Systematic transcriptome profiling of hPSC-derived osteoblasts unveils CORIN's mastery in governing osteogenesis through CEBPD modulation.

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect human pluripotent stem cell-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide chromatin immunoprecipitation enrichment and mechanistic studies show that p38 MAPK-mediated CCAAT enhancer binding protein delta (CEBPD) upregulation is required for CORIN-modulated osteogenesis. Contrastingly, the type I transmembrane heparan sulfate proteoglycan SDC1 enriched in mesenchymal stem cells exerts a negative regulatory effect on osteogenesis through a similar mechanism. Chromatin immunoprecipitation-seq, bulk and single-cell transcriptomes, and functional validations indicated that CEBPD plays a critical role in controlling osteogenesis. In summary, our findings uncover previously unrecognized CORIN-mediated CEBPD transcriptomic networks in driving human osteoblast lineage commitment.

Protective Effects of ß-Blockers on Bone in Older Adults with Dementia.

Increased ß-adrenergic receptor activity has been hypothesized to cause bone loss in those with dementia. We investigated the effect of long-term ß-blocker use on rate of bone loss in older adults with dementia. We used a linear mixed-effects model to estimate the relationship between long-term ß-blocker use and rate of bone loss in participants from the Health Aging and Body Composition study. Records of 1198 participants were analyzed, 44.7% were men. Among the men, 25.2% had dementia and 20.2% were on ß-blockers, while in the women, 22.5% had dementia and 16.6% received ß-blockers. In the 135 men with dementia, 23 were taking ß-blockers, while 15 of 149 women with dementia were using ß-blockers. In men with dementia, ß-blocker users had 0.00491 g/cm2 less bone mineral density (BMD) loss per year at the femoral neck (i.e., 0.63% less loss per year) than non-users (p < 0.05). No differences were detected in women with or without dementia and men without dementia. ß-blockers may be protective by slowing down bone loss in older men with dementia.

Outcomes After Operative Treatment of Pediatric Monteggia Fracture-Dislocations: Comparison Between Open and Closed Injuries.

BACKGROUND: Open pediatric Monteggia fracture-dislocations are a relatively uncommon injury pattern, with limited numbers reported in previous series. Open fracture-dislocations frequently represent more severe injury patterns with potential for contamination. We aim to determine differences in long-term clinical and functional outcomes in the operative management of closed versus open pediatric Monteggia fracture-dislocations. METHODS: A retrospective review of operatively treated pediatric Monteggia fracture-dislocations was performed. Closed versus open injuries were compared in both clinical outcomes, as well as patient-reported outcomes through Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire. RESULTS: Of 30 operatively treated injuries, 12/30 (40%) were open fracture-dislocations. Patients were followed clinically for an average of 15.65 months in open injuries and an average of 4.61 months in closed injuries. A trend toward increased time to union was observed, however, significance was not achieved; open injuries averaged 8.0 versus 5.8 weeks for closed injuries ( P =0.07). Two patients (11%) in the closed fracture group experienced postoperative complications; both were minor. Five patients (42%) in the open fracture-dislocation group experienced a total of 6 postoperative complications; 5 of the 6 complications were major. QuickDASH scores were obtained at an average of 5 years postoperatively; mean QuickDASH scores were higher in the open fracture group, 13.1, compared with the closed fracture group, 5.9 ( P =0.038). Increased QuickDASH scores were independently associated with presence of postoperative complications. QuickDASH score could be expected to increase by 12.5 points in those with major complications ( P =0.044). CONCLUSION: We present the largest single cohort of pediatric open Monteggia fracture-dislocation injuries to date. These injuries are predictive of poorer outcomes including trend toward increased time to union, increased risk of major complication, and can independently predict worse long-term patient-reported functional outcomes. LEVEL OF EVIDENCE: Level III-these data represent a retrospective comparative study of clinical and functional outcomes.

Lower femoral neck bone mineral density (BMD) in elderly women not on statins.

