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Although several different contouring instructional programs are available to radiation oncologists and trainees, very little is known about which methods and resources benefit learners most, and whether some learners may need alternate forms of instruction. This study aimed to determine the factors that were predictors of learners' success in anatomy, radiology, and contouring education.Participants in the online and face-to-face Anatomy and Radiology Contouring (ARC) Bootcamp completed pre- and postintervention evaluations that assessed anatomy/radiology knowledge, contouring skills, self-confidence, and spatial ability. Baseline factors were assessed as predictors of outcomes across multiple educational domains.One hundred and eighty (face-to-face: n = 40; online: n = 140) participants enrolled in the ARC Bootcamp, and 57 (face-to-face: n = 30; online: n = 27) participants completed both evaluations. Of the participants enrolled, 37% were female, and most were radiation oncology residents (62%). In the anatomy/radiology knowledge testing, all quartiles (based on baseline performance) improved numerically; however, the largest improvements occurred in learners with the lowest baseline scores (P.001). At the end of the Bootcamp, learners with lower-performing scores did not reach the level of learners with the highest baseline scores (Bonferroni-corrected P.001). Regarding the contouring assessment, improvements were only evident for the participants with lower-performing baseline scores (P.05). Spatial anatomy skills, as measured by the spatial anatomy task, were correlated to contouring ability. Overall, the greatest improvements were seen for learners in postgraduate year 1 to 3, those with no previous rotation experience in a given discipline, and those who attended from other programs (ie, medical physics residents and medical students).The ARC Bootcamp improved all levels of performers' anatomy and radiology knowledge but only lower-performers' contouring ability. The course alone does not help lower-performing learners reach the abilities of higher-performers. The ARC Bootcamp tends to be most beneficial for participants with less radiation oncology experience. Curriculum modifications can be made to help support ARC Bootcamp participants with lower performing scores.

The Anatomy and Radiology Contouring (ARC) Bootcamp was a face-to-face (F2F) intervention providing integrated education for radiation oncology (RO) residents and medical physicists. To increase access, we launched an online offering in 2019. We evaluated the effect of the online course on participants' knowledge acquisition, contouring skills, and self-confidence by comparing it with the F2F course.Using modules, the online course offers content similar to that of the F2F comparator. Participants from the 2019 F2F and the 2019-2020 online course completed pre- and postevaluations assessing anatomy and radiology knowledge, contouring skills, self-confidence, and course satisfaction.There were 180 individuals enrolled (F2F: n = 40; online: n = 140); 57 participants (F2F: n = 30; online: n = 27) completed both evaluations. The online course had a wider geographic participation (19 countries) than F2F (4 countries). F2F had primarily RO resident participation (80%), compared with online (41%). Both cohorts demonstrated similar improvements in self-confidence pertaining to anatomy and radiology knowledge, contouring skills, and interpreting radiology images (all P.001). Both the online (mean ± SD improvement: 6.6 ± 6.7 on a 40-point scale; P.001) and F2F (3.7 ± 5.7; P = .002) groups showed anatomy and radiology knowledge improvement. Only the F2F group demonstrated improvement with the contouring assessment (F2F: 0.10 ± 0.17 on a 1-point Dice scale; P = .004; online: 0.07 ± 0.16; P = .076). Both cohorts perceived the course as a positive experience (F2F: 4.8 ± 0.4 on a 5-point scale; online: 4.5 ± 0.6), stated it would improve their professional practice (F2F: 4.6 ± 0.5; online: 4.2 ± 0.8), and said they would recommend it to others (F2F: 4.8 ± 0.4; online: 4.4 ± 0.6).The online ARC Bootcamp demonstrated improved self-confidence, knowledge scores, and high satisfaction levels among participants. The offering had lower completion rates but was more accessible to geographic regions, provided a flexible learning experience, and allowed for ongoing education during the COVID-19 pandemic.

Background: We previously determined a nonlinear relationship between connexin 43 (Cx43) function and craniofacial phenotypic variation in the mutant mouse model G60S/+, and that this variation was driven by nasal bone deviation. While nonlinearities in the genotype-phenotype map appear to be common, few studies have looked at the developmental processes that underlie this nonlinearity. Here, we investigated the potential tissue-level developmental determinants of the variation in nasal bone phenotype in G60S/+ mice through postnatal development. Results: The deviated nasal bone phenotype arises by postnatal day 21 and becomes more severe by 3 months in G60S/+ mice. Measures of nasal bone remodeling including the number of osteoclasts, mineralizing surface, mineral apposition rate, and bone formation rate are significantly greater in G60S/+ mice compared to wild-type mice at 2 months, but these differences do not correspond with nasal bone deviation. The degree of nasal bone deviation does significantly and negatively correlate with the ratio between nasal bone and cartilaginous nasal septum length. Conclusions: Our findings indicate that the mean phenotypic changes observed between G60S/+ and wild-type mice are due to reduced bone growth, but the increased phenotypic variation found within mutant mice is due to discordant growth between nasal cartilage and bone.

