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Adhesive capsulitis of the shoulder involves loss of passive range of motion with associated pain and can develop spontaneously, with no obvious injury or inciting event. The pathomechanism of this disorder remains to be elucidated, but known risk factors for adhesive capsulitis include diabetes, female sex, and thyroid dysfunction. Additionally, transcriptional profiling and pedigree analyses have suggested a role for genetics. Identification of elements of genetic risk for adhesive capsulitis using population-based techniques can provide the basis for guiding both the personalized treatment of patients based on their genetic profiles and the development of new treatments by identification of the pathomechanism.A genome-wide association study (GWAS) was conducted using the U.K. Biobank (a collection of approximately 500,000 patients with genetic data and associated ICD-10 [International Classification of Diseases, 10th Revision] codes), comparing 2,142 patients with the ICD-10 code for adhesive capsulitis (M750) to those without. Separate GWASs were conducted controlling for 2 of the known risk factors of adhesive capsulitis-hypothyroidism and diabetes. Logistic regression analysis was conducted controlling for factors including sex, thyroid dysfunction, diabetes, shoulder dislocation, smoking, and genetics.Three loci of significance were identified: rs34315830 (in WNT7B; odds ratio [OR] = 1.28; 95% confidence interval [CI], 1.22 to 1.39), rs2965196 (in MAU2; OR = 1.67; 95% CI, 1.39 to 2.00), and rs1912256 (in POU1F1; OR = 1.22; 95% CI, 1.14 to 1.31). These loci retained significance when controlling for thyroid dysfunction and diabetes. The OR for total genetic risk was 5.81 (95% CI, 4.08 to 8.31), compared with 1.70 (95% CI, 1.18 to 2.36) for hypothyroidism and 4.23 (95% CI, 2.32 to 7.05) for diabetes.The total genetic risk associated with adhesive capsulitis was significant and similar to the risks associated with hypothyroidism and diabetes. Identification of WNT7B, POU1F1, and MAU2 implicates the Wnt pathway and cell proliferation response in the pathomechanism of adhesive capsulitis.Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background: Cannabidiol (CBD) is a cannabis derivative that has been popularized as a medicinal product with analgesic and anti-inflammatory effects. Given the anecdotal observations that several patients have reported use of CBD for spine-related pain, this study was designed to characterize CBD consumption patterns and perceived effects in patients with spine-related complaints. Methods: The study design was a cross-sectional survey. Over a 4-week period, an anonymous paper survey was administered to all patients presenting for evaluation by 1 of 9 spine surgeons at a single institution. Surveys were given upon registration for the office visit and collected by the office manager or nurse before evaluation by the surgeon. Patients were included regardless of surgical status (ie, preoperative, postoperative, or nonoperative) or region of pathology (lumbar, thoracic, or cervical). The survey consisted of multiple-choice questions on patient patterns of CBD use. Results: Out of 300 surveys, 214 (71%) were completed. CBD use for spine-related pain was reported by 54 (25.2%) patients. CBD was initially used for potential relief of back pain (66.7%), neck pain (37.0%), leg pain (35.2%), and/or arm pain (9.3%). Users also sought improvements in insomnia (25.9%) and mood (18.5%). Oil was the most popular formulation (64.8%). CBD was most often consumed 2–5 times (40.7%) or 6–10 times (31.5%) per week. The most common source of initial recommendation for CBD was friends or family (75.9%). Reported benefits were pain relief (46.3%), improved sleep (33.3%), and reduced anxiety (20.4%); however, 24.1% of patients reported no benefit from CBD use. The most reported side effect was fatigue (7.4%). Most users (63.0%) would recommend CBD to a friend for pain relief. Conclusion: CBD is already used by many patients, and further high-quality research on this supplement is essential. Level of Evidence: 4. Clinical Relevance: CBD is a commonly used by spine patients as an off label treatment.

