Aged G Protein-Coupled Receptor Kinase 3 (Grk3)-Deficient Mice Exhibit Enhanced Osteoclastogenesis and Develop Bone Lesions Analogous to Human Paget's Disease of Bone.

Paget's Disease of Bone (PDB) is a metabolic bone disease that is characterized by dysregulated osteoclast function leading to focal abnormalities of bone remodeling. It can lead to pain, fracture, and bone deformity. G protein-coupled receptor kinase 3 (GRK3) is an important negative regulator of G protein-coupled receptor (GPCR) signaling. GRK3 is known to regulate GPCR function in osteoblasts and preosteoblasts, but its regulatory function in osteoclasts is not well defined. Here, we report that Grk3 expression increases during osteoclast differentiation in both human and mouse primary cells and established cell lines. We also show that aged mice deficient in Grk3 develop bone lesions similar to those seen in human PDB and other Paget's Disease mouse models. We show that a deficiency in Grk3 expression enhances osteoclastogenesis in vitro and proliferation of hematopoietic osteoclast precursors in vivo but does not affect the osteoclast-mediated bone resorption function or cellular senescence pathway. Notably, we also observe decreased Grk3 expression in peripheral blood mononuclear cells of patients with PDB compared with age- and gender-matched healthy controls. Our data suggest that GRK3 has relevance to the regulation of osteoclast differentiation and that it may have relevance to the pathogenesis of PDB and other metabolic bone diseases associated with osteoclast activation.

What a Pandemic Has Taught Us About the Potential for Innovation in Rural Health: Commencing an Ethnography in Canada, the United States, Sweden, and Australia.

The COVID-19 pandemic coincided with a multi-national federally funded research project examining the potential for health and care services in small rural areas to identify and implement innovations in service delivery. The project has a strong focus on electronic health (eHealth) but covers other areas of innovation as well. The project has been designed as an ethnography to prelude a realist evaluation, asking the question under what conditions can local health and care services take responsibility for designing and implementing new service models that meet local needs? The project had already engaged with several health care practitioners and research students based in Canada, Sweden, Australia, and the United States. Our attention is particularly on rural communities with fewer than 5,000 residents and which are relatively isolated from larger service centres. Between March and September 2020, the project team undertook ethnographic and auto-ethnographic research in their own communities to investigate what the service model responses to the pandemic were, and the extent to which local service managers were able to customize their responses to suit the needs of their communities. An initial program theory drawn from the extant literature suggested that "successful" response to the pandemic would depend on a level of local autonomy, "absorptive capacity,*" strong service-community connections, an "anti-fragile†" approach to implementing change, and a realistic recognition of the historical barriers to implementing eHealth and other innovations in these types of rural communities. The field research in 2020 has refined the theory by focusing even more attention on absorptive capacity and community connections, and by suggesting that some level of ignorance of the barriers to innovation may be beneficial. The research also emphasized the role and power of external actors to the community which had not been well-explored in the literature. This paper will summarize both what the field research revealed about the capacity to respond well to the COVID-19 challenge and highlight the gaps in innovative strategies at a managerial level required for rapid response to system stress. *Absorptive Capacity is defined as the ability of an organization (community, clinic, hospital) to adapt to change. Organizations with flexible capacity can incorporate change in a productive fashion, while those with rigid capacity take longer to adapt, and may do so inappropriately. †Antifragility is defined as an entities' ability to gain stability through stress. Biological examples include building muscle through consistent use, and bones becoming stronger through subtle stress. Antifragility has been used as a guiding principle in programme implementation in the past.

Person-centered, non-pharmacological intervention in reducing psychotropic medications use among residents with dementia in Australian rural aged care homes.