Background As new treatments and technologies have been introduced in radiation oncology, the clinical roles of radiation therapists (RTs) have expanded. However, there are few formal learning opportunities for RTs. An online, anatomy, radiology and contouring bootcamp (ARC Bootcamp) originally designed for medical residents was identified as a prospective educational tool for RTs. The purpose of this study was to evaluate an RT edition of the ARC Bootcamp on knowledge, contouring, and confidence, as well as to identify areas for future modification. Methods Fifty licensed RTs were enrolled in an eight-week, multidisciplinary, online RT ARC Bootcamp. Contouring practice was available throughout the course using an online contouring platform. Outcomes were evaluated using a pre-course and post-course multiple-choice quiz (MCQ), contouring evaluation and qualitative self-efficacy and satisfaction survey. Results Of the fifty enrolled RTs, 30 completed the course, and 26 completed at least one of the post-tests. Nineteen contouring dice similarity coefficient (DSC) scores were available for paired pre- and post-course analysis. RTs demonstrated a statistically significant increase in mean DSC scoring pooled across all contouring structures (mean ± SD improvement: 0.09 ± 0.18 on a scale from 0 to 1, p=0.020). For individual contouring structures, 3/15 reached significance in contouring improvement. MCQ scores were available for 26 participants and increased after RT ARC Bootcamp participation with a mean ± SD pre-test score of 18.6 ± 4.2 (46.5%); on a 40-point scale vs. post-test score of 24.5 ± 4.3 (61.4%) (p < 0.001). RT confidence in contouring, anatomy knowledge and radiographic identification improved after course completion (p < 0.001). Feedback from RTs recommended more contouring instruction, less in-depth anatomy review and more time to complete the course. Conclusions The RT ARC Bootcamp was an effective tool for improving anatomy and radiographic knowledge among RTs. The course demonstrated improvements in contouring and overall confidence. However, only approximately half of the enrolled RTs completed the course, limiting statistical power. Future modifications will aim to increase relevance to RTs and improve completion rates.

© The Author(s) 2019. Background: Distal radius fracture reduction by internal fixation is most commonly achieved using volar locking plates (VLPs). Many standard VLP designs make little point contact with radius anatomy, and most postsurgical complications following fixation are attributed to poor implant fit. Sex differences may require consideration in implant design, as females more commonly require VLP removal. Therefore, the purpose of this research was to determine whether the relationships between measures of radius shape are proportional between the sexes. Methods: Three-dimensional radius bone geometries were created from 40 male and 34 female (mean age = 72.04 years) forearm computed tomographic scans in Mimics (Materialise NV, Leuven, Belgium). Eleven measures of radius shape were collected from each scan. Principal components analysis was performed on these measures to determine which shape variables account for the greatest differences in radius shape among individuals and between the sexes. Results: Principal component scores representing isometric radius size separated the sexes. Six anthropometric measures significantly correlated with isometric radius size for all specimens, whereas 3 and 1 measures significantly correlated with isometric radius size in males and females, respectively. Conclusions: Anthropometrics of male and female radii vary by different proportions. Using anthropometrics from both sexes to create a single implant system may not result in optimal patient fit for either sex.

BACKGROUND The Anatomy and Radiology Contouring (ARC) Bootcamp was a face-to-face (F2F) course designed to ensure radiation oncology residents were equipped with the knowledge and skillset to use radiation therapy techniques properly. The ARC Bootcamp was proven to be a useful educational intervention for improving learners’ knowledge of anatomy and radiology and contouring ability. An online version of the course was created to increase accessibility to the ARC Bootcamp and provide a flexible, self-paced learning environment. This study aimed to describe the instructional design model used to create the online offering and report participants’ motivation to enroll in the course and the online ARC Bootcamp's strengths and improvement areas. METHODS The creation of the online course followed the analysis, design, development, implementation, and evaluation (ADDIE) framework. The course was structured in a linear progression of locked modules consisting of radiology and contouring lectures, anatomy labs, and integrated evaluations. RESULTS The online course launched on the platform Teachable in November 2019, and by January 2021, 140 participants had enrolled in the course, with 27 participants completing all course components. The course had broad geographic participation with learners from 19 different countries. Of the participants enrolled, 34% were female, and most were radiation oncology residents (56%), followed by other programs (24%), such as medical physics residents or medical students. The primary motivator for participants to enroll was to improve their subject knowledge/skill (44%). The most common strength identified by participants was the course's quality (41%), and the most common improvement area was to incorporate more course content (41%). CONCLUSIONS The creation of the online ARC Bootcamp using the ADDIE framework was feasible. The course is accessible to diverse geographic regions and programs and provides a flexible learning environment; however, the course completion rate was low. Participants’ feedback regarding their experiences will inform future offerings of the online course.

