Single Cell Omics for Musculoskeletal Research.

PURPOSE OF REVIEW: The ability to analyze the molecular events occurring within individual cells as opposed to populations of cells is revolutionizing our understanding of musculoskeletal tissue development and disease. Single cell studies have the great potential of identifying cellular subpopulations that work in a synchronized fashion to regenerate and repair damaged tissues during normal homeostasis. In addition, such studies can elucidate how these processes break down in disease as well as identify cellular subpopulations that drive the disease. This review highlights three emerging technologies: single cell RNA sequencing (scRNA-seq), Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq), and Cytometry by Time-Of-Flight (CyTOF) mass cytometry. RECENT FINDINGS: Technological and bioinformatic tools to analyze the transcriptome, epigenome, and proteome at the individual cell level have advanced rapidly making data collection relatively easy; however, understanding how to access and interpret the data remains a challenge for many scientists. It is, therefore, of paramount significance to educate the musculoskeletal community on how single cell technologies can be used to answer research questions and advance translation. This article summarizes talks given during a workshop on "Single Cell Omics" at the 2020 annual meeting of the Orthopedic Research Society. Studies that applied scRNA-seq, ATAC-seq, and CyTOF mass cytometry to cartilage development and osteoarthritis are reviewed. This body of work shows how these cutting-edge tools can advance our understanding of the cellular heterogeneity and trajectories of lineage specification during development and disease.

Tratamiento exitoso con activador funcional removible en paciente clase II esqueletal con mordida en tijera, después del peak de crecimiento puberal: caso y revisión de la literatura / Successful treatment with removable functional activator in a skeletal class II patient with scissor bite, after pubertal growth peak: clinical case and literature review

INTRODUCCIÓN: En pacientes con crecimiento esqueletal clase II, el tratamiento ideal es etiológico modificando la cantidad y dirección de crecimiento mandibular. Con estos objetivos, se usan activadores funcionales (AF) que estimulan el crecimiento mandibular, redirigiéndolo posterosuperiormente a nivel condilar por medio del avance mandibular. Después del peak de crecimiento puberal, la corrección etiológica es quirúrgica. El objetivo del presente artículo es reportar un tratamiento exitoso de un paciente después de su peak de crecimiento puberal, tratado con un AF removible. MÉTODOS: Paciente de 13 años, 3 meses, braquifacial y con perfil facial convexo, presentaba clase II esqueletal debido a mandíbula retrognática. El paciente tenía dentición permanente completa, clase II de Angle, resalte incisivo y sobremordida aumentados, proinclinación incisiva bimaxilar y mordida en tijera de dientes #2.4 y #2.5. RESULTADOS: Después de ocho meses de tratamiento, se observó posición mandibular estable en clase I esqueletal, verificada mediante exámenes funcionales y radiográficos. Se logró resolución de la mordida en tijera. Mejoraron resalte incisivo y sobremordida, así como la proinclinación incisiva bimaxilar. CONCLUSIONES: El momento ideal para utilizar AF en tratamiento de clases II esqueletales es durante o ligeramente después del peak de crecimiento puberal. Sin embargo, los resultados clínicos del presente caso, permiten recomendar el avance mandibular con AF en pacientes braquifaciales clase II, a pesar de que se haya producido el peak de crecimiento puberal. En estos casos, el uso de AF está dirigido principalmente a beneficios dentarios, pero, al mismo tiempo, puede favorecer el crecimiento mandibular