BACKGROUND: High rates of psychotropic medications are prescribed in aged care homes despite their limited effectiveness and associated adverse effects. We aim to evaluate the changes in prescription patterns for elderly residents with dementia in the 'Harmony in the Bush Dementia Study'. Harmony in the Bush is a person-centered model of dementia care in nursing homes, based on the principles of Progressively Lowered Stress Threshold and person-centered music intervention. METHODS: Our larger study (12 weeks period) was a quasi-experimental design conducted in five rural nursing homes in Australia. Medication charts (n = 31) were collected retrospectively from three rural aged care facilities. Medication data for each resident was collected from a three-month medication charts, pre-intervention, and post-intervention. Fifty-three staff participated in 31 semi-structured interviews and 8 focus groups at post-intervention, and at 1-month and 3-months follow up. RESULTS: The median age of the participants was 83 years, and 68% of them were female. Polypharmacy was measured in 87% (n = 27) of the participants. Hypertension, hyperlipidemia, diabetes, and the Alzheimer's disease were the major comorbidities identified in residents. None of the residents received more than the maximum dose of psychotropic medications recommended by the guidelines. There was a reduction of 22.4% (77.4% vs 55%) in the use of at least any psychotropic medications, 19.6% (39% vs, 19.4%) reduction in antipsychotics and benzodiazepines (39% vs 19.4%), and 6.5% (42% vs 35.5%) reduction in antidepressants prescription medicines, when comparing residents' medication charts data covering 3-months pre- and post-intervention, however, these changes were not statistically significant. Additionally, there was a decreasing trend in the use of inappropriate medications. Psychotropic medications were prescribed in up to 43% and anti-dementia medications in 44% of participants for more than 6 months. Three themes extracted from qualitative data include decrease behavioral and psychiatric symptoms of dementia due to medication weaning or dose tapering, other strategies to reduce medication use, and environmental or noise control. CONCLUSIONS: Our findings indicate that the Harmony in the Bush model as a non-pharmacological approach reduces the prescription of psychotropic medications in rural nursing homes as supported by findings from both quantitative and qualitative data. TRIAL REGISTRATION: ANZCTR, ACTRN12618000263291 . Registered on 20th February 2018.

A digital collection of rare and endangered lemurs and other primates from the Duke Lemur Center.

Scientific study of lemurs, a group of primates found only on Madagascar, is crucial for understanding primate evolution. Unfortunately, lemurs are among the most endangered animals in the world, so there is a strong impetus to maximize as much scientific data as possible from available physical specimens. MicroCT scanning efforts at Duke University have resulted in scans of more than 100 strepsirrhine cadavers representing 18 species from the Duke Lemur Center. An error study of the microCT scanner recovered less than 0.3% error at multiple resolution levels. Scans include specimen overviews and focused, high-resolution selections of complex anatomical regions (e.g., cranium, hands, feet). Scans have been uploaded to MorphoSource, an online digital repository for 3D data. As captive (but free ranging) individuals, these specimens have a wealth of associated information that is largely unavailable for wild populations, including detailed life history data. This digital collection maximizes the information obtained from rare and endangered animals with minimal degradation of the original specimens.

Reverse Dissection and DiceCT Reveal Otherwise Hidden Data in the Evolution of the Primate Face.

Facial expressions, or facial displays, of social or emotional intent are produced by many mammalian taxa as a means of visually communicating with conspecifics at a close range. These displays are achieved by contraction of the mimetic muscles, which are skeletal muscle attached to the dermis of the face. Reverse dissection, removing the full facial mask from the skull and approaching mimetic muscles in reverse, is an effective but destructive way of revealing the morphology of mimetic muscles but it is destructive. DiceCT is a novel mechanism for visualizing skeletal muscles, including mimetic muscles, and isolating individual muscle fascicles for quantitative measurement. Additionally, DiceCT provides a non-destructive mechanism for visualizing muscles. The combined techniques of reverse dissection and DiceCT can be used to assess the evolutionary morphology of mimetic musculature as well as potential contraction strength and velocity in these muscles. This study further demonstrates that DiceCT can be used to accurately and reliably visualize mimetic muscles as well as reverse dissection and provide a non-destructive method for sampling mimetic muscles.

Inferring locomotor behaviours in Miocene New World monkeys using finite element analysis, geometric morphometrics and machine-learning classification techniques applied to talar morphology.

The talus is one of the most commonly preserved post-cranial elements in the platyrrhine fossil record. Talar morphology can provide information about postural adaptations because it is the anatomical structure responsible for transmitting body mass forces from the leg to the foot. The aim of this study is to test whether the locomotor behaviour of fossil Miocene platyrrhines could be inferred from their talus morphology. The extant sample was classified into three different locomotor categories and then talar strength was compared using finite-element analysis. Geometric morphometrics were used to quantify talar shape and to assess its association with biomechanical strength. Finally, several machine-learning (ML) algorithms were trained using both the biomechanical and morphometric data from the extant taxa to infer the possible locomotor behaviour of the Miocene fossil sample. The obtained results show that the different locomotor categories are distinguishable using either biomechanical or morphometric data. The ML algorithms categorized most of the fossil sample as arboreal quadrupeds. This study has shown that a combined approach can contribute to the understanding of platyrrhine talar morphology and its relationship with locomotion. This approach is likely to be beneficial for determining the locomotor habits in other fossil taxa.