Coronary artery disease (CAD) and osteoporosis, the two most frequently occurring chronic diseases of aging populations, share many risk factors including lack of estrogen, smoking, and low physical activity. CAD and low bone mineral density (BMD) are strongly associated. Statins, (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors), are used to prevent and treat CAD and have been associated with high BMD. This cross-sectional study examined associations of BMD with statin use and nonuse in elderly women with or without CAD. Multivariate regression analyses were conducted on 185 women aged ≥60 years who were referred between October 2010 and March 2015 to a geriatric osteoporosis clinic in Houston, Texas, for compromised skeletal health. Compared to the control group (without CAD and without statin use), patients with CAD and no statin use were more likely to have lower femoral neck BMD (ß: -0.46, 95% confidence interval: -0.75 to -0.18). The BMD of patients taking statins, regardless of presence of CAD, was similar to that of the control group. Statins may be protective in preventing bone loss in elderly women suffering from CAD. Prospective trials are warranted to determine if continued use of statins in them would help prevent both CAD and bone loss.

Association of Selective Serotonin Reuptake Inhibitors and Bone Mineral Density in Elderly Women.

Depression and osteoporosis are 2 common comorbidities in geriatric patients. There are concerns about the deleterious effects of selective serotonin reuptake inhibitor (SSRI) antidepressant use on bone mineral density (BMD). We examined the association between SSRI use and BMD in elderly women (≥65 yr) referred to a geriatric osteoporosis clinic for bone health evaluation. Cross-sectional analyses using the general linear model were performed on data collected retrospectively from August 2010 to April 2015. A total of 250 women were seen during the study period. Of these, 140 women had complete data on BMD measurements: 22 (15.7%) used an SSRI and 118 (84.3%) did not. The 2 groups, SSRI users and SSRI nonusers, did not differ significantly across any of the covariates tested (age, ethnicity, body mass index, and past and present osteoporosis treatment medications). After adjusting for covariates, there was no difference in the BMDs at the femoral neck (p = 0.887) or the spine (p = 0.275) between the 2 groups. Similarly, no difference was seen in the T-scores between SSRI users and nonusers at the femoral neck (p = 0.924) or at the spine level (p = 0.393). Our study did not show an association between SSRI use and BMD among elderly women referred for bone health evaluation. Other studies in the literature have been inconclusive, and therefore, robust longitudinal studies are needed to further assess the interaction between SSRI use and predictors of fracture such as BMD, bone turnover markers, and genes involved in bone turnover. Until then, clinicians should closely monitor the bone health of long-term SSRI users.

Lumbar Spine Trabecular Bone Score (TBS) Reflects Diminished Bone Quality in Patients With Diabetes Mellitus and Oral Glucocorticoid Therapy.

Trabecular bone score (TBS) is a texture parameter that measures the grayscale variation within dual-energy X-ray absorptiometry (DXA) images, and has been shown to significantly correlate with the 3-dimensional bone microarchitecture. The objective of this study was to determine whether TBS is a better clinical tool than traditionally used bone mineral density (BMD) to detect the skeletal deterioration seen in patients with diabetes (DM), patients undergoing oral glucocorticoid (GC) therapy, and patients who are both diabetic and taking steroids (GC + DM). We performed retrospective, cross-sectional study using DXA images of patients who visited UTHealth Department of Internal Medicine DXA clinic in Houston, TX, from May 30, 2014 to May 30, 2016. A total of 477 men and women, who were 55 years or older, were included in the study. Lumbar spine (LS) BMD and TBS were collected. Electronic medical records were reviewed to collect clinical information for each patient. When both men and women were analyzed as a single group, LS-BMD was significantly higher in the diabetic group than in the control group (1.14 vs 1.10, p = 0.038), whereas mean TBS of L1-L4 was significantly lower in the diabetic group (1.21 vs 1.26, p = 0.004). LS-TBS was also significantly lower in diabetic women than in nondiabetic women (1.20 vs 1.26, p = 0.002). Receiver operating characteristic curves and areas under the curve indicated that LS-TBS provided better ability than LS-BMD to discriminate between control subjects and those in the DM, GC, or GC + DM groups (areas under the curve between 0.645 and 0.697, p < 0.010 for all). LS-TBS is a BMD-independent parameter that is capable of capturing a larger portion of bone quality deterioration undetected by BMD alone in patients with DM and undergoing oral GC therapy.

