Two-year target vessel-related outcomes following use of off-the-shelf branched endografts for the treatment of thoracoabdominal aortic aneurysms.

OBJECTIVE: The aim of this study was to assess clinical outcomes and target vessel patency through 2 years following thoracoabdominal aortic aneurysms (TAAA) repair with the off-the-shelf Zenith t-Branch Thoracoabdominal Endovascular Graft (William Cook Europe). METHODS: This post-market observational study was conducted at three European sites with ambispective enrollment from 2012 to 2017. Patients underwent endovascular TAAA repair with the t-Branch graft and bridging stent grafts (BSGs) for the celiac (CA), superior mesenteric (SMA), left renal (LRA), and/or right renal (RRA) arteries. Follow-up was through 2 years, per sites' standard of care. Procedural and 1-year results were reported previously. RESULTS: Eighty patients (mean age, 71.0±7.4 years; 70.0% men) were enrolled; six patients had symptomatic TAAAs, and 15 patients had contained ruptures. Technical success was achieved in 98.8% of patients (79/80). Median follow-up was 22.2 months (interquartile range, 9.2-25.1 months). At 24 months, Kaplan-Meier (KM) freedom from all-cause and aneurysm-related mortality were 78.5% and 98.6%, respectively. Beyond 12 months, 38 adverse events occurred in 20 patients, including two aortic ruptures (one study aneurysm and one non-study aneurysm) and six deaths (none aneurysm-related, as reported by the site). Compared with postprocedure, maximum aneurysm diameter decreased (>5 mm) in 84.6% (44/52), remained unchanged in 3.8% (2/52), and increased (>5 mm) in 11.5% (6/52) of patients with imaging follow-up after 12 months. No conversions to open repair, and no t-Branch graft or other endograft component migration or integrity issues were reported. No loss of patency was reported in the t-Branch or iliac limb grafts throughout the study. Throughout study duration, four patients had five imaging-reported BSG compressions, none of which required secondary intervention. KM freedom from secondary intervention was 76.3% at 24 months. Fourteen target vessel-related secondary interventions were performed, primarily consisting of stent placement for endoleak, stenosis, or occlusion. KM freedom from loss of primary patency was 94.8%, 100%, 91.3%, and 89.3% for the CA, SMA, LRA, and RRA, respectively, at 24 months. KM freedom from loss of secondary patency in the CA, SMA, LRA, and RRA were 96.3%, 100%, 98.2%, and 98.3% at 24 months, respectively. A total of 298 vessels were targeted, of which 12 were occluded over the study period. CONCLUSIONS: Primary and secondary target vessel patency rates through 2 years demonstrated durable repair with the t-Branch graft in patients treated for symptomatic or asymptomatic thoracoabdominal aortic aneurysms.

Interleukin-6 (IL-6) deficiency enhances intramembranous osteogenesis following stress fracture in mice.

Interleukin-6 (IL-6) is highly upregulated in response to skeletal injury, suggesting it plays a role in the inflammatory phase of fracture repair. However, the impact of IL-6 on successful repair remains incompletely defined. Therefore, we investigated the role of IL-6 in two models of fracture repair (full fracture and stress fracture) using 12-week old IL-6 global knockout mice (IL-6 KO) and wild type (WT) littermate controls. Callus morphology and mineral density 14 days after full femur fracture did not differ between IL-6 knockout mice and controls. In contrast, IL-6 KO mice had an enhanced bone response 7 days after ulnar stress fracture compared to WT, with increased total callus volume (p = 0.020) and callus bone volume (p = 0.045). IL-6 KO did not alter the recruitment of immune cells (Gr-1 or F4/80 positive) to the stress fracture callus. IL-6 KO also did not alter the number of osteoclasts in the stress fracture callus. Using RNA-seq, we identified differentially expressed genes in stress fracture vs. contralateral control ulnae, and observed that IL-6 KO resulted in only modest alterations to the gene expression response to stress fracture (SFx). Wnt1 was more highly upregulated in IL-6 KO SFx callus at both day 1 (fold change 12.5 in KO vs. 5.7 in WT) and day 3 (fold change 4.7 in KO vs. 1.9 in WT). Finally, using tibial compression to induce bone formation without bone injury, we found that IL-6 KO directly impacted osteoblast function, increasing the propensity for woven bone formation. In summary, we report that IL-6 knockout enhanced formation of callus and bone following stress fracture injury, likely through direct action on the osteoblast's ability to produce woven bone. This suggests a novel role of IL-6 as a suppressor of intramembranous bone formation.

An animal trial to study damage and repair in ovariectomized rabbits.

