Influence of demographic factors on the occurrence of motion artefacts in HR-pQCT.

The study shows a high incidence of motion artefacts in a central European population and a significant increase of those artefacts with higher age. These findings may impact on the design and conduct of future in vivo HR-pQCT studies or at least help to estimate the potential number of drop outs due to unusable image quality. PURPOSE: Motion artefacts in high-resolution peripheral quantitative computed tomography (HR-pQCT) are challenging, as they introduce error into the resulting measurement data. The aim of this study was to assess the general occurrence of motion artefacts in healthy distal radius and to evaluate the influence of demographic factors. METHODS: The retrospective study is based on 525 distal radius second-generation HR-pQCT scans of 95 patients. All stacks were evaluated by two experienced observers and graded according to the visual grading scale recommended by the manufacturer, ranging from grade 1 (no visible motion artefacts) to grade 5 (severe motion artefacts). Correlations between demographic factors and image quality were evaluated using a linear mixed effects model analysis. RESULTS: The average visual grading was 2.7 (SD ± 0.7). Age and severity of motion artefacts significantly correlated (p = 0.026). Patients aged 65 years or above had an average image quality between grades 1 and 3 in 72.7% of cases, while patients younger than 65 had an average image quality between grades 1 and 3 in 91.9% of cases. Gender, smoking behaviour, and handedness had no significant influence on motion artefacts. CONCLUSION: This study showed a high incidence of motion artefacts in a representative central European population, but also a significant increase of motion artefacts with higher age. This could impact further study designs by planning for a sufficiently large and if possible a more selective study population to gain a representative amount of high-quality image data.

Tunnel widening after ACL reconstruction with different fixation techniques: aperture fixation with biodegradable interference screws versus all-inside technique with suspensory cortical buttons. 5-year data from a prospective randomized trial.

BACKGROUND: The aim of the present study was to examine tunnel widening and clinical outcomes after anterior cruciate ligament reconstruction (ACLR) using two different fixation methods: aperture fixation with biodegradable interference screws versus all-inside ACLR with suspensory cortical buttons. METHODS: Tunnel widening was assessed using volumetric and diameter measurements on magnetic resonance imaging (MRI) scans directly after surgery, as well as 6 months and 2 and 5 years postoperatively. Clinical outcomes were assessed after 5 years with instrumented tibial anteroposterior translation measurement (KT-1000), single-leg hop testing, and the IKDC, Lysholm, and Tegner activity scores. RESULTS: At the final follow-up, the study population consisted of 21 patients, 12 of whom underwent screw fixation and 9 of whom had button fixation. 3 patients with all-inside ACLR had sustained early repeat ruptures within 6 months after surgery and had to be excluded from the further analysis. With screw fixation, the tibial tunnel volume changed significantly more over time compared to all-inside button fixation, with a larger initial increase at 6 months (from postoperative 2.9 ± 0.2 to 3.3 ± 0.2 cm3 at 6 months versus 1.7 ± 0.1 to 1.9 ± 0.2 cm3) and a greater final decrease over 2-5 years postoperatively (from 3.1 ± 0.2 to 1.9 ± 0.2 cm3 versus 1.8 ± 0.2 ± 0.1 to 1.3 ± 0.1 cm3) (P < 0.001). The femoral tunnel volume remained comparable between the two groups throughout the follow-up period, with an initial 1.6 ± 0.1 cm3 in both groups and 1.2 ± 0.1 vs. 1.3 ± 0.1 after 5 years in the screw and button groups, respectively (P ≥ 0.314). The maximum tibial and femoral tunnel diameters were significantly larger with screw fixation at all four time points. Tibial diameters measured 11.1 ± 0.2, 12.3 ± 0.3, 12.3 ± 0.4, and 11.2 ± 0.4 mm in the screw group versus 8.1 ± 0.3, 8.9 ± 0.3, 9.1 ± 0.4 and 8.2 ± 0.5 mm in the button group (P < 0.001). Femoral diameters measured 8.6 ± 0.2, 10.5 ± 0.4, 10.2 ± 0.3, and 8.9 ± 0.3 versus 7.3 ± 0.3, 8.4 ± 0.4, 8.4 ± 0.3, 7.5 ± 0.3, respectively (P ≤ 0.007). Four patients (33%) in the screw group exceeded a diameter of 12 mm on the tibial side after 5 years versus none in the button group (not significant, P = 0.104). Tibial anteroposterior translation measurement with KT-1000 after 5 years was 2.3 ± 2.4 mm in the screw group versus 3.2 ± 3.5 mm in the button group (not significant, P = 0.602). There were no significant differences between the groups in any of the other clinical outcomes. CONCLUSION: Tibial tunnels in ACLR with screw fixation were associated with a larger increase in tunnel volume within the first 2 years and a greater decrease up to 5 years after surgery, while femoral tunnel volumes did not differ significantly. On the tibial side, the need for staged revision ACLR may be greater after biodegradable interference screw fixation if repeat ruptures occur, especially within the first 2 years after primary ACLR. Concerns may remain regarding a higher graft failure rate with all-inside ACLR. LEVEL OF EVIDENCE: II. RCT CONSORT: NCT01755819.

Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/ß receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/ß receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

The impact of motion induced artifacts in the evaluation of HR-pQCT scans of the scaphoid bone: an assessment of inter- and intraobserver variability and quantitative parameters.

Background: In-vivo high-resolution peripheral quantitative computed tomography (HR-pQCT) has high potential in scaphoid bone pathologies' scientific and clinical fields. The manufacturer's visual grading scale (VGS) classifies motion artifacts and divides scans into five quality grades ranging from grade 1 (good quality) to grade 5 (poor quality). This prospective study aimed to investigate the feasibility of the VGS and the influence of image quality on bone density and microarchitecture parameters for the scaphoid bone. Methods: Within one year, twenty-two patients with scaphoid fractures received up to six scans of their fractured and contralateral wrist (each consisting of three stacks) using second-generation HR-pQCT (total 256 scans). Three experienced observers graded each stack following the visual grading system, and inter- and intraobserver variability were assessed. The contralateral uninjured scaphoids were then compared pairwise within each patient to high-quality grade 1 scans to determine the influence of image quality on density and microarchitecture parameters. Results: Inter- and intraobserver variability among the three observers significantly revealed fair to moderate agreement, P<0.001 and P<0.05, respectively. Bone volume (BV) fraction tended to increase with poorer image quality but did not exceed four percent. Trabecular bone mineral density (Tb.BMD) decreased with poorer image quality but did not exceed five percent. Trabecular number and trabecular thickness significantly increased by 15.5% and 6.8% at grade five (P<0.001), respectively, and trabecular separation significantly decreased by 13.7% at grade five (P<0.001). Conclusions: This study revealed a considerable influence of motion on bone morphometry parameters of the scaphoid. Therefore, high image quality must be a central point in studies focusing on the histomorphometry of small objects. The high inter- and intraobserver variability limit the VGS. Future research may focus on other grading systems or automated techniques leading to more consistent and reproducible results. Currently, the use of microarchitectural analysis should be limited to cases without motion artefacts or, at most low graded motion artefacts.

Protective effects of spironolactone on vascular calcification in chronic kidney disease.

BACKGROUND: Vascular calcification is common in chronic kidney disease (CKD) and associated with increased cardiovascular mortality. Aldosterone has been implicated as an augmenting factor in the progression of vascular calcification. The present study further explored putative beneficial effects of aldosterone inhibition by the mineralocorticoid receptor antagonist spironolactone on vascular calcification in CKD. METHODS: Serum calcification propensity was determined in serum samples from the MiREnDa trial, a prospective, randomized controlled clinical trial to investigate efficacy and safety of spironolactone in maintenance hemodialysis patients. Experiments were conducted in mice with subtotal nephrectomy and cholecalciferol treatment, and in calcifying primary human aortic smooth muscle cells (HAoSMCs). RESULTS: Serum calcification propensity was improved by spironolactone treatment in patients on hemodialysis from the MiREnDa trial. In mouse models and HAoSMCs, spironolactone treatment ameliorated vascular calcification and expression of osteogenic markers. CONCLUSIONS: These observations support a putative benefit of spironolactone treatment in CKD-associated vascular calcification. Further research is required to investigate possible improvements in cardiovascular outcomes by spironolactone and whether the benefits outweigh the risks in patients with CKD.