Trabecular Bone Score Is a Valuable Addition to Bone Mineral Density for Bone Quality Assessment in Older Mexican American Women With Type 2 Diabetes.

Altered bone quality due to the underlying metabolic changes of type 2 diabetes (T2D) has been hypothesized to affect bone strength, leading to increased fracture risk in patients with T2D. Lumbar spine trabecular bone score (LS-TBS), an indirect measure of trabecular microarchitecture, provides information on bone quality and has been associated with T2D. However, trabecular bone score (TBS) is also affected by demographic patterns and body size, and is expected to be different in people from various ethnic or racial backgrounds. Therefore, it is important to understand associations between T2D and TBS for each ethnic or racial group separately. Although the relationship between TBS and age has been reported to be similar between non-Hispanic Caucasians and Mexican Americans (MAs), data on associations of LS-TBS with T2D in older MAs are lacking. Here, we report associations between TBS and T2D in 149 older MA men and women. Participants are part of a cohort known as the Cameron County Hispanic Cohort in Texas who have high prevalence of obesity and poor glycemic control. Bone mineral density was not altered for MA women with T2D, but was significantly higher in MA men with T2D compared with MA men without diabetes. Low LS-TBS was associated with T2D in women in our study. Although low TBS was associated with older age in men, TBS did not show any significant association with T2D for men. These results are similar to those found in other studies of non-Hispanic whites with diabetes. LS-TBS may add value in diagnosing poor bone quality in older MA women with T2D regardless of bone mineral density scoring.

The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations.

Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue characterized by bone fragility and low bone mass. Recently, our group and others reported that WNT1 recessive mutations cause OI, whereas WNT1 heterozygous mutations cause early onset osteoporosis. These findings support the hypothesis that WNT1 is an important WNT ligand regulating bone formation and bone homeostasis. While these studies provided strong human genetic and in vitro functional data, an in vivo animal model to study the mechanism of WNT1 function in bone is lacking. Here, we show that Swaying (Wnt1(sw/sw)) mice previously reported to carry a spontaneous mutation in Wnt1 share major features of OI including propensity to fractures and severe osteopenia. In addition, biomechanical and biochemical analyses showed that Wnt1(sw/sw) mice exhibit reduced bone strength with altered levels of mineral and collagen in the bone matrix that is also distinct from the type I collagen-related form of OI. Further histomorphometric analyses and gene expression studies demonstrate that the bone phenotype is associated with defects in osteoblast activity and function. Our study thus provides in vivo evidence that WNT1 mutations contribute to bone fragility in OI patients and demonstrates that the Wnt1(sw/sw) mouse is a murine model of OI caused by WNT1 mutations.

Do Transsacral-transiliac Screws Across Uninjured Sacroiliac Joints Affect Pain and Functional Outcomes in Trauma Patients?