Microdamage accumulates in bone matrix and is repaired through bone remodeling. Conditions such as osteoporosis and treatment with antiresorptive bisphosphonates can influence this remodeling process. In order to study microdamage accrual and repair in the context of osteoporosis and osteon structures, we set out to modify the rabbit forelimb fatigue model. New Zealand White rabbits (N = 43, 10 months old) received either ovariectomy (OVX) or sham surgeries and were used for forelimb fatigue loading. OVX increased fluorochrome labeling of intracortical and periosteal bone of the ulna, without changes in bone mass. Monotonic and cyclic loading of the forelimb did not reveal any statistical differences between stiffness, ultimate force, or displacement to failure between sham and OVX rabbits. Two levels of fatigue loading, chosen to represent "low" and "moderate" fatigue (25% and 40% of total displacement to failure, respectively), were used on OVX forelimbs to examine microdamage creation. However, neither group showed increased damage burden as compared to non-loaded controls. Following fatigue loading rabbit ulnae had increased intracortical remodeling and periosteal lamellar bone formation in "moderate" fatigue limbs, although no basic multicellular units or microdamage-targeted remodeling was observed. In summary, we adapted the rabbit forelimb fatigue model to accommodate OVX animals. However, loading parameters that could induce repeatable microdamage burden were not identified. Thus, while increased intracortical remodeling and periosteal bone formation were induced by our fatigue loading regimen, this preliminary study did not establish conditions to allow future study of the interactions between microdamage accrual and repair.

Transcriptional profiling of intramembranous and endochondral ossification after fracture in mice.

Bone fracture repair represents an important clinical challenge with nearly 1 million non-union fractures occurring annually in the U.S. Gene expression differs between non-union and healthy repair, suggesting there is a pattern of gene expression that is indicative of optimal repair. Despite this, the gene expression profile of fracture repair remains incompletely understood. In this work, we used RNA-seq of two well-established murine fracture models to describe gene expression of intramembranous and endochondral bone formation. We used top differentially expressed genes, enriched gene ontology terms and pathways, callus cellular phenotyping, and histology to describe and contrast these bone formation processes across time. Intramembranous repair, as modeled by ulnar stress fracture, and endochondral repair, as modeled by femur full fracture, exhibited vastly different transcriptional profiles throughout repair. Stress fracture healing had enriched differentially expressed genes associated with bone repair and osteoblasts, highlighting the strong osteogenic repair process of this model. Interestingly, the PI3K-Akt signaling pathway was one of only a few pathways uniquely enriched in stress fracture repair. Full fracture repair involved a higher level of inflammatory and immune cell related genes than did stress fracture repair. Full fracture repair also differed from stress fracture in a robust downregulation of ion channel genes following injury, the role of which in fracture repair is unclear. This study offers a broad description of gene expression in intramembranous and endochondral ossification across several time points throughout repair and suggests several potentially intriguing genes, pathways, and cells whose role in fracture repair requires further study.

Stiffness of resting lumbar myofascia in healthy young subjects quantified using a handheld myotonometer and concurrently with surface electromyography monitoring.

This study aimed to non-invasively quantify passive stiffness of superficial myofascia at a lower lumbar (L3-L4) anatomical level in young healthy male and female subjects and investigate its possible morphological variation. Resting prone lumbar myofascial measurements were quantified using MyotonPro(®) and statistically analyzed in 20 young healthy individuals over 3-weekly intervals, concurrently with surface electromyography (sEMG). Averaged mean ± SE stiffness (Newton/meter) over three weeks was significantly (p < 0.001) greater in males (247.8 ± 11.3) than females (208.4 ± 11.3), on the right (237.7 ± 12.8) than left sides (218.5 ± 12.3), at 10-min (231.4 ± 9.1) than initial baseline (224.8 ± 9.1) values. A polymorphism of stiffness values in 10 male and 10 female subjects was suggested by box plot analyses of the 3 weekly measurements and greater inter-individual than intra-individual variances. Greater knowledge of lumbar myofascial stiffness can improve understanding of their contributions in health and chronic low back disorders.

Greater Resting Lumbar Extensor Myofascial Stiffness in Younger Ankylosing Spondylitis Patients Than Age-Comparable Healthy Volunteers Quantified by Myotonometry.

OBJECTIVE: To quantify resting lumbar erector myofascial stiffness in younger patients with ankylosing spondylitis (AS) and age-comparable healthy control subjects using a handheld mechanical impulse-based myotonometric device. DESIGN: A case-control study of 24 patients with AS and 24 age-comparable healthy control subjects. SETTING: University physical therapy department. PARTICIPANTS: Patients with AS (men: n=19; women: n=5; total: N=24) and healthy volunteers (men: n=19; women: n=5; total: N=24) without low back pain (age range, 18-46y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Lumbar myofascial stiffness. RESULTS: At the initial measurements, median stiffness (Nm) of the averaged right- and left-sided values was greater (P=.021) in 24 patients with AS than 24 control subjects (268.9 vs 238.9, respectively). Repeated measurements after a 10-minute prone resting period were also greater (P=.007) in patients with AS than control subjects (281.0 vs 241.4, respectively). The 48 averaged right- and left-sided values from baseline and 10-minute measurements were compared in each subject group. The patients with AS more frequently (P=.012) had stiffness values >250 Nm (35 [72.9%] vs 22 [45.8%] in control subjects). CONCLUSIONS: Lumbar myofascial stiffness was greater in 24 patients with AS than in the control subjects. A hypothesized biomechanical concept of increased resting lumbar myofascial stiffness in AS may be supported by this preliminary controlled study.