INTRODUCTION: In growing skeletal class II patients, the ideal treatment is etiological and is obtained by modifying the amount and direction of mandibular growth. With this objective in mind, functional activators (FA) are used as they stimulate growth, redirecting it at the condylar level through forward mandibular advancement. After pubertal growth peak, etiological correction is surgical. OBJECTIVE: The present article aims to report a successful treatment in a patient after pubertal growth peak treated with a removable FA. METHODS: >A 13 years 3 months male patient, skeletal class II due to retrognathic mandible, brachyfacial and with a convex facial profile. The patient had complete permanent dentition, Angle class II, increased overjet and overbite. Maxillary and mandibular incisive proclination. Scissor bite of teeth #2.4 and #2.5. RESULTS: Treatment started using a FA for one year after first evaluation. Following eight months of treatment, stable mandibular position was observed in skeletal class I, verified by functional and radiographic examinations. Resolution of scissor bite was accomplished. Overjet and overbite, and bimaxillary incisive proclination were improved. CONCLUSIONS: The ideal time to use FAs for skeletal management in skeletal class II is during, or slightly after peak pubertal growth. However, the clinical results of present case, allows recommending the forward mandibular advancement in brachyfacial skeletal class II patients, even though pubertal growth peak had occurred. In these cases, the use of FA is primarily aimed at the dental benefits, but, at the same time, favoring mandibular growth

Sport-specific musculoskeletal growth and postural control in female artistic gymnasts: a 12 month cohort study.

Female gymnasts have been evidenced to experience sport-specific growth, of which broad shoulders and narrow hips are common characteristics. In addition to being a central component of handstand performance, postural control mechanisms, including whole-body and lumbo-pelvic stability, have been identified as risk factors for overuse spinal pathology. The study aimed to develop a fundamental understanding of musculoskeletal growth and postural control responses of female artistic gymnasts in order to extend longitudinal insights into overuse spinal pathology risk. Whole-body anthropometric measures were collected for 12 competitive female gymnasts (age at recruitment: nine to 15 years) at three time points across a 12 month period. Musculoskeletal growth was partially defined as the rate of bicristal-to-biacromial breadth ratio development, and informed shoulder- and pelvis-dominant growth sub-groups. Kinematic and kinetic indicators of postural control were determined for a total of 700 handstand trials. The shoulder-dominant (gymnastics-specific) growth group was found to have significantly greater biomechanical risk for general stability (p < 0.001) than the pelvis-dominant group. Significantly greater lumbo-pelvic risk was demonstrated for the pelvis-dominant group (p < 0.001). Extended idiosyncratic examination of proportional sport-specific growth measures alongside multi-faceted risk monitoring was advocated for the effective development of future overuse pathology prevention protocols.

Suplementación con vitamina D y salud musculoesquelética. Una necesidad discutida / Vitamin D supplementation and musculoskeletal health. A controversial necessity

No disponible

Bracing in Adolescent Idiopathic Scoliosis Trial (BrAIST): Development and Validation of a Prognostic Model in Untreated Adolescent Idiopathic Scoliosis Using the Simplified Skeletal Maturity System.

STUDY DESIGN: Prognostic study and validation using prospective clinical trial data. OBJECTIVE: To derive and validate a model predicting curve progression to ≥45° before skeletal maturity in untreated patients with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Studies have linked the natural history of AIS with characteristics such as sex, skeletal maturity, curve magnitude, and pattern. The Simplified Skeletal Maturity Scoring System may be of particular prognostic utility for the study of curve progression. The reliability of the system has been addressed; however, its value as a prognostic marker for the outcomes of AIS has not. The BrAIST trial followed a sample of untreated AIS patients from enrollment to skeletal maturity, providing a rare source of prospective data for prognostic modeling. METHODS: The development sample included 115 untreated BrAIST participants. Logistic regression was used to predict curve progression to ≥45° (or surgery) before skeletal maturity. Predictors included the Cobb angle, age, sex, curve type, triradiate cartilage, and skeletal maturity stage (SMS). Internal and external validity was evaluated using jackknifed samples of the BrAIST data set and an independent cohort (n = 152). Indices of discrimination and calibration were estimated. A risk classification was created and the accuracy evaluated via the positive (PPV) and negative predictive values (NPV). RESULTS: The final model included the SMS, Cobb angle, and curve type. The model demonstrated strong discrimination (c-statistics 0.89-0.91) and calibration in all data sets. The classification system resulted in PPVs of 0.71-0.72 and NPVs of 0.85-0.93. CONCLUSIONS: This study provides the first rigorously validated model predicting a short-term outcome of untreated AIS. The resultant estimates can serve two important functions: 1) setting benchmarks for comparative effectiveness studies and 2) most importantly, providing clinicians and families with individual risk estimates to guide treatment decisions. LEVEL OF EVIDENCE: Level 1, prognostic.