BACKGROUND: Patients with pelvic ring displacement and instability can benefit from surgical reduction and instrumentation to stabilize the pelvis and improve functional outcomes. Current treatments include iliosacral screw or transsacral-transiliac screw, which provides greater biomechanical stability. However, controversy exists regarding the effects of placement of a screw across an uninjured sacroiliac joint for pelvis stabilization after trauma. QUESTIONS/PURPOSES: Does transsacral-transiliac screw fixation of an uninjured sacroiliac joint increase pain and worsen functional outcomes at minimum 1-year followup compared with patients undergoing standard iliosacral screw fixation across the injured sacroiliac joint in patients who have sustained pelvic trauma? METHODS: All patients between ages 18 and 84 years who sustained injuries to the pelvic ring (AO/OTA 61 A, B, C) who were surgically treated between 2011 and 2013 at an academic Level I trauma center were identified for selection. We included patients with unilateral sacroiliac disruption or sacral fractures treated with standard iliosacral screws across an injured hemipelvis and/or transsacral-transiliac screws placed in the posterior ring. Transsacral-transiliac screws were generally more likely to be used in patients with vertically unstable sacral injuries of the posterior ring as a result of previous reports of failures or in osteopenic patients. We excluded patients with bilateral posterior pelvic ring injuries, fixation with a device other than a screw, previous pelvic or acetabular fractures, associated acetabular fractures, and ankylosing spondylitis. Of the 110 patients who met study criteria, 53 (44%) were available for followup at least 12 months postinjury. Sixty patients were unable to be contacted by phone or mail and seven declined to participate in the study. Outcomes were obtained by members of the research team using the visual analog scale (VAS) pain score for both posterior sacroiliac joints, Short Musculoskeletal Functional Assessment (SMFA), and Majeed scores. Patients completed the forms by themselves when able to return to the clinic. A phone interview was performed for others after they received the outcome forms by mail or email. RESULTS: There were no differences between iliosacral and transsacral-transiliac in terms of VAS injured (2.9 ± 2.9 versus 3.0 ± 2.8, mean difference = 0.1 [95% confidence interval, -1.6 to 1.7], p = 0.91), VAS uninjured (1.8 ± 2.4 versus 2.0 ± 2.6, mean difference = 0.2 [-1.3 to 1.6], p = 0.82), Majeed (80.3 ± 19.9, 79.3 ± 17.5, mean difference = 1.0 [-11.6 to 9.6], p = 0.92), SMFA Function (22.8 ± 22.2, 21.0 ± 17.6, mean difference = 1.8 [-13.2 to 9.6], p = 0.29, and SMFA Bother (24.3 ± 23.8, 29.7 ± 23.4, mean difference = 5.4 [-7.8 to 18.6], p = 0.42). CONCLUSIONS: Placement of fixation across a contralateral, uninjured sacroiliac joint resulted in no differences in pain and function when compared with standard iliosacral screw placement across an injured hemipelvis at least 1 year after instrumentation. When needed for biomechanical stability, transsacral-transiliac fixation across an uninjured sacroiliac joint can be used without expectation of positive or negative effects on pain or functional outcomes at minimum 1-year followup. LEVEL OF EVIDENCE: Level III, therapeutic study.

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-ß in the bone microenvironment.

TGF-ß is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-ß bioavailability by attenuating maturation of pro-TGF-ß during cartilage homeostasis. However, whether regulation of intracellular TGF-ß maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1(-/-) mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1(-/-) osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1(-/-) osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast-osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1(-/-) calvaria exhibit an elevated mature TGF-ß/pro-TGF-ß ratio, with increased expression of TGF-ß downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan-TGF-ß antibody, significantly improved the low bone mass of Esl-1(-/-) mice, suggesting that elevated TGF-ß signaling is the major cause of osteopenia in Esl-1(-/-) mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-ß maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast-osteoclast coupling.

A Data-Driven Methodology to Comprehensively Assess Bone Drilling Using Radar Plots.

Background: The study aims to develop a data-driven methodology to assess bone drilling in preparation for future clinical trials in residency training. The existing assessment methods are either subjective or do not consider the interdependence among individual skill factors, such as time and accuracy. This study uses quantitative data and radar plots to visualize the balance of the selected skill factors. Methods: In the experiment, straight vertical drilling was assessed across 3 skill levels: expert surgeons (N = 10), intermediate residents (postgraduate year-2-5, N = 5), and novice residents (postgraduate year-1, N = 10). Motion and force were measured for each drilling trial, and data from multiple trials were then converted into 5 performance indicators, including overshoot, drilling time, overshoot consistency, time consistency, and force fluctuation. Each indicator was then scored between 0 and 10, with 10 being the best, and plotted into a radar plot. Results: Statistical difference (p < 0.05) was confirmed among 3 skill levels in force, time, and overshoot data. The radar plots revealed that the novice group exhibited the most distorted pentagons compared with the well-formed pentagons observed in the case of expert participants. The intermediate group showed slight distortion that was between the expert and novice groups. Conclusion/Clinical Relevance: This research shows the utility of radar plots in drilling assessment in a comprehensive manner and lays the groundwork for a data-driven training scheme to prepare novice residents for clinical practice.