Background We compared skull shape and variation among genetically modified mice that exhibit different levels of connexin43 (Cx43) channel function, to determine whether Cx43 contributes to craniofacial phenotypic robustness. Specifically, we used two heterozygous mutant mouse models (G60S/+ and I130T/+) that, when compared to their wildtype counterparts, have an ~80% and ~50% reduction in Cx43 function, respectively. Results Both mutant strains showed significant differences in skull shape compared to wildtype littermates and while these differences were more severe in the G60S/+ mouse, shape differences were localized to similar regions of the skull in both mutants. However, increased skull shape variation was observed in G60S/+ mutants only. Additionally, covariation of skull structures was disrupted in the G60S/+ mutants only, indicating that while a 50% reduction in Cx43 function is sufficient to cause a shift in mean skull shape, the threshold for Cx43 function for disrupting craniofacial phenotypic robustness is lower. Conclusions Collectively, our results indicate Cx43 can contribute to phenotypic robustness of the skull through a nonlinear relationship between Cx43 gap junctional function and phenotypic outcomes.

BACKGROUND Prenatal alcohol exposure (PAE) can result in developmental defects that include growth restriction, craniofacial anomalies, and cognitive behavioral deficits, though the presence and severity of these adverse outcomes can vary dramatically among exposed individuals. Preclinical animal models have demonstrated that the dose and timing of PAE account for much, but not all, of this phenotypic variation, suggesting that additional factors mitigate the effects of PAE. Here, we used a mouse model to investigate whether maternal age modulates the effects of PAE on the severity and variation in offspring growth and craniofacial outcomes. METHODS Nulliparous C57BL/6N dams received either an intraperitoneal injection of ethanol (EtOH) or vehicle solution on gestational day 7.5. Dams were divided into four groups: (1) EtOH-treated young dams (6 to 10 weeks); (2) control young dams; (3) EtOH-treated old dams (6 to 7 months); and (4) old control dams. Neonate offspring growth restriction was measured through body mass and organ-to-body mass ratios, while skeletal craniofacial features were imaged using micro-CT and analyzed for size, shape, and variation. RESULTS PAE and advanced maternal age each increased the risk of low birthweight and growth restriction in offspring, but these factors in combination changed the nature of the growth restriction. Similarly, both PAE and advanced maternal age individually caused changes to craniofacial morphology such as smaller skull size, dysmorphic skull shape, and greater skull shape variation and asymmetry. Interestingly, while the combination of PAE and advanced maternal age did not affect mean skull shape or size, it significantly increased the variation and asymmetry of those measures. CONCLUSION Our results indicate that maternal age modulates the effects of PAE, but that the effects of this combination on offspring outcomes are more complex than simply scaling the effects of either factor.

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Mutations in the gene encoding the gap-junctional protein connexin43 (Cx43) are the cause of the human disease oculodentodigital dysplasia (ODDD). The mandible is often affected in this disease, with clinical reports describing both mandibular overgrowth and conversely, retrognathia. These seemingly opposing observations underscore our relative lack of understanding of how ODDD affects mandibular morphology. Using two mutant mouse models that mimic the ODDD phenotype (I130T/+ and G60S/+), we sought to uncover how altered Cx43 function may affect mandibular development. Specifically, mandibles of newborn mice were imaged using micro-CT, to enable statistical comparisons of shape. Tissue-level comparisons of key regions of the mandible were conducted using histomorphology, and we quantified the mRNA expression of several cartilage and bone cell differentiation markers. Both G60S/+ and I130T/+ mutant mice had altered mandibular morphology compared to their wildtype counterparts, and the morphological effects were similarly localized for both mutants. Specifically, the biggest phenotypic differences in mutant mice were focused in regions exposed to mechanical forces, such as alveolar bone, muscular attachment sites, and articular surfaces. Histological analyses revealed differences in ossification of the intramembranous bone of the mandibles of both mutant mice compared to their wildtype littermates. However, chondrocyte organization within the secondary cartilages of the mandible was unaffected in the mutant mice. Overall, our results suggest that the morphological differences seen in G60S/+ and I130T/+ mouse mandibles are due to delayed ossification and suggest that mechanical forces may exacerbate the effects of ODDD on the skeleton.

© 2020 Wiley Periodicals LLC Background & Objectives: Radical inguinal lymph node dissections (rILND) for penile cancer risk significant postoperative lymphocele and lymphedema. However, reducing the risk of lymphatic complications is limited by our understanding of lymphatic anatomy. Therefore, this study aims to elucidate the lymphatic anatomy within the current surgical borders of a rILND. Methods: To visualize the position of the lymph nodes, tissue packets excised from the inguinal region of five fresh, male cadavers were imaged using microcomputed tomography (µCT). To standardize the position, rotation and size between specimens, each lymph node packet was aligned using a Generalized Procrustes analysis. Results: There was a median of 13.5 lymph nodes (range = 8-18) per packet, with the majority (99%) clustered within a 6 cm radius of the saphenofemoral junction; a region 39%-41% smaller than current surgical borders. No difference existed between the number of nodes between sides, or distribution around the saphenofemoral junction. Conclusions: This study provides the first 3D, in situ, standardized characterization of lymph node anatomy in the inguinal region using µCT. By using knowledge of the normal lymphatic anatomy, this study can help inform the reduction in borders of rILND to limit disruption and ensure a complete lymphadenectomy.