Background Mice with a loss of function mutation in Wdpcp were described previously to display severe birth defects in the developing heart, neural tube, and limb buds. Further characterization of the skeletal phenotype of Wdpcp null mice was limited by perinatal lethality. Results We utilized Prx1-Cre mice to generate limb bud mesenchyme specific deletion of Wdpcp. These mice recapitulated the appendicular skeletal phenotype of the Wdpcp null mice including polydactyl and limb bud signaling defects. Examination of late stages of limb development demonstrated decreased size of cartilage anlagen, delayed calcification, and abnormal growth plates. Utilizing in vitro assays, we demonstrated that loss of Wdpcp in skeletal progenitors lead to loss of hedgehog signaling responsiveness and associated proliferative response. In vitro chondrogenesis assays showed this loss of hedgehog and proliferative response was associated with decreased expression of early chondrogenic marker N-Cadherin. E14.5 forelimbs demonstrated delayed ossification and expression of osteoblast markers Runx2 and Sp7. P0 growth plates demonstrated loss of hedgehog signaling markers and expansion of the hypertrophic zones of the growth plate. In vitro osteogenesis assays demonstrated decreased osteogenic differentiation of Wdpcp null mesenchymal progenitors in response to hedgehog stimulation. Conclusions These findings demonstrate how Wdpcp and associated regulation of the hedgehog signaling pathway plays an important role at multiple stages of skeletal development. Wdpcp is necessary for positive regulation of hedgehog signaling and associated proliferation is key to the initiation of chondrogenesis. At later stages, Wdpcp facilitates the robust hedgehog response necessary for chondrocyte hypertrophy and osteogenic differentiation.

End-stage knee osteoarthritis (OA) is a highly debilitating disease for which total knee arthroplasty (TKA) serves as an effective treatment option. Although a genetic component to OA in general has been described, evaluation of the genetic contribution to end-stage OA of the knee is limited. To this end, we present a genome-wide association study involving patients undergoing TKA for primary knee OA to characterize the genetic features of severe disease on a population level.Individuals with the diagnosis of knee OA who underwent primary TKA were identified in the U.K. Biobank using administrative codes. The U.K. Biobank is a data repository containing prospectively collected clinical and genomic data for500,000 patients. A genome-wide association analysis was performed using the REGENIE software package. Logistic regression was also used to compare the total genetic risk between subgroups stratified by age and body mass index (BMI).A total of 16,032 patients with end-stage knee OA who underwent primary TKA were identified. Seven genetic loci were found to be significantly associated with end-stage knee OA. The odds ratio (OR) for developing end-stage knee OA attributable to genetics was 1.12 (95% confidence interval [CI], 1.10 to 1.14), which was lower than the OR associated with BMI (OR = 1.81; 95% CI, 1.78 to 1.83) and age (OR = 2.38; 95% CI, 2.32 to 2.45). The magnitude of the OR for developing end-stage knee OA attributable to genetics was greater in patients60 years old than in patients ≥60 years old (p = 0.002).This population-level genome-wide association study of end-stage knee OA treated with primary TKA was notable for identifying multiple significant genetic variants. These loci involve genes responsible for cartilage development, cartilage homeostasis, cell signaling, and metabolism. Age and BMI appear to have a greater impact on the risk of developing end-stage disease compared with genetic factors. The genetic contribution to the development of severe disease is greater in younger patients.Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Cartilage defects of the patellofemoral joint are commonly found in association with patellar instability owing to abnormal biomechanics. Strategies to address chondral defects of the patellofemoral joint secondary to instability should first address causes of recurrent instability. Most patellofemoral chondral defects associated with instability are less than 2 cm2 and do not generally require intervention beyond chondroplasty. Larger defects of the patella and/or the trochlea can be repaired with osteochondral or surface cartilage repair.

