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Glucocorticoids may be given prior to major orthopedic surgery to decrease postoperative nausea, vomiting, and pain. Additionally, many orthopedic patients may be on chronic glucocorticoid therapy. The aim of our study was to investigate whether glucocorticoid administration influences Orthopedic-Device-Related Infection (ODRI) in a rat model. Screws colonized with Staphylococcus epidermidis were implanted in the tibia of skeletally mature female Wistar rats. The treated groups received either a single shot of dexamethasone in a short-term risk study, or a daily dose of dexamethasone in a longer-term interference study. In both phases, bone changes in the vicinity of the implant were monitored with microCT. There were no statistically significant differences in bacteriological outcome with or without dexamethasone. In the interference study, new bone formation was statistically higher in the dexamethasone-treated group (p = 0.0005) as revealed by CT and histopathological analysis, although with relatively low direct osseointegration of the implant. In conclusion, dexamethasone does not increase the risk of developing periprosthetic osteolysis or infection in a pre-clinical model of ODRI. Long-term administration of dexamethasone seemed to offer a benefit in terms of new bone formation around the implant, but with low osseointegration.

In this essay I explain that the Christian doctrine of the Trinity was first developed as a response to Jewish claims of Christian apostasy and polytheism. At the beginning of Christianity, most of its converts were observant Jews. The Jewish authorities took steps to reclaim their lost sheep and to stem the flow of departures. Their primary intellectual ammunition in that effort was the claim that the Christians were polytheists, because they claimed to believe in two Gods–the Father and His Son, Jesus Christ. The Christians’ apostasy was manifest by simple referring to the Mosaic commandment that righteous Israel should have only one God. This Jewish accusation of polytheism also neatly answered the inflammatory Christian charge that the Jews had crucified God and raised significant doubt about their claims of a special resurrection. The doctrine of the Trinity answered all those criticisms. God and Jesus Christ together were the one true God. But the nature of that oneness took some time to work out, and it is within a process of contending with pagan philosophical arguments and intra-Christian heretical positions, that a Christian doctrine of the Trinity begins to congeal. The work of Ante-Nicene Fathers—Justin Martyr, Theophilus of Antioch, Clement of Alexandria, Tertullian, Origen, Novatian, and others—whose voices we allow to be heard below—contain a trajectory of ideas that explain how the tri-unity is expressed in the momentous Creeds of Nicaea (AD 325) and Constantinople (381).

Abstract Background The onset of the COVID-19 pandemic necessitated a rapid shift in primary health care from predominantly in-person to high volumes of virtual care. The pandemic afforded the opportunity to conduct a deep regional examination of virtual care by family physicians in London and Middlesex County, Ontario, Canada that would inform the foundation for virtual care in our region post-pandemic. Objectives: (1) to determine volumes of in-person and virtual family physicians visits and characteristics of the family physicians and patients using them during the early COVID-19 pandemic; (2) to determine how virtual visit volumes changed over the pandemic, compared to in-person; and (3) to explore family physicians’ experience in virtual visit adoption and implementation. Methods We conducted a concurrent mixed-methods study of family physicians from March to October 2020. The quantitative component examined mean weekly number of total, in-person and virtual visits using health administrative data. Differences in outcomes according to physician and practice characteristics for pandemic periods were compared to pre-pandemic. The qualitative study employed Constructivist Grounded Theory, conducting semi-structured family physicians interviews; analyzing data iteratively using constant comparative analysis. We mapped themes from the qualitative analysis to quantitative findings. Results Initial volumes of patients decreased, driven by fewer in-person visits. Virtual visit volumes increased dramatically; family physicians described using telephone almost entirely. Rural family physicians reported video connectivity issues. By early second wave, total family physician visit volume returned to pre-pandemic volumes. In-person visits increased substantially; family physicians reported this happened because previously scarce personal protective equipment became available. Patients seen during the pandemic were older, sicker, and more materially deprived. Conclusion These results can inform the future of virtual family physician care including the importance of continued virtual care compensation, the need for equitable family physician payment models, and the need to attend to equity for vulnerable patients. Given the move to virtual care was primarily a move to telephone care, the modality of care delivery that is acceptable to both family physicians and their patients must be considered.