Transparent anemone shrimp (Ancylomenes pedersoni) become opaque after exercise and physiological stress in correlation with increased hemolymph perfusion.

Whole-body transparency, an effective camouflage strategy in many aquatic species, can be disrupted by environmental and/or physiological stressors. We found that tail-flip escape responses temporarily disrupt the transparency of the anemone shrimp Ancylomenes pedersoni After as few as three tail flips, the previously transparent abdominal muscle became cloudy. Eliciting additional tail flips to the point of exhaustion (16±1 s.e.m.; n=23) resulted in complete opacity, though the original transparency returned after 20-60 min of inactivity. We hypothesized that an exercise-induced increase in blood volume between muscle fibers creates regions of low refractive index fluid between high refractive index muscles, thereby increasing light scattering. We documented pre- and post-contraction perfusion by injecting Alexa Fluor 594 wheat germ agglutinin that labeled sarcolemmal surfaces and endothelial cells in contact with hemolymph and found more hemolymph perfused through the abdominal tissue post-exercise, presumably owing to more capillaries opening. In addition, we altered salinity (to 55‰ and 8‰), perforated the abdomen and injected a vasodilator. All three treatments increased both perfusion and opacity, lending further support to our hypothesis that increased hemolymph perfusion to the abdomen is one mechanism that can disrupt a shrimp's transparency. The fact that transparent shrimp at rest have little to no evidence of perfusion to their abdominal musculature (unlike the opaque shrimp Lysmata pederseni, which had more perfusion even at rest) indicates that they may experience significant physiological trade-offs in order to maintain their transparency; specifically, limiting blood flow and thereby reducing oxygen delivery may result in reduced performance.

The evolution of the platyrrhine talus: A comparative analysis of the phenetic affinities of the Miocene platyrrhines with their modern relatives.

Platyrrhines are a diverse group of primates that presently occupy a broad range of tropical-equatorial environments in the Americas. However, most of the fossil platyrrhine species of the early Miocene have been found at middle and high latitudes. Although the fossil record of New World monkeys has improved considerably over the past several years, it is still difficult to trace the origin of major modern clades. One of the most commonly preserved anatomical structures of early platyrrhines is the talus. This work provides an analysis of the phenetic affinities of extant platyrrhine tali and their Miocene counterparts through geometric morphometrics and a series of phylogenetic comparative analyses. Geometric morphometrics was used to quantify talar shape affinities, while locomotor mode percentages (LMPs) were used to test if talar shape is associated with locomotion. Comparative analyses were used to test if there was convergence in talar morphology, as well as different models that could explain the evolution of talar shape and size in platyrrhines. Body mass predictions for the fossil sample were also computed using the available articular surfaces. The results showed that most analyzed fossils exhibit a generalized morphology that is similar to some 'generalist' modern species. It was found that talar shape covaries with LMPs, thus allowing the inference of locomotion from talar morphology. The results further suggest that talar shape diversification can be explained by invoking a model of shifts in adaptive peak to three optima representing a phylogenetic hypothesis in which each platyrrhine family occupied a separate adaptive peak. The analyses indicate that platyrrhine talar centroid size diversification was characterized by an early differentiation related to a multidimensional niche model. Finally, the ancestral platyrrhine condition was reconstructed as a medium-sized, generalized, arboreal, quadruped.

Measuring organisational-level Aboriginal cultural climate to tailor cultural safety strategies.

INTRODUCTION: Australian medical schools have taken on a social accountability mandate to provide culturally safe contexts in order to encourage Aboriginal and Torres Strait Islander people to engage in medical education and to ensure that present and future clinicians provide health services that contribute to improving the health outcomes of Aboriginal and Torres Strait Islander peoples. Many programs have sought to improve cultural safety through training at an individual level; however, it is well recognised that learners tend to internalise the patterns of behaviour to which they are commonly exposed. This project aimed to measure and reflect on the cultural climate of an Australian rural clinical school (RCS) as a whole and the collective attitudes of three different professional groups: clinicians, clinical academics and professional staff. The project then drew on Mezirow's Transformative Learning theory to design strategies to build on the cultural safety of the organisation. METHODS: Clinicians, academic and professional staff at an Australian RCS were invited to participate in an online survey expressing their views on Aboriginal health using part of a previously validated tool. RESULTS: Survey response rate was 63%. All three groups saw Aboriginal health as a social priority. All groups recognised the fundamental role of community control in Aboriginal health; however, clinical academics were considerably more likely to disagree that the Western medical model suited the health needs of Aboriginal people. Clinicians were more likely to perceive that they treated Aboriginal patients the same as other patients. There was only weak evidence of future commitments to Aboriginal health. Importantly, clinicians, academics and professional staff demonstrated differences in their cultural safety profile which indicated the need for a tailored approach to cultural safety learning in the future. CONCLUSIONS: Through tailored approaches to cross-cultural training opportunities we are likely to ensure participants are able to engage with the material and reflect upon implications of a challenging cultural climate on the health and wellbeing outcomes of Aboriginal people.