Objectives: The concept of the “inverted pear” glenoid was introduced by Lo and Burkhart as an indicator of significant attritional glenoid bone loss that predisposes patients to recurrent instability and higher failure of arthroscopic Bankart repair. Coracoid transfer (Latarjet) is often performed in this setting, and evaluation of coracoid dimensions may improve patient-specific preoperative planning. The purpose of this study was to utilize computed tomography (CT) to determine a reproducible method for coracoid measurement and develop a preoperative planning algorithm for glenoid pear restoration using the traditional Latarjet technique or congruent arc modification (CAM). We hypothesized that classic Latarjet technique would sufficiently restore at least 100% of the glenoid diameter, up to 30% of anterior bone loss. We also hypothesized that most female patients would have a coracoid thickness Methods: Multiplanar reconstructed (MPR) shoulder CT scans were reviewed for patients aged 18-45. This age group was selected to capture an adult population that typically undergoes anterior shoulder stabilization surgery. Patients were excluded if CT scan demonstrated glenoid or humeral osteophyte formation, glenoid dysplasia, coracoid fracture, or tumor involving the glenoid or coracoid. All CT scans were obtained with the arm at the patient’s side, palm facing up, and the shoulder in external rotation. CT scans were performed by acquiring thin-slice data from the volumetric CT in the axial plane with a Discovery CT750 HD scanner (GE Healthcare) and the following scan parameters: 0.625-mm slice thickness, 0.313-mm slice spacing, reconstruction matrix of 512 × 512 pixels, reconstruction field of view of 40 to 45 cm, and pitch factor of 0.516. All measurements were performed using a PACS system (Sectra Workstation, Sectra AB, Linkoping, Sweden) by a board-certified musculoskeletal radiologist and two orthopaedic surgeons. The coracoid base was aligned in the coronal plane, and the long axis of the coracoid was aligned in the axial and sagittal planes (Figure 1). The coracoid length (proximal to distal) was measured on the modified axial view as the distance from the base to the tip along the long axis. The width (medial to lateral) and thickness (anterior to posterior) were measured on the modified coronal view. Coracoid dimensions were compared by sex and correlated with patient height and body mass index (BMI). Best-fit circle technique was used to quantify glenoid diameter and bone loss required for complete graft apposition of a 20- or 25-mm long coracoid graft to the glenoid neck. The proportion of glenoid diameter able to be restored using the classic Latarjet technique and the CAM was calculated and compared. The proportion of patients in which at least 20%, 30%, 35% or 40% of glenoid diameter could be restored using the classic Latarjet technique and the CAM was determined and compared. Based on these findings, a treatment algorithm was proposed considering glenoid bone loss, glenoid diameter and coracoid dimensions. Results: A total of 120 CT scans were reviewed, and three were excluded (two with osteophytes and one with severe glenoid dysplasia). Measurements were performed and dimensions recorded on 117 CT scans (69.2% males). Coracoid dimensions varied considerably among patients (length: 17.5-31.8mm, width: 9.1-20.5mm, thickness: 6.1-15.7mm, Table 1). There was a strong positive correlation between patient height and coracoid length (r=0.629, p=0.000) and a moderate positive correlation between patient height and coracoid thickness (r=0.408, p=0.000). Mean coracoid and glenoid dimensions were larger in males than females (all p10mm (84.0% vs 27.8%, p20 mm (96.3% vs 94.4%, p=0.65), a higher proportion of males had coracoid length >25mm (48.2% vs 13.9%, p=0.0009). Compared to the classic Latarjet technique, the CAM was able to restore more native glenoid diameter in both males and females (Males: 54.1±6.6% vs 39.1±4.9%, pConclusions: We describe a reliable method of measuring coracoid dimensions for preoperative planning of glenoid pear restoration. The traditional Latarjet technique reliably restores the glenoid AP diameter with bone loss of up to 30%. The majority of females have coracoid thickness [Table: see text][Table: see text]

SUMMARY In this article, we present a novel patella fixation technique using a low-profile highly contoured dorsal mini-fragment locking plate. This procedure is ideally indicated in patients with fracture patterns that are transverse without significant comminution. Long-term clinical studies are being performed to evaluate the effectiveness of this surgical technique.

The published article contained four sentences with incorrect reference citations. Here, those sentences and the reference list are corrected.

With higher healthcare costs compared to other similarly developed countries, US regulations are increasingly shifting away from fee-for-service based reimbursement and more towards bundled reimbursements for episodic care.