Globally, thousands of institutions house nearly three billion scientific collections offering unparallelled resources that contribute to both science and society. For herbaria alone - facilities housing dried plant collections - there are over 3,000 herbaria worldwide with an estimated 350 million specimens that have been collected over the past four centuries. Digitisation has greatly enhanced the use of herbarium data in scientific research, impacting diverse research areas, including biodiversity informatics, global climate change, analyses using next-generation sequencing technologies and many others. Despite the entrance of herbaria into a new era with enhanced scientific, educational and societal relevance, museum specimens remain underused. Natural history museums can enhance learning and engagement in science, particularly for school-age and undergraduate students. Here, we outline a novel approach of a natural history museum using touchscreen technology that formed part of an interactive kiosk in a temporary museum exhibit on biological specimens. We provide some preliminary analysis investigating the efficacy of the tool, based on the Zooniverse platform, in an exhibit environment to engage patrons in the collection of biological data. We conclude there is great potential in using crowd‐sourced science, coupled with online technology to unlock data and information from digital images of natural history specimens themselves. Sixty percent of the records generated by community scientists (citizen scientists) were of high enough quality to be utilised by researchers. All age groups produced valid, high quality data that could be used by researchers, including children (10 and under), teens and adults. Significantly, the paper outlines the implementation of experiential learning through an undergraduate mathematics course that focuses on projects with actual data to gain a deep, practical knowledge of the subject, including observations, the collection of data, analysis and problem solving. We here promote an intergenerational model including children, high school students, undergraduate students, early career scientists and senior scientists, combining experiential learning, museum patrons, researchers and data derived from natural history collections. Natural history museums with their dual remit of education and collections-based research can play a significant role in the field of community engagement and people-powered research. There also remains much to investigate on the use of interactive displays to help learners interpret and appreciate authentic research. We conclude with a brief insight into the next phase of our ongoing people-powered research activities developed and designed by high school students using the Zooniverse platform.

Abstract Bone tissue engineering is a rapidly developing field with potential for the regeneration of craniomaxillofacial (CMF) bones, with 3D printing being a suitable fabrication tool for patient‐specific implants. The CMF region includes a variety of different bones with distinct functions. The clinical implementation of tissue engineering concepts is currently poor, likely due to multiple reasons including the complexity of the CMF anatomy and biology, and the limited relevance of the currently used preclinical models. The ‘recapitulation of a human disease’ is a core requisite of preclinical animal models, but this aspect is often neglected, with a vast majority of studies failing to identify the specific clinical indication they are targeting and/or the rationale for choosing one animal model over another. Currently, there are no suitable guidelines that propose the most appropriate animal model to address a specific CMF pathology and no standards are established to test the efficacy of biomaterials or tissue engineered constructs in the CMF field. This review reports the current clinical scenario of CMF reconstruction, then discusses the numerous limitations of currently used preclinical animal models employed for validating 3D‐printed tissue engineered constructs and the need to reduce animal work that does not address a specific clinical question. We will highlight critical research aspects to consider, to pave a clinically driven path for the development of new tissue engineered materials for CMF reconstruction.

Objective: Bone infections are challenging to treat because of limited capability of systemic antibiotics to accumulate at the bone site. To enhance therapeutic action, systemic treatments are commonly combined with local antibiotic-loaded materials. Nevertheless, available drug carriers have undesirable properties, including inappropriate antibiotic release profiles and nonbiodegradability. To alleviate such limitations, we aim to develop a drug delivery system (DDS) for local administration that can interact strongly with bone mineral, releasing antibiotics at the infected bone site. Methods: Biodegradable polyesters (poly (ε-caprolactone) or poly (D,l-lactic acid)) were selected to fabricate antibiotic-loaded microspheres by oil in water emulsion. Antibiotic release and antimicrobial effects on Staphylococcus aureus were assessed by zone of inhibition measurements. Microsphere bone affinity was increased by functionalising the bisphosphonate drug alendronate to the microsphere surface using carbodiimide chemistry. Effect of bone targeting microspheres on bone homeostasis was tested by looking at the resorption potential of osteoclasts exposed to the developed microspheres. Results: In vitro, the antibiotic release profile from the microspheres was shown to be dependent on the polymer used and the microsphere preparation method. Mineral binding assays revealed that microsphere surface modification with alendronate significantly enhanced interaction with bone-like materials. Additionally, alendronate functionalised microspheres did not differentially affect osteoclast mineral resorption in vitro, compared with nonfunctionalised microspheres. Conclusion: We report the development and characterisation of a DDS which can release antibiotics in a sustained manner. Surface-grafted alendronate groups enhanced bone affinity of the microsphere construct, resulting in a bone targeting DDS. The Translational Potential of this Article: The DDS presented can be loaded with hydrophobic antibiotics, representing a potential, versatile and biodegradable candidate to locally treat bone infection. Keywords: Alendronate, Bone infection, Bone targeting, Drug delivery, Microparticle, Osteomyelitis