Biomechanical Function and Size of the Anteromedial and Posterolateral Bundles of the ACL Change Differently with Skeletal Growth in the Pig Model.

BACKGROUND: ACL injuries are becoming increasingly common in children and adolescents, but little is known regarding age-specific ACL function in these patients. To improve our understanding of changes in musculoskeletal tissues during growth and given the limited availability of pediatric human cadaveric specimens, tissue structure and function can be assessed in large animal models, such as the pig. QUESTIONS/PURPOSES: Using cadaveric porcine specimens ranging throughout skeletal growth, we aimed to assess age-dependent changes in (1) joint kinematics under applied AP loads and varus-valgus moments, (2) biomechanical function of the ACL under the same loads, (3) the relative biomechanical function of the anteromedial and posterolateral bundles of the ACL; and (4) size and orientation of the anteromedial and posterolateral bundles. METHODS: Stifle joints (analogous to the human knee) were collected from female Yorkshire crossbreed pigs at five ages ranging from early youth to late adolescence (1.5, 3, 4.5, 6, and 18 months; n = 6 pigs per age group, 30 total), and MRIs were performed. A robotic testing system was used to determine joint kinematics (AP tibial translation and varus-valgus rotation) and in situ forces in the ACL and its bundles in response to applied anterior tibial loads and varus-valgus moments. To see if morphological changes to the ACL compared with biomechanical changes, ACL and bundle cross-sectional area, length, and orientation were calculated from MR images. RESULTS: Joint kinematics decreased with increasing age. Normalized AP tibial translation decreased by 44% from 1.5 months (0.34 ± 0.08) to 18 months (0.19 ± 0.02) at 60° of flexion (p < 0.001) and varus-valgus rotation decreased from 25° ± 2° at 1.5 months to 6° ± 2° at 18 months (p < 0.001). The ACL provided the majority of the resistance to anterior tibial loading at all age groups (75% to 111% of the applied anterior force; p = 0.630 between ages). Anteromedial and posterolateral bundle function in response to anterior loading and varus torque were similar in pigs of young ages. During adolescence (4.5 to 18 months), the in situ force carried by the anteromedial bundle increased relative to that carried by the posterolateral bundle, shifting from 59% ± 22% at 4.5 months to 92% ± 12% at 18 months (data for 60° of flexion, p < 0.001 between 4.5 and 18 months). The cross-sectional area of the anteromedial bundle increased by 30 mm throughout growth from 1.5 months (5 ± 2 mm) through 18 months (35 ± 8 mm; p < 0.001 between 1.5 and 18 months), while the cross-sectional area of the posterolateral bundle increased by 12 mm from 1.5 months (7 ± 2 mm) to 4.5 months (19 ± 5 mm; p = 0.004 between 1.5 and 4.5 months), with no further growth (17 ± 7 mm at 18 months; p = 0.999 between 4.5 and 18 months). However, changes in length and orientation were similar between the bundles. CONCLUSION: We showed that the stifle joint (knee equivalent) in the pig has greater translational and rotational laxity in early youth (1.5 to 3 months) compared with adolescence (4.5 to 18 months), that the ACL functions as a primary stabilizer throughout growth, and that the relative biomechanical function and size of the anteromedial and posterolateral bundles change differently with growth. CLINICAL RELEVANCE: Given the large effects observed here, the age- and bundle-specific function, size, and orientation of the ACL may need to be considered regarding surgical timing, graft selection, and graft placement. In addition, the findings of this study will be used to motivate pre-clinical studies on the impact of partial and complete ACL injuries during skeletal growth.