The potential of suspended chitosan nanoparticles as a surgical irrigation fluid.

In this study, we sought to synthesize chitosan nanoparticles (CS-NPs) and characterize their morphology, efficacy in inhibiting bacterial attachment, and efficacy in eradicating bacteria established on implantable hardware. CS-NPs possess desirable properties, including antibacterial properties in biofilm-mediated infections. CS-NPs were produced using ionic gelation and characterized via scanning electron microscope imaging. Staphylococcus aureus was incubated with CS-NPs at various concentrations and compared to a 1% povidone-iodine with 1% H2 O2 control in 24-well plates. Stainless steel bone screws were placed in six-well plates and inoculated with S. aureus. After 24 h, the screws were transferred to one of three solutions (saline, 40 mg/mL CS-NP, or 1% povidone-iodine with 1% H2 O2 ). Four screws from each group were vortexed in saline and plated. The remaining screw from each group was prepped and imaged to map the location of persistent bacteria. Synthesized CS-NPs had a mean diameter of 0.39 ± 0.13 µm and circularity of 0.87 ± 0.05. The percent inhibition of bacterial attachment was 73% at 20 mg/mL, 73% at 30 mg/mL, 75% at 40 mg/mL, 79% at 50 mg/mL, and 78% at 60 mg/mL. When compared to saline, the 40 mg/mL CS-NP solution reduced bacteria on the screws by 76%. No bacteria were retrieved from the 1% povidone-iodine with 1% H2 O2 group. This study demonstrated that CS-NP solution effectively inhibited S. aureus bacterial attachment and was more effective than saline in eradicating bacteria from orthopedic hardware, suggesting that CS-NPs have the potential for prevention and treatment of musculoskeletal infections as a component of an intraoperative surgical irrigation solution.

The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in patients with OI type V. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with an increase in the skeletal progenitor cell population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 had decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.

Quantitative analysis of torsional stiffness in supplemental one-third tubular plate fixation in the management of isolated syndesmosis injuries: a biomechanical study.

BACKGROUND: Disruption of the distal tibia and fibula articulation or syndesmosis can occur without fracture, and isolated syndesmotic disruption is often treated operatively. Following syndesmotic screw removal, a period of protected weight-bearing usually follows to allow the screw holes to heal. Our hypothesis was that supplementing transsyndesmotic fixation with a one-third tubular plate would potentially increase the torsional stiffness about the ankle, thus reducing the risk of fracture after screw removal and potentially allowing a faster return to weight-bearing and sport. METHODS: Ten pairs of fresh frozen cadaveric specimens were divided into 2 groups. In group 1 (7 pairs), each left extremity underwent the placement, and subsequent removal, of a 4.5-mm transsyndesmotic screw in a tricortical fashion. The matching right extremity underwent the same procedure but with the addition of a one-third tubular plate, which remained in situ after screw removal. In group 2 (3 pairs), the left specimens had a screw placed and removed while the right limbs remained intact. All specimens were tested under an axial preload and a torsional load until failure. RESULTS: In group 1, the results demonstrated an increase in torsional stiffness in 5 of 7 specimens with supplemental fixation of a one-third tubular plate. In group 2, the presence of the screw hole alone reduced the torsional stiffness in all specimens tested when compared with intact specimens. However, neither of these differences were statistically significant. CONCLUSION: From this study, we can conclude that the use of supplementary one-third tubular plate fixation demonstrated a trend toward increasing the torsional stiffness following transsyndesmotic screw removal. CLINICAL RELEVANCE: We believe the trend toward improved stiffness justifies the continued use of our technique, although further studies are necessary to confirm it.