Abstract Snus is an oral smokeless tobacco product which is usually placed behind the upper lip, either in a loose form or in portioned sachets, and is primarily used in Sweden and Norway. The purpose of this review is to examine the reported effects of snus use in relation to specified health effects, namely lung cancer, cardiovascular disease, pancreatic cancer, diabetes, oral cancer and non-neoplastic oral disease. The review also examines the harm reduction potential of snus as an alternative to cigarettes by comparing the prevalence of snus use and cigarette smoking, and the reported incidence of tobacco-related diseases across European Union countries. The scientific literature generally indicates that the use of snus is not a significant risk factor for developing lung cancer, cardiovascular disease, pancreatic cancer or oral cancer. Studies investigating snus use and diabetes have reported that high consumption of snus (estimated as being four or more cans per week) may be associated with a higher risk of developing diabetes or components of metabolic syndrome; however, overall results are not conclusive. Snus use is associated with the presence of non-neoplastic oral mucosal lesions which are reported to heal rapidly once use has stopped. The most recent Eurobarometer data from 2017 reported that Sweden had the lowest prevalence of daily cigarette use in the European Union at 5% whilst daily “oral tobacco” use was reported to be 20%. European data published by the World Health Organisation in 2018 indicated that Sweden had the lowest rate of tobacco-related mortality and the lowest incidence of male lung cancer. Overall, prevalence statistics and epidemiological data indicate that the use of snus confers a significant harm reduction benefit which is reflected in the comparatively low levels of tobacco-related disease in Sweden when compared with the rest of Europe. The available scientific data, including long-term population studies conducted by independent bodies, demonstrates that the health risks associated with snus are considerably lower than those associated with cigarette smoking.

Biomechanical stability plays an important role in fracture healing, with unstable fixation being associated with healing disturbances. A lack of stability is also considered a risk factor for fracture-related infection (FRI), although confirmatory studies and an understanding of the underlying mechanisms are lacking. In the present study, we investigate whether biomechanical (in)stability can lead to altered immune responses in mice under sterile or experimentally inoculated conditions. In non-inoculated C57BL/6 mice, instability resulted in an early increase of inflammatory markers such as granulocyte-colony stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin (IL)-6 within the bone. When inoculated with Staphylococcus epidermidis, instability resulted in a further significant increase in G-CSF, IL-6 and KC in bone tissue. Staphylococcus aureus infection led to rapid osteolysis and instability in all animals and was not further studied. Gene expression measurements also showed significant upregulation in CCL2 and G-CSF in these mice. IL-17A was found to be upregulated in all S. epidermidis infected mice, with higher systemic IL-17A cell responses in mice that cleared the infection, which was found to be produced by CD4+ and γδ+ T cells in the bone marrow. IL-17A knock-out (KO) mice displayed a trend of delayed clearance of infection (P=0.22, Fisher’s exact test) and an increase in interferon (IFN)-γ production. Biomechanical instability leads to a more pronounced local inflammatory response, which is exaggerated by bacterial infection. This study provides insights into long-held beliefs that biomechanics are crucial not only for fracture healing, but also for control of infection.