Musculoskeletal disorders constitute a substantial disease burden. Neither conservative management nor surgical intervention provides adequate treatment for several pathologies. As an element of regenerative medicine, stem cell therapies may overcome the poor innate healing capacity of several musculoskeletal tissues. This review highlights promising results of preclinical studies in which stem cell therapies have been applied to individual tissues of the musculoskeletal system (bone, articular cartilage, tendon and ligament, meniscus, intervertebral disc, and skeletal muscle) as well as transitions between tissues (osteochondral interfaces and tendon–bone interfaces). Clinical studies, although limited in number, are also reviewed. Challenges to the translation of stem cell therapies from bench to bedside are discussed and possible solutions are highlighted.

To use computed tomography (CT) to determine a reproducible method of coracoid measurement to compare the ability of the classic Latarjet technique and the congruent arc modification (CAM) to restore native glenoid diameter and to develop a preoperative planning algorithm for glenoid restoration with a goal of achieving an on-track shoulder.Coracoid dimensions were measured on multiplanar reconstructed shoulder CT scans of patients aged 18 to 45 years obtained between December 1, 2019, and March 13, 2020. Patients were excluded if CT demonstrated osteophyte formation, glenoid dysplasia, coracoid fracture, or tumor. The proportion of glenoid diameter able to be restored using classic Latarjet technique and CAM were calculated. A treatment algorithm was proposed considering the amount of bone loss present and coracoid dimensions.Coracoid dimensions of 117 consecutive patients were measured and varied considerably (length: 17.5-31.8 mm, width: 9.1-20.5 mm, thickness: 6.1-15.7 mm). While most patients had harvestable coracoid length ≥20 mm (male: 96.3% vs female: 94.4%, P = .65), only 27.8% of female patients had coracoid thickness ≥10 mm. When comparing Latarjet techniques, there was no difference in the proportion of patients in whom 30% glenoid diameter could be fully restored, but CAM was able to restore at least 35% in more male and female patients (98.8% vs 79.0% and 100% vs 61.1%, respectively, P = .00001). Intra- and inter-rater reliability was excellent ( intraclass correlation coefficient ≥0.950 for all dimensions).We describe a reliable method of measuring coracoid dimensions for preoperative planning of glenoid restoration. The classic Latarjet technique reliably restores the glenoid anteroposterior diameter with bone loss of up to 30%. The majority of female patients have coracoid thickness10 mm, which may increase the risk of graft fracture when using CAM. The decision to use the classic Latarjet technique or CAM considers each individual's glenoid and coracoid dimensions with a goal of achieving an on-track shoulder.Our reliable method of coracoid measurement demonstrated the differing abilities of the classic Latarjet and CAM to restore the native glenoid diameter. An evidence-based algorithm using these measurements was developed to assist in preoperative planning for glenohumeral instability in the setting of bone loss, with a goal of achieving an on-track shoulder. Alternative techniques may be considered if an on-track shoulder cannot be achieved with Latarjet.

Bone has well documented natural healing capacity that normally is sufficient to repair fractures and other common injuries. However, the properties of bone change throughout life, and aging is accompanied by increased incidence of bone diseases and compromised fracture healing capacity, which necessitate effective therapies capable of enhancing bone regeneration. The therapeutic potential of adult mesenchymal stem cells (MSCs) for bone repair has been long proposed and examined. Actions of MSCs may include direct differentiation to become bone cells, attraction and recruitment of other cells, or creation of a regenerative environment via production of trophic growth factors. With systemic aging, MSCs also undergo functional decline, which has been well investigated in a number of recent studies. In this review, we first describe the changes in MSCs during aging and discuss how these alterations can affect bone regeneration. We next review current research findings on bone tissue engineering, which is considered a promising and viable therapeutic solution for structural and functional restoration of bone. In particular, the importance of MSCs and bioscaffolds is highlighted. Finally, potential approaches for the prevention of MSC aging and the rejuvenation of aged MSC are discussed.

Injuries of tendon, ligament, and meniscus affect more than 10 million people in the United States annually. Unfortunately, most of the current clinical reparative interventions do not adequately address the requirements of the tissue junction sites, resulting in high failure rates of surgery and readmission upon overuse. This chapter reviews the nature and current treatments for such injuries and summarizes selected clinical trials in specific categories. Adult stem cells, or mesenchymal stem cells, are of particular therapeutic interest for these skeletal soft tissues in part because of the relative ease of isolation and enrichment, and freedom from ethical issues. Successful cell-based therapies will require the use of biomimetic biomaterial scaffolds to support and promote cell differentiation and tissue regeneration. The challenges and promises of combining stem/progenitor cells, scaffolds, and bioactive factors, for ligament, tendon, and meniscus tissue engineering and regenerative medicine approaches are highlighted in this review.