First use of anatomical networks to study modularity and integration of heads, forelimbs and hindlimbs in abnormal anencephalic and cyclopic vs normal human development.

The ill-named "logic of monsters" hypothesis of Pere Alberch - one of the founders of modern evo-devo - emphasized the importance of "internal rules" due to strong developmental constraints, linked teratologies to developmental processes and patterns, and contradicted hypotheses arguing that birth defects are related to a chaotic and random disarray of developmental mechanisms. We test these hypotheses using, for the first time, anatomical network analysis (AnNA) to study and compare the musculoskeletal modularity and integration of both the heads and the fore- and hindlimbs of abnormal cyclopic trisomy 18 and anencephalic human fetuses, and of normal fetal, newborn, and adult humans. Our previous works have shown that superficial gross anatomical analyses of these specimens strongly support the "logic of monsters" hypothesis, in the sense that there is an 'order' or 'logic' within the gross anatomical patterns observed in both the normal and abnormal individuals. Interestingly, the results of the AnNA done in the present work reveal a somewhat different pattern: at least concerning the musculoskeletal modules obtained in our AnNA, we observe a hybrid between the "logic of monsters" and the "lack of homeostasis" hypotheses. For instance, as predicted by the latter hypothesis, we found a high level of left-right asymmetry in the forelimbs and/or hindlimbs of the abnormal cyclopic trisomy 18 and anencephalic human fetuses. That is, a network analysis of the organization of/connection between the musculoskeletal structures of these fetuses reveals a more "chaotic" pattern than that detected by superficial gross anatomical comparisons. We discuss the broader developmental, evolutionary, and medical implications of these results.

Effects of hyperthyroidism in the development of the appendicular skeleton and muscles of zebrafish, with notes on evolutionary developmental pathology (Evo-Devo-Path).

The hypothalamus-pituitary-thyroid (HPT) axis plays a crucial role in the metabolism, homeostasis, somatic growth and development of teleostean fishes. Thyroid hormones regulate essential biological functions such as growth and development, regulation of stress, energy expenditure, tissue compound, and psychological processes. Teleost thyroid follicles produce the same thyroid hormones as in other vertebrates: thyroxin (T4) and triiodothyronine (T3), making the zebrafish a very useful model to study hypo- and hyperthyroidism in other vertebrate taxa, including humans. Here we investigate morphological changes in T3 hyperthyroid cases in the zebrafish to better understand malformations provoked by alterations of T3 levels. In particular, we describe musculoskeletal abnormalities during the development of the zebrafish appendicular skeleton and muscles, compare our observations with those recently done by us on the normal developmental of the zebrafish, and discuss these comparisons within the context of evolutionary developmental pathology (Evo-Devo-Path), including human pathologies.

Exercise, fitness and musculoskeletal health of undergraduate nursing students: A cross-sectional study.

AIMS: To describe the exercise, physical fitness and musculoskeletal health of nursing students. BACKGROUND: Nursing students are prone to musculoskeletal disorders restricting work ability. Physical fitness and leisure-time exercise may affect responses to workplace exposures and risk for work-related musculoskeletal disorders. DESIGN: A cross-sectional study. METHOD: Between August 2013 and April 2015, a convenience sample of 111 nursing students performed submaximal exercise tests. Nursing work, exercise and musculoskeletal health were surveyed and analysed descriptively. RESULTS: Students' mean age was 30.0 years, 89.2% were female and 20.0% worked in nursing while studying. Highest annual prevalence of musculoskeletal trouble was in low back (45.6%), neck (32.0%) and shoulder (18.5%) regions. Most exercised regularly but did not meet weekly cardiorespiratory, resistance, neuromotor and flexibility exercise recommendations and had poor to average fitness levels. Approximately 40% were overweight or obese; 26.1% had risk for obesity-related disease. CONCLUSIONS: Interventions to improve nursing students' physical condition before entering the nursing workforce appear warranted. IMPACT: Imbalance between physical work capacity and demanding workloads increases musculoskeletal disorder risk amongst undergraduate nursing students. A large proportion studied reported recent musculoskeletal trouble (particularly low back, neck and shoulder). They exhibited modifiable characteristics of overweight/obese, poor fitness and inadequate leisure-time exercise, predisposing them to work-related musculoskeletal disorders. Undergraduate preparation should raise nursing students' health literacy about physical fitness and ways to achieve it, for their musculoskeletal health and work capacity. Improving nursing students' fitness may enhance their work preparedness and help them achieve longevity in this physically demanding occupation.