Predicting euarchontan body mass: A comparison of tarsal and dental variables.

OBJECTIVE: Multiple meaningful ecological characterizations of a species revolve around body mass. Because body mass cannot be directly measured in extinct taxa, reliable body mass predictors are needed. Many published body mass prediction equations rely on dental dimensions, but certain skeletal dimensions may have a more direct and consistent relationship with body mass. We seek to evaluate the reliability of prediction equations for inferring euarchontan body mass based on measurements of the articular facet areas of the astragalus and calcaneus. METHODS: Surface areas of five astragalar facets (n = 217 specimens) and two calcaneal facets (n = 163) were measured. Separate ordinary least squares and multiple regression equations are presented for different levels of taxonomic inclusivity, and the reliability of each equation is evaluated with the coefficient of determination, standard error of the estimate, mean prediction error, and the prediction sum of squares statistic. We compare prediction errors to published prediction equations that utilize dental and/or tarsal measures. Finally, we examine the effects of taxonomically specific regressions and apply our equations to a diverse set of non-primates. RESULTS: Our results reveal that predictions based on facet areas are more reliable than most linear dental or tarsal predictors. Multivariate approaches are often better than univariate methods, but require more information (making them less useful for fragmentary fossils). While some taxonomically specific regressions improve predictive ability, this is not true for all primate groups. CONCLUSIONS: Among individual facets, the ectal and fibular facets of the astragalus and the calcaneal cuboid facet are the best body mass predictors. Since these facets have primarily concave curvature and scale with positive allometry relative to body mass, it appears that candidate skeletal proxies for body mass can be identified based on their curvature and scaling coefficients.

A new fully automated approach for aligning and comparing shapes.

Three-dimensional geometric morphometric (3DGM) methods for placing landmarks on digitized bones have become increasingly sophisticated in the last 20 years, including greater degrees of automation. One aspect shared by all 3DGM methods is that the researcher must designate initial landmarks. Thus, researcher interpretations of homology and correspondence are required for and influence representations of shape. We present an algorithm allowing fully automatic placement of correspondence points on samples of 3D digital models representing bones of different individuals/species, which can then be input into standard 3DGM software and analyzed with dimension reduction techniques. We test this algorithm against several samples, primarily a dataset of 106 primate calcanei represented by 1,024 correspondence points per bone. Results of our automated analysis of these samples are compared to a published study using a traditional 3DGM approach with 27 landmarks on each bone. Data were analyzed with morphologika(2.5) and PAST. Our analyses returned strong correlations between principal component scores, similar variance partitioning among components, and similarities between the shape spaces generated by the automatic and traditional methods. While cluster analyses of both automatically generated and traditional datasets produced broadly similar patterns, there were also differences. Overall these results suggest to us that automatic quantifications can lead to shape spaces that are as meaningful as those based on observer landmarks, thereby presenting potential to save time in data collection, increase completeness of morphological quantification, eliminate observer error, and allow comparisons of shape diversity between different types of bones. We provide an R package for implementing this analysis.

Evolution and allometry of calcaneal elongation in living and extinct primates.

Specialized acrobatic leaping has been recognized as a key adaptive trait tied to the origin and subsequent radiation of euprimates based on its observed frequency in extant primates and inferred frequency in extinct early euprimates. Hypothesized skeletal correlates include elongated tarsal elements, which would be expected to aid leaping by allowing for increased rates and durations of propulsive acceleration at takeoff. Alternatively, authors of a recent study argued that pronounced distal calcaneal elongation of euprimates (compared to other mammalian taxa) was related primarily to specialized pedal grasping. Testing for correlations between calcaneal elongation and leaping versus grasping is complicated by body size differences and associated allometric affects. We re-assess allometric constraints on, and the functional significance of, calcaneal elongation using phylogenetic comparative methods, and present an evolutionary hypothesis for the evolution of calcaneal elongation in primates using a Bayesian approach to ancestral state reconstruction (ASR). Results show that among all primates, logged ratios of distal calcaneal length to total calcaneal length are inversely correlated with logged body mass proxies derived from the area of the calcaneal facet for the cuboid. Results from phylogenetic ANOVA on residuals from this allometric line suggest that deviations are explained by degree of leaping specialization in prosimians, but not anthropoids. Results from ASR suggest that non-allometric increases in calcaneal elongation began in the primate stem lineage and continued independently in haplorhines and strepsirrhines. Anthropoid and lorisid lineages show stasis and decreasing elongation, respectively. Initial increases in calcaneal elongation in primate evolution may be related to either development of hallucal-grasping or a combination of grasping and more specialized leaping behaviors. As has been previously suggested, subsequent increases in calcaneal elongation are likely adaptations for more effective acrobatic leaping, highlighting the importance of this behavior in early euprimate evolution.