This review surveys the use of pluripotent and multipotent stem cells in skeletal tissue engineering. Specific emphasis is focused on evaluating the function and activities of these cells in the context of development in vivo, and how technologies and methods of stem cell-based tissue engineering for stem cells must draw inspiration from developmental biology. Information on the embryonic origin and in vivo differentiation of skeletal tissues is first reviewed, to shed light on the persistence and activities of adult stem cells that remain in skeletal tissues after embryogenesis. Next, the development and differentiation of pluripotent stem cells is discussed, and some of their advantages and disadvantages in the context of tissue engineering are presented. The final section highlights current use of multipotent adult mesenchymal stem cells, reviewing their origin, differentiation capacity, and potential applications to tissue engineering.

The bones and connective tissues of the body are derived from two embryonic origins, the mesoderm and neural crest. The appendicular skeleton arises from the lateral plate mesoderm, the axial skeleton from the paraxial mesoderm, and the craniofacial skeleton from a combination of cephalic paraxial mesoderm and neural crest cells. Bones are formed through one of two processes: Endochondral ossification involves the formation of primordial cartilaginous anlagen that are subsequently replaced by bone via the growth plates. Intramembranous ossification is characterized by the direct differentiation of mesenchymal cells to osteogenic tissue. The growth plate can be divided into a resting zone, a proliferating zone, a pre-hypertrophic zone, and a hypertrophic zone, reflecting a gradient of chondrocyte differentiation that is regulated by antagonism between bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signaling pathways and gradients of IHH and PTHrP. Replacement of cartilage by osteoblasts is dependent upon prior mineralization of the cartilage matrix and vascular invasion. The activities of the hypertrophic chondrocytes and of the osteoblasts are regulated by RUNX2. Osteoclasts are of hematopoietic origin (monocyte), and with osteoblasts, they remodel bone throughout an individual’s lifetime to adapt to mechanical demands. Joints and intra-articular structures arise from a cohort of progenitor cells distinct from those of the bones and are labeled by GDF5 and TGFBRII expression. Somites are formed from the segmental plate through the interaction of a cell-autonomous oscillator and a morphogenetic wave that coordinates somite boundary formation via the Notch-Delta juxtacrine system and epithelialization via WNT paracrine system and cadherin activity. Dysregulation of this developmental process leads to congenital scoliosis. The axial skeleton is derived from the ventro-medial sclerotome of somites. Differentiation of the somite is regulated by paracrine factors from surrounding tissues and the sclerotome in particular is induced by SHH. Tendons and ligaments develop from the interaction of mesodermal mesenchyme with myoblasts. The nucleus pulposus of the intervertebral disc is initially derived from the notochord. The gradual loss of “embryonic cells” from the disc may be related to disc degeneration and back pain.

The utility of restriction endonucleases as a tool in molecular biology is in large part due to the high degree of specificity with which they cleave well-characterized DNA recognition sequences. The specificity of restriction endonucleases is not absolute, yet many commonly used assays of biological phenomena and contemporary molecular biology techniques rely on the premise that restriction enzymes will cleave only perfect cognate recognition sites. In vitro, mispaired heteroduplex DNAs are commonly formed, especially subsequent to polymerase chain reaction amplification. We investigated a panel of restriction endonucleases to determine their ability to cleave mispaired heteroduplex DNA substrates. Two straightforward, non-radioactive assays are used to evaluate mispaired heteroduplex DNA cleavage: a PCR amplification method and an oligonucleotide-based assay. These assays demonstrated that most restriction endonucleases are capable of site-specific double-strand cleavage with heteroduplex mispaired DNA substrates, however, certain mispaired substrates do effectively abrogate cleavage to undetectable levels. These data are consistent with mispaired substrate cleavage previously reported for Eco RI and, importantly, extend our knowledge of mispaired heteroduplex substrate cleavage to 13 additional enzymes.