Development, repair, and regeneration of the limb musculoskeletal system.

The limb musculoskeletal system provides a primary means for locomotion, manipulation of objects and protection for most vertebrate organisms. Intricate integration of the bone, tendon and muscle tissues are required for function. These three tissues arise largely independent of one another, but the connections formed during later development are maintained throughout life and are re-established following injury. Each of these tissues also have mesenchymal stem/progenitor cells that function in maintenance and repair. Here in, we will review the major events in the development of limb skeleton, tendon, and muscle tissues, their response to injury, and discuss current knowledge regarding resident progenitor/stem cells within each tissue that participate in development, repair, and regeneration in vivo.

Jitterbug/Filamin and Myosin-II form a complex in tendon cells required to maintain epithelial shape and polarity during musculoskeletal system development.

During musculoskeletal system development, mechanical tension is generated between muscles and tendon-cells. This tension is required for muscle differentiation and is counterbalanced by tendon-cells avoiding tissue deformation. Both, Jbug/Filamin, an actin-meshwork organizing protein, and non-muscle Myosin-II (Myo-II) are required to maintain the shape and cell orientation of the Drosophila notum epithelium during flight muscle attachment to tendon cells. Here we show that halving the genetic dose of Rho kinase (Drok), the main activator of Myosin-II, enhances the epithelial deformation and bristle orientation defects associated with jbug/Filamin knockdown. Drok and activated Myo-II localize at the apical cell junctions, tendon processes and are associated to the myotendinous junction. Further, we found that Jbug/Filamin co-distribute at tendon cells with activated Myo-II. Finally, we found that Jbug/Filamin and Myo-II are in the same molecular complex and that the actin-binding domain of Jbug/Filamin is necessary for this interaction. These data together suggest that Jbug/Filamin and Myo-II proteins may act together in tendon cells to balance the tension generated during development of muscles-tendon interaction, maintaining the shape and polarity of the Drosophila notum epithelium.

Effect of age on electrical nerve conduction in the somatosensory pathway and its correlation with somatometry and plasma concentrations of musculoskeletal enzymes in male rhesus monkeys (Macaca mulatta) held in captivity.

BACKGROUND: Somatosensory evoked potentials (SEPs) make it possible to obtain functional data on the activity of somatosensory pathway. OBJECTIVE: To evaluate the ontogeny of electrical nerve conduction in male rhesus monkeys using SEPs in correlation with the development of the musculoskeletal system based on somatometry and musculoskeletal enzymes. METHODS: Somatosensory evoked potentials of the medial and tibial nerves were performed, and somatometric measurements were obtained: total length, arm and forearm length, and thigh and calf length. Analysis of the musculoskeletal enzymes, lactic dehydrogenase, and creatininase was conducted using blood samples in 20 rhesus monkeys divided into 5 groups. RESULTS: Statistical analysis manifested a delay in the appearance of latencies as age increased. Also evident was a strong, direct relation between the lengths and the value of the latencies of the SEP, together with an inverse relation between the musculoskeletal enzymes. CONCLUSIONS: These findings contribute to standardizing this animal model in the neurophysiological sciences.

Stresses and strains on the human fetal skeleton during development.