A calcaneus attributable to the primitive late Eocene anthropoid Proteopithecus sylviae: phenetic affinities and phylogenetic implications.

A well-preserved calcaneus referrable to Proteopithecus sylviae from the late Eocene Quarry L-41 in the Fayum Depression, Egypt, provides new evidence relevant to this taxon's uncertain phylogenetic position. We assess morphological affinities of the new specimen using three-dimensional geometric morphometric analyses with a comparative sample of primate calcanei representing major extinct and extant radiations (n = 58 genera, 106 specimens). Our analyses reveal that the calcaneal morphology of Proteopithecus is most similar to that of the younger Fayum parapithecid Apidium. Principal components analysis places Apidium and Proteopithecus in an intermediate position between primitive euprimates and crown anthropoids, based primarily on landmark configurations corresponding to moderate distal elongation, a more distal position of the peroneal tubercle, and a relatively "unflexed" calcaneal body. Proteopithecus and Apidium are similar to cercopithecoids and some omomyiforms in having an ectal facet that is more tightly curved, along with a larger degree of proximal calcaneal elongation, whereas other Fayum anthropoids, platyrrhines and adapiforms have a more open facet with less proximal elongation. The similarity to cercopithecoids is most plausibly interpreted as convergence given the less tightly curved ectal facets of stem catarrhines. The primary similarities between Proteopithecus and platyrrhines are mainly in the moderate distal elongation and the more distal position of the peroneal tubercle, both of which are not unique to these groups. Proteopithecus and Apidium exhibit derived anthropoid features, but also a suite of primitive retentions. The calcaneal morphology of Proteopithecus is consistent with our cladistic analysis, which places proteopithecids as a sister group of Parapithecoidea.

Evaluating the long-term effectiveness of the Maternity Emergency Care course in remote Australia.

BACKGROUND: The Council for Remote Area Nurses of Australia deliver the MEC course which is the only short-course on maternity emergencies offered to non-midwifery qualified remote area nurses and Aboriginal Health Workers. The aim of the course is to improve the maternity emergency skills and knowledge of health service providers who do not have midwifery qualifications. There has been no long-term evaluation of the course since its inception. RESEARCH OBJECTIVE: To review the longer-term effectiveness of the maternity emergency care (MEC) course which was developed in consultation with the Australian College of Midwives (ACM) and rural and remote practitioners in 2003. PARTICIPANTS AND METHODS: Fifty-seven clinicians who completed the MEC course since 2003 responded to a survey. Seven remote area health managers and two course facilitators were interviewed. RESULTS: This study provides an evaluation of the experiences of non-midwives who manage maternity emergencies in the rural and remote setting; their perception of the skills, knowledge and confidence acquired through participation in the MEC program. CONCLUSIONS: The MEC course is valued by both remote health managers and practitioners. The learning activities, skills and knowledge gained are reported to be very beneficial and used by remote health practitioners.

Ethical research in partnership with an Indigenous community.

OBJECTIVE: The aim of this paper is to describe the implementation of the Community Safety Research Project (CSRP) focusing on violence prevention among Aboriginal communities in western NSW in order to examine how practice converges with contemporary ethical guidelines. METHOD: A comparison was made of key project elements with the principles outlined in existing ethical guidelines, outlining the concrete issues that need to be confronted in practice. RESULTS: The approach being pursued is consonant with the principles of contemporary guidelines; the results of the first phase qualitative study inquiring into workers' perceptions of violence revealed some differences in the understanding of violence between Aboriginal and non-Aboriginal workers, with some ethical implications. CONCLUSIONS: Ethical approaches to research among Aboriginal communities include, but extend well beyond, the principle of avoiding harm. A comprehensive approach to ethical research requires significant ongoing expenditure of effort and resources with implications for project development, management and funding.