Biomechanical properties of splint materials while curing.

Many studies have evaluated splint strength at maturity with multiple splint materials, methods, and configurations but none have analyzed splints as they cure. The purpose of this study is to evaluate the properties of different splint materials immediately following activation and as they mature. Splints were dipped for three seconds in two temperatures of water and an additional group of fiberglass with no water was tested as well. Splint weight was taken as an additional measurement to assure homogenous groups. All splints were tested in three-point bending at a constant displacement. The generalized linear model (GLM) including all time frames showed differences in yield load and ultimate loads after three minutes. All ultimate loads occurred at greater than 20° of angulation. Plaster had a much lower displacement at its yield load at all times after 3 min. Plaster had a higher stiffness at 1° of angulation at all time points after six minutes. The GLM that excluded the three-day time showed that the higher temperature increased initial stiffness in the splints at three and six minutes. Fiberglass has a higher yield point and ultimate load when compared to plaster. However, these loads were measured at significant splint angulation for the fiberglass, suggesting that plaster is acting as a true splint. Fiberglass is stronger and faster to cure than plaster. In situations where the surgeon desires the strongest splint, fiberglass may be preferable. However, the initial stiffness of plaster is superior to fiberglass.

An objective assessment for bone drilling: A pilot study on vertical drilling.

The purpose of this study is to propose a quantitative assessment scheme to help with surgical bone drilling training. This pilot study gathered and compared motion and force data from expert surgeons (n = 3) and novice residents (n = 6). The experiment used three-dimensional printed bone simulants of young bone (YB) and osteoporotic bone (OB), and drilling overshoot, time, and force were measured. There was no statistically significant difference in overshoot between the two groups (p = 0.217 for YB and 0.215 for OB). The results, however, show that the experts took less time (mean = 4.01 s) than the novices (mean = 9.98 s), with a statistical difference (p = 0.003 for YB and 0.0001 for OB). In addition, the expert group performed more consistently than the novices. The force analysis further revealed that experts used a higher force to drill the first cortical section and a noticeably lower force in the second cortex to control the overshoot (approximate reduction of 5.5 N). Finally, when drilling time and overshoot distance were combined, the motion data distinguished the skill gap between expert and novice drilling; the force data provided insight into the drilling mechanism and performance outcomes. This study lays the groundwork for a data-driven training scheme to prepare novice residents for clinical practice.

Vascular injury risk stratification for lateral lumbar interbody fusion (LLIF) at L4-L5: a morphometric study using magnetic resonance imaging.

Background: Proper vascular injury risk stratification (VIRS) methods for L4-L5 lateral lumbar interbody fusion (LLIF) surgery have not been well-described. The objective of this study was to propose a novel VIRS method for L4-L5 LLIF surgery via the transpsoas approach. Methods: Axial magnetic resonance imaging (MRI) of adult patients were obtained and analyzed. The VIRS scores were assessed using anterior disc line to posterior vessel wall distance, the disc vessel angle (DVA), and the disc edge to vessel distance at the level of L4-L5 disc space. Results: Ninety-one consecutive adult patients were included in the study. The right common iliac vein (CIV) had a high risk of injury with both right- and left-sided approaches. The left CIV had a moderate risk with a left-sided approach when the iliocaval confluence was above the L4-L5 disc space but had a high risk when the confluence was at the L4-L5 disc space. The left CIV had a high risk with a right-sided approach when the confluence was above the L4-L5 disc space but had a moderate risk when the confluence was at the L4-L5 disc space. The inferior vena cava (IVC) had a high risk with both right- and left-sided approaches. The aorta had a moderate risk regardless of the right or left-sided approaches. The left common iliac artery (CIA) had a moderate risk with a right-sided approach and a low risk with a left-sided approach. The right CIA had a low risk with both right- and left-sided approaches. Conclusions: There are significant vascular anatomic variations at the L4-L5 disc level and a proper VIRS can be performed utilizing a combination of anterior disc line to posterior vessel wall distance, DVA, and disc edge to vessel distance, on the axial MRI.