© 2020 Elsevier Inc. Purpose: Simulation-based medical education is an effective tool for medical teaching, but simulation-based medical education deployment in radiation oncology (RO) is limited. Flexible nasopharyngoscopy (FNP), an essential skill for RO residents, requires practice that typically occurs on volunteer patients, introducing the potential for stress and discomfort. We sought to develop a high-fidelity simulator and intervention that provides RO residents the opportunity to develop FNP skills in a low-pressure environment. Methods and Materials: Computed tomography images were used to create an anatomically accurate 3-dimensional–printed model of the head and neck region. An intervention incorporating didactic instruction, multimedia content, and FNP practice on the model was designed and administered to RO residents attending the Anatomy and Radiology Contouring Bootcamp. Participants completed pre- and postintervention evaluations of the training session and model fidelity, and self-assessments of FNP skill and confidence performing FNP. Participants were video recorded performing FNP pre- and postintervention. Videos were scored by a blinded observer on a predefined rubric. Changes in scores were evaluated using the Wilcoxon signed-rank test. Results: Twenty-four participants from 17 institutions and 4 countries completed the intervention, 50% were women, and most were senior residents. Postintervention, FNP confidence and FNP performance improved significantly (mean ± standard deviation on a 10-point scale: 1.8 ± 1.8, P < .001; 2.2 ± 2.0, P < .001, respectively). Participants felt the model was helpful (mean ± standard deviation on a 5-point scale: 4.2 ± 0.6), anatomically correct (4.1 ± 0.9), and aided in spatial comprehension (4.3 ± 0.8). Overall satisfaction for the intervention was high (4.3 ± 0.8). Participants strongly agreed the intervention should be integrated into RO training programs (4.3 ± 0.8). Conclusions: A 3-dimensional–printed model and associated intervention were effective at improving FNP performance and the teaching method was rated highly by participants. RO residents may benefit from broader dissemination of this technique to improve trainee performance.

© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory spondyloarthropathy identified radiographically by calcification of the ligaments and/or entheses along the anterolateral aspect of the vertebral column. The etiology and pathogenesis of calcifications are unknown, and the diagnosis of DISH is currently based on radiographic criteria associated with advanced disease. To characterize the features of calcifications associated with DISH, we used micro-computed tomographic imaging to evaluate a cohort of 19 human cadaveric vertebral columns. Fifty-three percent of the cohort (n = 10; 3 females, 7 males, mean age of death = 81 years, range 67–94) met the radiographic criteria for DISH, with calcification of four or more contiguous vertebral segments. In almost all cases, the lower thoracic regions (T8-12) were affected by calcifications, consisting primarily of large, horizontal outgrowths of bony material. In contrast, calcifications localized to the upper thoracic regions demonstrated variability in their presentation and were categorized as either “continuous vertical bands” or “discontinuous-patchy” lesions. In addition to the variable morphology of the calcifications, our analysis demonstrated remarkable heterogeneity in the densities of calcifications, ranging from internal components below the density of cortical bone to regions of hyper-dense material that exceeded cortical bone. These findings establish that the current radiographic criteria for DISH capture heterogeneous presentations of ectopic spine calcification that can be differentiated based on morphology and density. These findings may indicate a naturally heterogenous disease, potential stage(s) in the natural progression of DISH, or distinct pathologies of ectopic calcifications. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Abstract: Pannexins (Panxs), large-pore channel forming glycoproteins, are expressed in a wide variety of tissues including the skin, bone, and cochlea. To date, the use of single knock-out mouse models of both Panx1 and Panx3 have demonstrated their roles in skin development, bone formation, and auditory phenotypes. Due to sequence homology between Panx1 and Panx3, when one Panx is ablated from germline, the other may be upregulated in a compensatory mechanism to maintain tissue homeostasis and function. To evaluate the roles of Panx1 and Panx3 in the skin, bone, and cochlea, we created the first Panx1/Panx3 double knock-out mouse model (dKO). These mice had smaller litters and reduced body weight compared to wildtype controls. The dKO dorsal skin had decreased epidermal and dermal area as well as decreased hypodermal area in neonatal but not in older mice. In addition, mouse skull shape and size were altered, and long bone length was decreased in neonatal dKO mice. Finally, auditory tests revealed that dKO mice did not exhibit hearing loss and were even slightly protected against noise-induced hearing damage at mid-frequency regions. Taken together, our findings suggest that Panx1 and Panx3 are important at early stages of development in the skin and bone but may be redundant in the auditory system. Key messages: Panx double KO mice had smaller litters and reduced body weight.dKO skin had decreased epidermal and dermal area in neonatal mice.Skull shape and size changed plus long bone length decreased in neonatal dKO mice.dKO had no hearing loss and were slightly protected against noise-induced damage.