Mechanical forces generated by fetal kicks and movements result in stimulation of the fetal skeleton in the form of stress and strain. This stimulation is known to be critical for prenatal musculoskeletal development; indeed, abnormal or absent movements have been implicated in multiple congenital disorders. However, the mechanical stress and strain experienced by the developing human skeleton in utero have never before been characterized. Here, we quantify the biomechanics of fetal movements during the second half of gestation by modelling fetal movements captured using novel cine-magnetic resonance imaging technology. By tracking these movements, quantifying fetal kick and muscle forces, and applying them to three-dimensional geometries of the fetal skeleton, we test the hypothesis that stress and strain change over ontogeny. We find that fetal kick force increases significantly from 20 to 30 weeks' gestation, before decreasing towards term. However, stress and strain in the fetal skeleton rises significantly over the latter half of gestation. This increasing trend with gestational age is important because changes in fetal movement patterns in late pregnancy have been linked to poor fetal outcomes and musculoskeletal malformations. This research represents the first quantification of kick force and mechanical stress and strain due to fetal movements in the human skeleton in utero, thus advancing our understanding of the biomechanical environment of the uterus. Further, by revealing a potential link between fetal biomechanics and skeletal malformations, our work will stimulate future research in tissue engineering and mechanobiology.

Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation through specific gene expression.

Transcriptional regulation can be tightly orchestrated by epigenetic regulators. Among these, ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) is reported to have diverse epigenetic functions, including regulation of DNA methylation. However, the physiological functions of Uhrf1 in skeletal tissues remain unclear. Here, we show that limb mesenchymal cell-specific Uhrf1 conditional knockout mice (Uhrf1ΔLimb/ΔLimb ) exhibit remarkably shortened long bones that have morphological deformities due to dysregulated chondrocyte differentiation and proliferation. RNA-seq performed on primary cultured chondrocytes obtained from Uhrf1ΔLimb/ΔLimb mice showed abnormal chondrocyte differentiation. In addition, integrative analyses using RNA-seq and MBD-seq revealed that Uhrf1 deficiency decreased genome-wide DNA methylation and increased gene expression through reduced DNA methylation in the promoter regions of 28 genes, including Hspb1, which is reported to be an IL1-related gene and to affect chondrocyte differentiation. Hspb1 knockdown in cKO chondrocytes can normalize abnormal expression of genes involved in chondrocyte differentiation, such as Mmp13 These results indicate that Uhrf1 governs cell type-specific transcriptional regulation by controlling the genome-wide DNA methylation status and regulating consequent cell differentiation and skeletal maturation.

Mechanical regulation of musculoskeletal system development.

During embryogenesis, the musculoskeletal system develops while containing within itself a force generator in the form of the musculature. This generator becomes functional relatively early in development, exerting an increasing mechanical load on neighboring tissues as development proceeds. A growing body of evidence indicates that such mechanical forces can be translated into signals that combine with the genetic program of organogenesis. This unique situation presents both a major challenge and an opportunity to the other tissues of the musculoskeletal system, namely bones, joints, tendons, ligaments and the tissues connecting them. Here, we summarize the involvement of muscle-induced mechanical forces in the development of various vertebrate musculoskeletal components and their integration into one functional unit.

Expanding our perspectives on research in musculoskeletal science and practice.

INTRODUCTION: The quantity and quality of scientific research within physiotherapy has unquestionably grown and matured over the last few decades, especially since the "formal" onset of evidence-based physiotherapy in the 1990s. The urgent need to evaluate our practice for effectiveness and efficiency has been responded to with thought and respect to both scientific integrity and shop-floor clinical needs. However, after thirty years or more of a professionally-governed and strategic approach to research activity, it is now timely to reflect, review, and consider the next chapter in the relationship between scientific research and clinical practice. PURPOSE: This masterclass aims to develop a research vision for the future of physiotherapy. It is proposed that a crisis is evident within evidence-based physiotherapy, particular so given the assumed complexity and context-sensitivity of our clinical practice. This crisis period has highlighted fundamental limitations within the way research and practice are currently related. These limitations are presented and framed within the problematisation of empirical and philosophical concerns. As research becomes increasingly aligned to traditional scientific principles, examination of the real world context in which its outcomes are intended expose critical challenges for both research and clinical practice. IMPLICATIONS: A reconceptualisation of fundamental elements of scientific research may allow more meaningful relationships between research and clinical practice. A proposed research vision encourages scientific activity to embrace real-world complexity in a way that it is presently unable to. An enhanced person-centered, scientifically-informed world of effective musculoskeletal practice is envisaged.

