dose reductions and outpatient visits, and potential cost savings. The oncology nurse plays a multifaceted role in the care of patients with HCC and RCC, but more evidence from nurse-led interventions is required to guide optimal multidisciplinary care of patients with these conditions. [ABSTRACT FROM AUTHOR]

Abstract: Baseline information on the biodiversity of plantation forests, including how it varies with silvicultural methods and along geographic and edaphic gradients, is fundamental when designing conservation and enhancement programmes. Ground flora communities in Sitka spruce (Picea sitchensis), ash (Fraxinus excelsior) and Japanese larch (Larix kaempferi) forests at the main stages of stand structural development, and located across the Republic of Ireland on a range of varied site types, are examined. Using flexible beta clustering and indicator species analysis, eight distinct ground flora community types are identified, varying in composition, structure and/or diversity: (i) grassland, (ii) heath, (iii) basophilic forest, (iv) closed-canopy conifer forest: first stage, (v) closed-canopy conifer forest: second stage, (vi) acidophilic forest: bryophyte-dominated, (vii) acidophilic forest: grass-dominated, and (viii) bramble-dominated. Canonical correspondence analysis (CCA) and variance partitioning are used to assess the relative influence of silvicultural, geographic and edaphic factors on ground flora composition. While geographic (e.g. previous land-use, underlying geology, proximity to old woodland and elevation) and edaphic (e.g. soil pH, organic matter content and extractable Mg and P) factors are important influences, our results demonstrate considerable scope for manipulating ground flora communities through silvicultural operations. We show, in particular, the opportunity for managing stand structure as a means of enhancing ground flora diversity and composition at the plantation scale. [Copyright &y& Elsevier]