Oculodentodigital dysplasia (ODDD) is a disease caused by mutations in the GJA1 gene that encodes the gap-junctional protein connexin43 (Cx43). ODDD affects multiple organs, but craniofacial anomalies are typical. However, details on the timing of phenotypic presentation of these abnormalities and their correspondence with potential cellular changes are incomplete. Here, we perform the first assessment of the development of the ODDD craniofacial phenotype in the Cx43I130T/+ mouse model and show that the phenotypic features commonly found in patients with the disorder arise in mice between E17.5 and birth and become more profound with age. Using mice heterozygous for the I130T mutation of Gja1, we provide a detailed analysis of the craniofacial phenotype in this ODDD model using shape analyses based on micro-CT images. Results show that in addition to differences in facial bone morphology, there are significant shape differences in the cranial base. Mutant mice display delayed ossification at E17.5 and birth, particularly in bones of the face and cranial vault but ossification is normal at three months. Our immunohistochemical analyses of the palatine bone indicate that osteoblast differentiation is delayed in Cx43I130T/+ mice compared to their wildtype littermates, which likely contributes to the phenotypic variations observed in the facial bones. Our histological and immunohistochemical analyses of the synchondroses of the cranial base show no differences in molecular indicators of chondrocyte differentiation in mutant mice, suggesting that the differences to cranial base morphology displayed by Cx43I130T/+ mice are not due to differences in chondrocyte proliferation or differentiation. Together, our findings suggest that Cx43I130T/+ mice represent a surrogate model to not only inform about the craniofacial anomalies found in ODDD patients but also to show that reduced Cx43 function leads to phenotypic changes that are largely due to osteoblast defects.

Objectives: Determining the genetic architecture of quantitative traits and genetic correlations among them is important for understanding morphological evolution patterns. We address two questions regarding papionin evolution: (1) what effect do body and cranial size, age, and sex have on phenotypic (VP) and additive genetic (VA) variation in baboon crania, and (2) how might additive genetic correlations between craniofacial traits and body mass affect morphological evolution? Materials and Methods: We use a large captive pedigreed baboon sample to estimate quantitative genetic parameters for craniofacial dimensions (EIDs). Our models include nested combinations of the covariates listed above. We also simulate the correlated response of a given EID due to selection on body mass alone. Results: Covariates account for 1.2-91% of craniofacial VP. EID VA decreases across models as more covariates are included. The median genetic correlation estimate between each EID and body mass is 0.33. Analysis of the multivariate response to selection reveals that observed patterns of craniofacial variation in extant baboons cannot be attributed solely to correlated response to selection on body mass, particularly in males. Discussion: Because a relatively large proportion of EID VA is shared with body mass variation, different methods of correcting for allometry by statistically controlling for size can alter residual VP patterns. This may conflate direct selection effects on craniofacial variation with those resulting from a correlated response to body mass selection. This shared genetic variation may partially explain how selection for increased body mass in two different papionin lineages produced remarkably similar craniofacial phenotypes.

© 2016 Anatomical Society. Pannexins form single-membrane channels that allow passage of small molecules between the intracellular and extracellular compartments. Of the three pannexin family members, Pannexin3 (Panx3) is the least studied but is highly expressed in skeletal tissues and is thought to play a role in the regulation of chondrocyte and osteoblast proliferation and differentiation. The purpose of our study is to closely examine the in vivo effects of Panx3 ablation on long bone morphology using micro-computed tomography. Using Panx3 knockout (KO) and wildtype (WT) adult mice, we measured and compared aspects of phenotypic shape, bone mineral density (BMD), cross-sectional geometric properties of right femora and humeri, and lean mass. We found that KO mice have absolutely and relatively shorter diaphyseal shafts compared with WT mice, and relatively larger areas of muscle attachment sites. No differences in BMD or lean mass were found between WT and KO mice. Interestingly, KO mice had more robust femora and humeri compared with WT mice when assessed in cross-section at the midshaft. Our results clearly show that Panx3 ablation produces phenotypic effects in mouse femora and humeri, and support the premise that Panx3 has a role in regulating long bone growth and development.

In this study we compare patterns of mandibular integration between mice and baboons using both phenotypic and quantitative genetic data. Specifically, we test how well each species fits with the mosaic model of mandibular integration suggested by Atchley and Hall (Biol Rev Camb Philos Soc 66:101-157, 1991) based on developmental modules. We hypothesize that patterns of integration will be similar for mice and baboons and that both species will show strong integration within developmental modules and weaker integration between modules. Corresponding landmark data were collected from the hemi-mandibles of an advanced intercross mouse sample (N = 1239) and mandibles from a baboon sample of known pedigree from the Southwest Foundation for Biomedical Research (N = 430). We used four methods of analysis to quantify and compare the degree of mandibular integration between species including two methods based on a priori assumptions, and two a posteriori analyses. We found that patterns of integration are broadly similar for baboon and mouse mandibles, with both species displaying a modular pattern of integration. While there is a general trend of similarity in integration patterns between species, there were some marked differences. Mice are strongly correlated among distances within the coronoid process and the incisive alveolar region, whereas baboons are strongly integrated within the condylar process. We discuss the potential evolutionary implications of the similar patterns of integration between these species with an emphasis on the role of modularity.