Short-chain fatty acids (SCFAs) produced by the gut microbiota have previously been demonstrated to play a role in numerous chronic inflammatory diseases and to be key mediators in the gut-bone signaling axis. However, the role of SCFAs in bone fracture healing and its impact on systemic inflammation during the regeneration process has not been extensively investigated yet. The aim of this study was to first determine the effects of the SCFA butyrate on key cells involved in fracture healing in vitro, namely, osteoclasts and mesenchymal stromal cells (MSCs), and second, to assess if butyrate supplementation or antibiotic therapy impacts bone healing, systemic immune status, and inflammation levels in a murine osteotomy model. Butyrate significantly reduced osteoclast formation and resorption activity in a dose-dependent manner and displayed a trend for increased calcium deposits in MSC cultures. Numerous genes associated with osteoclast differentiation were differentially expressed in osteoclast precursor cells upon butyrate exposure. In vivo, antibiotic-treated mice showed reduced SCFA levels in the cecum, as well as a distinct gut microbiome composition. Furthermore, circulating proinflammatory TNFα, IL-17a, and IL-17f levels, and bone preserving osteoprotegerin (OPG), were increased in antibiotic-treated mice compared to controls. Antibiotic-treated mice also displayed a trend towards delayed bone healing as revealed by reduced mineral apposition at the defect site and higher circulating levels of the bone turnover marker PINP. Butyrate supplementation resulted in a lower abundance of monocyte/macrophages in the bone marrow, as well as reduced circulating proinflammatory IL-6 levels compared to antibiotic- and control-treated mice. In conclusion, this study supports our hypothesis that SCFAs, in particular butyrate, are important contributors to successful bone healing by modulating key cells involved in fracture healing as well as systemic inflammation and immune responses.

Although most bone fractures typically heal without complications, a small proportion of patients (≤10%) experience delayed healing or potential progression to non-union. Interleukin-1 (IL-1β) plays a crucial role in fracture healing as an early driver of inflammation. However, the effects of IL-1β can impede the healing process if they persist long after the establishment of a fracture hematoma, making it a promising target for novel therapies. Accordingly, the overall objective of this study was to develop a novel gene-based therapy that mitigates the negative effects of IL-1β-driven inflammation while providing a structural template for new bone formation. A collagen-hydroxyapatite scaffold (CHA) was used as a platform for the delivery of nanoparticles composed of pDNA, encoding for IL-1 receptor antagonist (IL-1Ra), complexed to the robust non-viral gene delivery vector, polyethyleneimine (PEI). Utilizing pDNA encoding for Gaussia luciferase and GFP as reporter genes, we found that PEI-pDNA nanoparticles induced a transient gene expression profile in rat bone marrow-derived mesenchymal stromal cells (BM-MSCs), with a transfection efficiency of 14.8 ± 1.8% in 2D. BM-MSC viability was significantly affected by PEI-pDNA nanoparticles as evaluated using CellTiter Blue; however, after 10 days in culture this effect was negligible. Transfection with PEI-pIL-1Ra nanoparticles led to functional IL-1Ra production, capable of antagonizing IL-1β-induced expression of secreted embryonic alkaline phosphatase from HEK-Blue-IL-1β reporter cells. Sustained treatment with IL-1β (0.1, 1, and 10 ng/ml) had a dose-dependent negative effect on BM-MSC osteogenesis, both in terms of gene expression (Alpl and Ibsp) and calcium deposition. BM-MSCs transfected with PEI-IL-1Ra nanoparticles were found to be capable of overcoming the inhibitory effects of sustained IL-1β (1 ng/ml) treatments on in vitro osteogenesis. Ultimately, IL-1Ra gene-activated CHA scaffolds supported mineralization of BM-MSCs under chronic inflammatory conditions in vitro, demonstrating potential for future therapeutic applications in vivo.

Total joint arthroplasty (TJA) surgeries are common orthopedic procedures, but bacterial infection remains a concern. The aim of this study was to assess interactions between wear particles (WPs) and immune cells in vitro and to investigate if WPs affect the severity, or response to antibiotic therapy, of a Staphylococcus epidermidis orthopedic device-related infection (ODRI) in a rodent model. Biofilms grown on WPs were challenged with rifampin and cefazolin (100 µg/mL) to determine antibiotic efficacy. Neutrophils or peripheral blood mononuclear cells (PBMCs) were incubated with or without S. epidermidis and WPs, and myeloperoxidase (MPO) and cytokine release were analyzed, respectively. In the ODRI rodent model, rats (n = 36) had a sterile or S. epidermidis-inoculated screw implanted in the presence or absence of WPs, and a subgroup was treated with antibiotics. Bone changes were monitored using microCT scanning. The presence of WPs decreased antibiotic efficacy against biofilm-resident bacteria and promoted MPO and pro-inflammatory cytokine production in vitro. WPs exacerbated osteolytic responses to S. epidermidis infection and markedly reduced antibiotic efficacy in vivo. Overall, this work shows that the presence of titanium WPs reduces antibiotic efficacy in vitro and in vivo, induces proinflammatory cytokine release, and exacerbates S. epidermidis-induced osteolysis.