The Effect of Locking Screws on Distal Component Fixation in Total Wrist Arthroplasty Using a Cadaver Model.

Purpose: The advent of total wrist arthroplasty has allowed for motion-sparing surgical treatment for wrist arthritis. The Integra Freedom Total Wrist Arthroplasty recently incorporated locking caps into its distal component fixation to minimize implant micromotion and improve osseous integration. The purpose of this study was to assess the kinematic effect of locking caps in a cadaveric model. Methods: The Integra Freedom was implanted in 4 matched-pair cadavers and tested with and without the use of the locking caps, with the testing order randomized. Each specimen was tested on a custom testing system in a position of 15° of radial deviation, neutral position, and 15° of ulnar deviation with 25 N, 50 N, 75 N, and 100 N of compressive force. The rotation of the capitate, trapezoid, and hamate at all positions was measured using a 3-dimensional digitizer. Results: Statistical analysis showed no difference in carpal rotation between the nonlocking cap and locking cap groups at all testing loads and wrist positions. The absolute motion of the distal row was minimal. However, of the total 216 loads/positions tested, only 4 (1.8%) showed a rotation of greater than 2° and only 34 (15.7%) showed a rotation of greater than 1°. Conclusions: This study shows that in a time zero cadaveric model, the initial osseous fixation of the distal component in the Integra Freedom is robust with or without locking caps. The addition of locking caps did not have a kinematic effect on distal carpal row fixation. However, further investigation into its clinical role is necessary. Clinical Relevance: At time zero, there is minimal carpal motion after implantation of the Integra Freedom Total Wrist with functional loading. The addition of locking caps did not lead to any decrease in carpal motion.

Micro-computed tomography assessment of bone structure in aging mice.

High-resolution computed tomography (CT) is widely used to assess bone structure under physiological and pathological conditions. Although the analytic protocols and parameters for micro-CT (µCT) analyses in mice are standardized for long bones, vertebrae, and the palms in aging mice, they have not yet been established for craniofacial bones. In this study, we conducted a morphometric assessment of craniofacial bones, in comparison with long bones, in aging mice. Although age-related changes were observed in the microarchitecture of the femur, tibia, vertebra, and basisphenoid bone, and were more pronounced in females than in males, the microarchitecture of both the interparietal bone and body of the mandible, which develop by intramembranous ossification, was less affected by age and sex. By contrast, the condyle of the mandible was more affected by aging in males compared to females. Taken together, our results indicate that mouse craniofacial bones are uniquely affected by age and sex.

4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long-bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis. Herein, we used 4-phenylbutiric acid (4-PBA), an established chemical chaperone, to determine if treatment of Aga2+/- mice, a model for moderately severe OI due to a Col1a1 structural mutation, could attenuate the phenotype. In vitro, Aga2+/- osteoblasts show increased protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation protein levels, which improved upon treatment with 4-PBA. The in vivo data demonstrate that a postweaning 5-week 4-PBA treatment increased total body length and weight, decreased fracture incidence, increased femoral bone volume fraction (BV/TV), and increased cortical thickness. These findings were associated with in vivo evidence of decreased bone-derived protein levels of the ER stress markers binding immunoglobulin protein (BiP), CCAAT/-enhancer-binding protein homologous protein (CHOP), and activating transcription factor 4 (ATF4) as well as increased levels of the autophagosome marker light chain 3A/B (LC3A/B). Genetic ablation of CHOP in Aga2+/- mice resulted in increased severity of the Aga2+/- phenotype, suggesting that the reduction in CHOP observed in vitro after treatment is a consequence rather than a cause of reduced ER stress. These findings suggest the potential use of chemical chaperones as an adjunct treatment for forms of OI associated with ER stress. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).