The articles published in this issue of Evolutionary Biology were originally presented in a symposium entitled ‘‘Patterns and Processes of Morphological Integration in Primate and Human Evolution’’, held at the 77th annual meeting of the American Association of Physical Anthropologists in Columbus, Ohio, in April 2008. The symposium marked the 50th anniversary of Everett Olson and Robert Miller’s seminal book ‘‘Morphological Integration’’, and sought to capture the current state of affairs in studies of morphological integration, particularly in relation to primate and human evolutionary biology. In its simplest form, morphological integration is the inter-dependence between sets of traits within an individual, reflecting a common influence from functional and/or developmental factors. The concept of integration is not a new one. In fact, the Principle of the Correlation of Parts, the idea that in order to be viable, organisms must be comprised of organs that are functionally coordinated with each other, was a major theme in the work of French anatomist Georges Cuvier (1769–1832, see Mayr 1982:460). Perhaps not surprisingly, Charles Darwin also discussed this ubiquitous feature of complex organisms in the Origin of Species under the term ‘‘Correlation of Growth’’: ‘‘I mean by this expression that the whole organization is so tied together during its growth and development, that when slight variations in one part occur, and are accumulated through natural selection, other parts become modified’’ (On the Origin of Species, 1859: 147). Thus, whereas Cuvier’s work emphasized the influence of shared functions on covariation and correlation among traits, Darwin recognized that interactions between these structures during ontogeny could also bias the production of variation within and among traits, and understood the consequences of such a bias on the evolution of complex organisms. Olson and Miller synthesized these earlier views, suggesting that both developmental and functional interactions were important sources of correlation among parts, each contributing towards building ‘integrated’ organisms in which different parts function in harmony with all others. The process by which such holistic phenotypes are built is what Olson and Miller called morphological integration, i.e., ‘‘the summation of the totality of characters which, in their interdependency of form, produce an organism’’ (1958, p. v). Olson and Miller were also aware of the importance of integration—as a variational property of populations—for the capacity of organismal traits to evolve independently of one another. Olson and Miller also deserve credit for providing the first quantitative methods, mostly based on statistical correlation, for empirically identifying groups of phenotypic traits that are more strongly integrated on the basis of shared developmental and/or functional factors (q-groups). Despite this important insight into a fundamental emergent property of organisms, Olson and Miller’s theory of integration did not immediately gain traction among evolutionary biologists. Reasons for this might be that their approach was pattern-based, relying heavily on statistical rather than biological criteria for grouping sets of correlated traits, and inferring in a post-hoc manner developmental and functional reasons for increased correlation among C. Rolian (&) Department of Cell Biology and Anatomy, University of Calgary, G503-3330 Hospital Dr NW, Calgary, AB T2N 4N1, USA e-mail: cprolian@ucalgary.ca

Variability contrasts with variation in that variability describes the potential for variation, not simply the expressed variation. The power of studying variability lies in creating a conceptual framework around which the relationship between the genotype and phenotype can be understood. Here, we attempt to demonstrate the importance of phenotypic variability, how it structures variation, and how fundamental developmental processes structure variability. Given the broad scope of this topic, we focus on three widely studied properties of variability: canalization, developmental stability and morphological integration. We have organized the paper to emphasize the importance of differentiating between the theory surrounding these components of phenotypic variability, their measurement and the biological factors surrounding their expression. First, we define these properties of variability, how they relate to each other and to variability as a whole. Second, we summarize the common methods of measurement for canalization, developmental stability and morphological integration and the reasoning behind these methods. Finally, we focus on jaw development as an example of how the basic processes of development affect variability and the resultant variation, with emphasis on how processes at all levels of the organismal hierarchy interact with one another and contribute to phenotypic variability.

The mammalian skull performs a variety of functions and its growth and development mirrors this complexity. Cranial growth and development have been actively studied for many years. Despite this interest, the variation in the patterns and processes of skull growth has attracted little attention. An important and unanswered question is the extent to which patterns of cranial covariation and variation are dynamically reworked throughout postnatal growth. To address this question, we examine patterns of variability in random-bred mouse skulls aged 35, 90, and 150 days. Using a battery of both Procrustes coordinate and Euclidean distance-based methods, we measure mean shape, canalization, developmental stability, and morphological integration in these skulls. We predict that the patterns of variability are dynamic, particularly between the youngest and the two oldest age groups due to the influence of functional effects such as postweaning mastication. We also hypothesize that patterns of variability are structured by the same functional and developmental factors that have been shown to influence cranial growth in primates. Our results indicate that contrary to our predictions, patterns of canalization, developmental stability, and morphological integration are stabilized before 35 days. The mean shape, however, changed significantly with growth. We found that only the facial region showed significant integration as predicted by the functional matrix model used in other studies of integration. These results indicate that phenotypic integration in these mice does not closely match those found for primate species, suggesting that comparisons between species should be made with care.

This study measures the correlation between within- and among-individual variance to gain a greater understanding of the relationship of the underlying mechanisms governing developmental stability and canalization. Twenty-six landmarks were digitized in three dimensions from the crania of 228 adult macaques from Cayo Santiago. The phenotypic variance between individuals was measured and divided into its genetic and environmental components using matriline information. Within-individual variance was measured as the fluctuating asymmetry between bilateral landmarks. We found positive and significant correlations between the phenotypic, environmental, and fluctuating asymmetry variances for interlandmark distances. We also found low but significant correspondences between the covariation structures of the three variability components using both Procrustes and interlandmark distance data. Therefore, we find that in macaque skulls traits that exhibit greater levels of asymmetry deviations also exhibit greater levels of environmental variance, and that the covariances of absolute symmetry deviations partly correspond to covariances of mean deviations at the individual level. These results suggest that the underlying processes that determine canalization and developmental stability are at least partly overlapping. However, the low correlations reported here are also evidence for a degree of independence between these variability components.