A major challenge for managing impacts and implementing effective mitigation measures and adaptation strategies for coastal zones affected by future sea level (SL) rise is our limited capacity to predict SL change at the coast on relevant spatial and temporal scales. Predicting coastal SL requires the ability to monitor and simulate a multitude of physical processes affecting SL, from local effects of wind waves and river runoff to remote influences of the large-scale ocean circulation on the coast. Here we assess our current understanding of the causes of coastal SL variability on monthly to multi-decadal timescales, including geodetic, oceanographic and atmospheric aspects of the problem, and review available observing systems informing on coastal SL. We also review the ability of existing models and data assimilation systems to estimate coastal SL variations and of atmosphere-ocean global coupled models and related regional downscaling efforts to project future SL changes. We discuss (1) observational gaps and uncertainties, and priorities for the development of an optimal and integrated coastal SL observing system, (2) strategies for advancing model capabilities in forecasting short-term processes and projecting long-term changes affecting coastal SL, and (3) possible future developments of sea level services enabling better connection of scientists and user communities and facilitating assessment and decision making for adaptation to future coastal SL change.

Orthopedic device-related infection (ODRI) is a potentially devastating complication arising from the colonization of the device with bacteria, such as Staphylococcus aureus. The aim of this study was to determine if intraoperative loading of a clinically approved calcium phosphate (CaP) coating with gentamicin can protect from ODRI in vivo. First, CaP-coated titanium aluminium niobium (TAN) discs were used to investigate the adsorption and release kinetics of gentamicin in vitro. Gentamicin loading and subsequent release from the coating were both rapid, with maximum loading occurring following one second of immersion, and >95% gentamicin released within 15 min in aqueous solution, respectively. Second, efficacy of the gentamicin-loaded CaP coating for preventing ODRI in vivo was investigated using a CaP-coated unicortical TAN screw implanted into the proximal tibia of skeletally mature female Wistar rats, following inoculation of the implant site with S. aureus. Gentamicin-loading prevented ODRI in 7/8 animals, whereas 9/9 of the non-gentamicin treated animals were infected after 7 days. In conclusion, gentamicin can be rapidly and simply loaded onto, and released from, CaP-based implant coatings, and this is an effective strategy for preventing peri-operative S. aureus-induced ODRI in vivo.

The ability of bone-marrow-derived mesenchymal stem/stromal cells (BM-MSCs) to differentiate into osteoblasts makes them the ideal candidate for cell-based therapies targeting bone-diseases. Polyphosphate (polyP) is increasingly being studied as a potential inorganic source of phosphate for extracellular matrix mineralisation. The aim of this study is to investigate whether polyP can effectively be used as a phosphate source during the in vitro osteogenic differentiation of human BM-MSCs. Human BM-MSCs are cultivated under osteogenic conditions for 28 days with phosphate provided in the form of organic β-glycerolphosphate (BGP) or calcium-polyP nanoparticles (polyP-NP). Mineralisation is demonstrated using Alizarin red staining, cellular ATP content, and free phosphate levels are measured in both the cells and the medium. The effects of BGP or polyP-NP on alkaline phosphatase (ALP) activity and gene expression of a range of osteogenic-related markers are also assessed. PolyP-NP supplementation displays comparable effects to the classical BGP-containing osteogenic media in terms of mineralisation, ALP activity and expression of osteogenesis-associated genes. This study shows that polyP-NP act as an effective source of phosphate during mineralisation of BM-MSC. These results open new possibilities with BM-MSC-based approaches for bone repair to be achieved through doping of conventional biomaterials with polyP-NP.