Promoter architecture and transcriptional regulation of musculoskeletal embryonic nuclear protein 1b (mustn1b) gene in zebrafish.

BACKGROUND: Mustn1 is a specific musculoskeletal protein that plays a critical role in myogenesis and chondrogenesis in vertebrates. Whole-mount in situ hybridization revealed that mustn1b mRNAs are specifically expressed in skeletal and cardiac muscles in Zebrafish embryos. However, the precise function and the regulatory elements required for its muscle-specific expression are largely unknown. RESULTS: The purpose of this study was to explore and uncover the target genomic regions that regulate mustn1b gene expression by in vivo functional characterization of the mustn1b promoter. We report here stable expression analyses of eGFP from fluorescent transgenic reporter Zebrafish line containing a 0.8kb_mustn1b-Tol2-eGFP construct. eGFP expression was specifically found in the skeletal and cardiac muscle tissues. We show that reporter Zebrafish lines generated replicate the endogenous mustn1b expression pattern in early Zebrafish embryos. Specific site directed-mutagenesis analysis revealed that promoter activity resides in two annotated genomic regulatory regions, each one corresponding to a specific functional transcription factor binding site. CONCLUSIONS: Our data indicate that mustn1b is specifically expressed in skeletal and cardiac muscle tissues and its muscle specificity is controlled by the 0.2-kb promoter and flanking sequences and in vivo regulated by the action of two sequence-specific families of transcription factors. Developmental Dynamics 246:992-1000, 2017. © 2017 Wiley Periodicals, Inc.

"Children are not small adults": avoiding common pitfalls of normal developmental variants in pediatric imaging.

Imaging of children is complicated with a vast array of normal variants, congenital or developmental disorders, and age-dependent differential considerations. We present imaging findings of several common anatomic variants as well as physiological and maturational processes that occur in children. We compare and contrast them with pathological entities so that the reader can successfully distinguish them when interpreting pediatric imaging examinations. The content has been accrued from the authors' collective experience at a tertiary-care pediatric hospital, teaching and consulting with radiology trainees and clinicians, as well as a comprehensive review of the literature, and is intended to represent a useful error prevention tool for radiologists interpreting pediatric studies.

Ultrasound in juvenile idiopathic arthritis.

BACKGROUND: In the recent years, musculoskeletal ultrasound (MSUS) has been regarded as especially promising in the assessment of juvenile idiopathic arthritis (JIA), as a reliable method to precisely document and monitor the synovial inflammation process. MAIN CONTENT: MSUS is particularly suited for examination of joints in children due to several advantages over other imaging modalities. Some challenges should be considered for correct interpretation of MSUS findings in children, due to the peculiar features of the growing skeleton. MSUS in JIA is considered particularly useful for its ability to detect subclinical synovitis, to improve the classification of patients in JIA subtypes, for the definition of remission, as guidance to intraarticular corticosteroid injections and for capturing early articular damage. Current evidence and applications of MSUS in JIA are documented by several authors. Recent advances and insights into further investigations on MSUS in healthy children and in JIA patients are presented and discussed in the present review. CONCLUSIONS: MSUS shows great promise in the assessment and management of children with JIA. Nonetheless, anatomical knowledge of sonographic changes over time, underlying immunopathophysiology, standardization and validation of MSUS in healthy children and in patients with JIA are still under investigation. Further research and educational efforts are required for expanding this imaging modality to more clinicians in their daily practice.