Evolutionary developmental biology of primates will be driven largely by the developmental biology of the house mouse. Inferences from how known developmental perturbations produce phenotypic effects in model organisms, such as mice, to how the same perturbations would affect craniofacial form in primates must be informed by comparisons of phenotypic variation and variability in mice and the primate species of interest. We use morphometric methods to compare patterns of cranial variability in homologous datasets obtained for two strains of laboratory mice and rhesus macaques. C57BL/6J represents a common genetic background for transgenic models. A/WySnJ mice exhibit altered facial morphology which results from reduction in the growth of the maxillary process during formation of the face. This is relevant to evolutionary changes in facial prognathism in nonhuman primate and human evolution. Rhesus macaques represent a nonhuman primate about which a great deal of phenotypic and genetic information is available. We find significant similarities in covariation patterns between the C57BL/6J mice and macaques. Among-trait variation in genetic and phenotypic variances are fairly concordant among the three groups, but among-trait variation in developmental stability is not. Finally, analysis of modularity based on phenotypic and genetic correlations did not reveal a consistent pattern in the three groups. We discuss the implications of these results for the study of evolutionary developmental biology of primates and outline a research strategy for integrating mouse genomics and developmental biology into this emerging field.

© 2015 Elsevier Inc. All rights reserved. Background Radiation therapy treatment planning has advanced over the past 2 decades, with increased emphasis on 3-dimensional imaging for target and organ-at-risk (OAR) delineation. Recent studies suggest a need for improved resident instruction in this area. We developed and evaluated an intensive national educational course ("boot camp") designed to provide dedicated instruction in site-specific anatomy, radiology, and contouring using a multidisciplinary (MDT) approach. Methods The anatomy and radiology contouring (ARC) boot camp was modeled after prior single-institution pilot studies and a needs-assessment survey. The boot camp incorporated joint lectures from radiation oncologists, anatomists, radiologists, and surgeons, with hands-on contouring instruction and small group interactive seminars using cadaveric prosections and correlative axial radiographs. Outcomes were evaluated using pretesting and posttesting, including anatomy/radiology multiple-choice questions (MCQ), timed contouring sessions (evaluated relative to a gold standard using Dice similarity metrics), and qualitative questions on satisfaction and perceived effectiveness. Analyses of pretest versus posttest scores were performed using nonparametric paired testing. Results Twenty-nine radiation oncology residents from 10 Canadian universities participated. As part of their current training, 29%, 75%, and 21% receive anatomy, radiology, and contouring instruction, respectively. On posttest scores, the MCQ knowledge scores improved significantly (pretest mean 60% vs posttest mean 80%, P

A body plan is a suite of characters shared by a group of phylogenetically related animals at some point during their development. The concept of bauplane, or body plans, has played and continues to play a central role in the study of evolutionary developmental biology (evo-devo). Despite the importance of the body plan concept in evo-devo, many researchers may not be familiar with the progression of ideas that have led to our current understanding of body plans, and/or current research on the origin and maintenance of body plans. This lack of familiarity, as well as former ties between the body plan concept and metaphysical ideology is likely responsible for our underappreciation of the body plan concept in its own right, as well as its role in evo-devo. My aim in this review is to outline how we have arrived at our modern definition of body plan, the controversies associated with the concept, its role in evo-devo, and how current research is informing us on body plans. To this end, I integrate concepts such as the nature of phyla, the Cambrian explosion, constraint, evolvability, and results from recent research on gene regulatory networks with the much older concept of the body plan.

Determination of how the underlying cause(s) of variation in metric and nonmetric skeletal traits compare has remained elusive despite active research (Bennett 1965 ; Berry and Berry 1967 ; Kellock and Parsons 1970; Rightmire 1972 ; Corruccini 1976 ; Cheverud et al. 1979 ; Cheverud and Buikstra 1982 ; Richtsmeier et al. 1984 ; Hartl et al. 1995 ). This question has been of particular importance to anthropologists trying to measure the biological or the genetic distance between populations, using fragmentary skeletal material (Berry and Berry 1967 ; Kellock and Parsons 1970 ; Rightmire 1972 ; Konigsberg 1988 ; Ishida and Dodo 1993 ; Prowse and Lovell 1996 ; Gonzalez-Jose et al. 2001 ; Hallgrimsson et al. 2004, and others).

Evolutionary change in a character is due to a combination of the direct effects of selection on that character and the indirect effects of selection on characters that are genetically correlated with the character in question (Lande and Arnold 1983 ; Cheverud 1996 ). Therefore, selection on a single component within a correlated unit will result in coordinated evolution of the entire complex (Lande 1979 ; Cheverud 1982, 1984 ; Falconer and MacKay 1996 ). Due to the ubiquity of phenotypic correlations among traits, natural selection appears to act on many characters simultaneously. However, genetic correlations among traits can pose constraints on phenotypic evolution because these correlations are capable of altering both the rate and direction of evolution from the optimal path defi ned by natural selection (Cheverud 1984 ; Wagner and Altenberg 1996 ). If traits that are inherited together ultimately evolve together, then the challenge in explaining the correlated appearance of particular characters and understanding coordinated evolution lies in identifying genetically integrated morphological traits.