Staphylococcus epidermidis is a permanent member of the normal human microbiota, commonly found on skin and mucous membranes. By adhering to tissue surface moieties of the host via specific adhesins, S. epidermidis is capable of establishing a lifelong commensal relationship with humans that begins early in life. In its role as a commensal organism, S. epidermidis is thought to provide benefits to human host, including out-competing more virulent pathogens. However, largely due to its capacity to form biofilm on implanted foreign bodies, S. epidermidis has emerged as an important opportunistic pathogen in patients receiving medical devices. S. epidermidis causes approximately 20% of all orthopedic device-related infections (ODRIs), increasing up to 50% in late-developing infections. Despite this prevalence, it remains underrepresented in the scientific literature, in particular lagging behind the study of the S. aureus. This review aims to provide an overview of the interactions of S. epidermidis with the human host, both as a commensal and as a pathogen. The mechanisms retained by S. epidermidis that enable colonization of human skin as well as invasive infection, will be described, with a particular focus upon biofilm formation. The host immune responses to these infections are also described, including how S. epidermidis seems to trigger low levels of pro-inflammatory cytokines and high levels of interleukin-10, which may contribute to the sub-acute and persistent nature often associated with these infections. The adaptive immune response to S. epidermidis remains poorly described, and represents an area which may provide significant new discoveries in the coming years.

Krill oil is a rich source of the long-chain n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which may alter immune function after exercise. The aim of the study was to determine the effects of krill oil supplementation on post exercise immune function and performance.Nineteen males and 18 females (age: 25.8 ± 5.3 years; mean ± S.D.) were randomly assigned to 2 g/day of krill oil (n = 18) or placebo (n = 19) supplementation for 6 weeks. A maximal incremental exercise test and cycling time trial (time to complete set amount of work) were performed pre-supplementation with the time trial repeated post-supplementation. Blood samples collected pre- and post- supplementation at rest, and immediately, 1 and 3h post-exercise. Plasma IL-6 and thiobarbituric acid reactive substances (TBARS) concentrations and, erythrocyte fatty acid composition were measured. Natural killer (NK) cell cytotoxic activity and peripheral blood mononuclear cell (PBMC) IL-2, IL-4, IL-10, IL-17 and IFNγ production were also measured.No effects of gender were noted for any variable. PBMC IL-2 and NK cell cytotoxic activity were greater (P < 0.05) 3h post exercise in the krill oil compared to the control group. Plasma IL-6 and TBARS, PBMC IL-4, IL-10, IL-17 and IFNγ production, along with performance and physiological measures during exercise, were not different between groups.Six weeks of krill oil supplementation can increase PBMC IL-2 production and NK cell cytotoxic activity 3h post-exercise in both healthy young males and females. Krill oil does not modify exercise performance.

Heated tobacco products represent a novel category of tobacco products in which a tobacco consumable is heated to a temperature that releases nicotine from the tobacco leaf but not to a temperature sufficient to cause combustion. Heated tobacco products may therefore have the potential to be a less harmful alternative for adult smokers that would otherwise continue to smoke conventional cigarettes. Given the rapid development of this product category, the aim of this review was to examine the available peer-reviewed scientific evidence related to heated tobacco products and highlight any research gaps. In recent years, manufacturers of heated tobacco products have published a number of studies on their respective heated tobacco products. Whilst there is limited research that is independent of commercial interests, the available scientific evidence indicates that heated tobacco products produce a much simpler aerosol than conventional cigarette smoke, with fewer and substantially lower levels of harmful toxicants. Toxicology assessments indicate these reductions in aerosol toxicants translate to reduced biological effects. Biomarker and clinical data from studies in which product use is controlled within a clinical setting, indicate changes in biomarker levels and clinical end-points similar to observations in cessation studies, indicating the potential for reduced harm. The scientific evidence also indicates that exposure of non-users to emissions from heated tobacco products in indoor environments is significantly reduced compared to exposure resulting from smoking conventional cigarettes. Overall, the available scientific evidence indicates that heated tobacco products hold promise as a less harmful alternative to conventional cigarettes, but more independent data is required to validate industry findings. As a growing product category, epidemiological studies and independent population modelling studies are outstanding, and empirical data on how dual tobacco product category use by consumers affects their risk profile is lacking.