Sexual dimorphism is a widespread phenomenon and contributes greatly to intraspecies variation. Despite a long history of active research, the genetic basis of dimorphism for complex traits remains unknown. Understanding the sex-specific differences in genetic architecture for cranial traits in a highly dimorphic species could identify possible mechanisms through which selection acts to produce dimorphism. Using distances calculated from three-dimensional landmark data from CT scans of 402 baboon skulls from a known genealogy, we estimated genetic variance parameters in both sexes to determine the presence of gene-by-sex (G × S) interactions and X-linked heritability. We hypothesize that traits exhibiting the greatest degree of sexual dimorphism (facial traits in baboons) will demonstrate either stronger G × S interactions or X-linked effects. We found G × S interactions and X-linked effects for a few measures that span the areas connecting the face to the neurocranium but for no traits restricted to the face. This finding suggests that facial traits will have a limited response to selection for further evolution of dimorphism in this population. We discuss the implications of our results with respect to the origins of cranial sexual dimorphism in this baboon sample, and how the genetic architecture of these traits affects their potential for future evolution.

The semi-dominant Br mutation affects presphenoid growth, producing the facial retrognathism and globular neurocranial vault that characterize heterozygotes. We analysed the impact of this mutation on skull shape, comparing heterozygotes to wildtype mice, to determine if the effects are skull-wide or confined to the sphenoid region targeted by the mutation. In addition, we examined patterns of variability of shape for the skull as a whole and for three regions (basicranium, face and neurocranium). We found that the Br mice differed significantly from wildtype mice in skull shape in all three regions as well as in the shape of the skull as a whole. However, the significant increases in variance and fluctuating asymmetry were found only in the basicranium of mutant mice. These results suggest that the mutation has a significant effect on the underlying developmental architecture of the skull, which produces an increase in phenotypic variability that is localized to the anatomical region in which the mean phenotype is most dramatically affected. These results suggest that the same developmental mechanisms that produce the change in phenotypic mean also produce the change in variance.

Publisher Summary This chapter attempts to emphasize the importance of differentiating between the causes of developmental noise and the mechanisms that create developmental stability. It is necessary to understand the factors that can disturb the system and the mechanisms that maintain normal development. This chapter describes the causes of developmental noise and outlines the mechanisms used to buffer developmental noise to confer developmental stability. It also highlights the different levels that developmental noise and developmental stability work within the organism. Traditionally, developmental stability has been studied at the level of the organism, and developmental noise has been vaguely described as unknown thermodynamic noise. However, with the recent advances made in molecular biology and renewed interest in genotype to phenotype mapping, it has been possible to study developmental stability at the molecular level and to describe more accurately the factors that cause developmental noise. Both the causes of noise and the mechanisms of stability are reviewed at three phenotypic levels: the molecular level, the developmental systems level, and the level of the trait or organism. The chapter describes the importance of differentiating between developmental stability and developmental noise as well as the importance of understanding both phenomena from an entire systems approach.

Canalization and developmental stability refer to the tendency of developmental processes to follow particular trajectories, despite external or internal pertur- bation. Canalization is the tendency for development of a specific genotype to follow the same trajectory under differ- ent conditions (different environments or different genetic backgrounds), while developmental stability is the tendency for the development of a specific genotype to follow the same trajectory under the same conditions. Morphological integra- tion refers to the tendency for structures to show correlated variation because they develop in response to shared devel- opmental processes or function in concert with other struc- tures. All three phenomena are emergent properties of de- velopmental systems that can affect the interaction of development and evolution. In this paper, we review the topics of canalization, developmental stability, and morpho- logical integration and their relevance to primate and hu- man evolution. We then test three developmentally moti- vated hypotheses about the patterning of variability components in the mammalian limb. We find that environ- mental variances and fluctuating asymmetries (FA) increase distally along the limb in adult macaques but not in fetal mice. We infer that the greater variability of more distal segments in macaques is due to postnatal mechanical ef- fects. We also find that heritability and FA are significantly correlated when different limb measurements are compared in fetal mice. This supports the idea that the mechanisms underlying canalization and developmental stability are re- lated. Finally, we report that the covariation structure of fore- and hindlimb skeletal elements shows evidence for morphological integration between serially homologous structures between the limbs. This is evidence for the exis- tence of developmental modules that link structures be- tween the limbs. Such modules would produce covariation that would need to be overcome by selection for divergence in hind- and forelimb morphology. Yrbk Phys Anthropol 45: 131-158, 2002. © 2002 Wiley-Liss, Inc.

Pannexin 3 (Panx3) is a channel-forming glycoprotein that is expressed in skin, mammary gland and skeletal tissues. In vitro studies have shown that Panx3 is induced at the growth plate where it is...