Genome-wide association study identifies genetic variants which predict the response of bone mineral density to teriparatide therapy.

OBJECTIVES: Teriparatide (TPTD) is an effective treatment for osteoporosis but the individual response to therapy is variable for reasons that are unclear. This study aimed to determine whether the response to TPTD might be influenced by genetic factors. METHODS: We searched for predictors of the response of bone mineral density (BMD) to TPTD using a two-stage genome-wide association study in 437 patients with osteoporosis from three referral centres. Demographic and clinical data including the response of BMD to treatment at the lumbar spine and hip were extracted from the medical records of each participant. RESULTS: Allelic variation at rs6430612 on chromosome 2, close to the CXCR4 gene was associated with the response of spine BMD to TPTD at a genome wide significant level (p=9.2×10-9 beta=-0.35 (-0.47 to -0.23)). The increase in BMD was almost twice as great in AA homozygotes at rs6430612 as compared with GG homozygotes with intermediate values in heterozygotes. The same variant was also associated with response of femoral neck and total hip BMD (p=0.007). An additional locus on chromosome 19 tagged by rs73056959 was associated with the response of femoral neck BMD to TPTD (p=3.5×10-9, beta=-1.61 (-2.14 to -1.07)). CONCLUSIONS: Genetic factors influence the response to TPTD at the lumbar spine and hip with a magnitude of effect that is clinically relevant. Further studies are required to identify the causal genetic variants and underlying mechanisms as well as to explore how genetic testing for these variants might be implemented in clinical practice.

Incorporating gout guideline advice into urate reports is associated with reduced hospital admissions: results of an observational study.

OBJECTIVE: To evaluate the impact of incorporating treatment guidance into reporting of urate test results. METHODS: Urate targets for clinically confirmed gout were added to urate results above 0.36 mmol/l requested after September 2014 within NHS Lothian. Scotland-wide data on urate-lowering therapy prescriptions and hospital admissions with gout were analysed between 2009 and 2020. Local data on urate tests were analysed between 2014 and 2015. RESULTS: Admissions with a primary diagnosis of gout in Lothian reduced modestly following the intervention from 111/year in 2010-2014 to 104/year in 2015-2019, a non-significant difference (P = 0.32). In contrast there was a significant increase in admissions to remaining NHS Scotland health boards (556/year vs 606/year, P < 0.01). For a secondary diagnosis of gout the number of admissions in NHS Lothian reduced significantly (58/year vs 39/year, P < 0.01) contrasting with a significant increase in remaining Scottish health boards (220/year vs 290/year, P < 0.01). The relative rate of admissions to NHS Lothian compared with remaining Scottish boards using a 2009 baseline were significantly reduced for both primary diagnosis of gout (1.06 vs 1.25, P < 0.001) and secondary diagnoses of gout (0.64 compared with 1.4, P < 0.001) after the intervention; however, there was no difference before the intervention. A relative increase in the prescription rates of allopurinol 300 mg tablets and febuxostat 120 mg tablets may have contributed to the improved outcomes seen. CONCLUSION: Incorporation of clinical guideline advice into routine reporting of urate results was associated with reduced rates of admission with gout in NHS Lothian, in comparison with other Scottish health boards.

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout.

OBJECTIVE: Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout. METHODS: Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout. RESULTS: We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10-5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry. CONCLUSION: Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.

Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus.

OBJECTIVE: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. METHODS: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. RESULTS: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). CONCLUSION: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.

Long-Term Effects of Teriparatide Followed by Antiresorptive Therapy on Clinical Outcomes in Patients with Severe Spinal Osteoporosis.

Teriparatide (TPTD) is the most widely used anabolic agent in the treatment of patients with osteoporosis although its use is restricted in many countries. A recent randomised trial confirmed that TPTD was superior to risedronate at preventing vertebral fractures over a 2-year period. There is limited information on the relative effectiveness of TPTD compared with standard care in routine clinical practice. In this paper, we report the results of an extended observational study of 724 women referred to a specialist clinic with severe osteoporosis over an 11.5-year period, who were considered for TPTD therapy. Of these patients, 496 (68.5%) were treated with TPTD, whereas the remaining 228 (31.5%) received other treatments. This was either because they were unwilling or unable to self-inject (52.6%), because they had already been established on oral bisphosphonates (31.1%) or because of contraindications (12.7%). The TPTD group were younger than the standard care group (69.6 vs. 74.1 years) and had a lower 10-year fracture risk (25.7% vs. 28.6%). Those treated with TPTD had a greater increase in BMD at the lumbar spine compared with standard care (13.3% vs. 8.2%, p < 0.001) after approximately 2 years and had a lower incidence of vertebral fractures (4.8% vs. 10.1%, p = 0.01) over the course of our observation. There was no difference between groups with respect to either BMD change at the femoral neck or incidence of non-vertebral fractures. This study confirms that TPTD is superior to standard care at reducing the risk of vertebral fracture in patients with severe osteoporosis.

Lower limb alignment becomes more varus and hyperextended from supine to bipedal stance in asymptomatic, osteoarthritic and prosthetic neutral or varus knees.

PURPOSE: Knee alignment is a fundamental measurement in the assessment, monitoring and surgical management of patients with osteoarthritis. There is a lack of data regarding how static tibiofemoral alignment varies between supine and standing conditions. This study aimed to quantify the relationship between supine and standing lower limb alignment in asymptomatic, osteoarthritic (OA) and prosthetic (TKA) knees. METHODS: A non-invasive position capture system was used to assess knee alignment for 30 asymptomatic controls and 31 patients with OA both before and after TKA. Coronal and sagittal mechanical femorotibial angles were measured supine with the lower limb in extension and in bipedal stance. Changes between conditions were analysed using paired ttests. Vector plots of ankle centre displacement relative to the knee centre from supine to standing were produced to allow three-dimensional visualisation. RESULTS: All groups showed a trend towards varus and extension when going from supine to standing. Mean change for asymptomatic knees was 1.2° more varus (p = 0.001) and 3.8° more extended (p < 0.001). For OA knees this was 1.1° more varus (p = 0.009) and 5.9° more extended (p < 0.001) and TKA knees 1.9° more varus (p < 0.001) and 5.6° more extended (p < 0.001). CONCLUSION: The observed consistent changes in lower limb alignment between supine and standing positions across knee types suggests the soft tissue envelope restraining the knee may have a greater influence on dynamic alignment changes than the underlying bony deformity. This highlights the importance of quantifying soft tissue behaviour when planning, performing and evaluating alignment dependent surgical interventions of the knee. When routinely assessing any type of knee, clinicians should be aware that subtle consistent alignment changes occur under weightbearing conditions and tailor their treatments accordingly. LEVEL OF EVIDENCE: II.

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

Identification of Movement Strategies During the Sit-to-Walk Movement in Patients With Knee Osteoarthritis.

Patients with osteoarthritis of the knee commonly alter their movement to compensate for lower limb weakness and alleviate joint pain. Movement alterations may lead to weight-bearing asymmetries, and potentially to the progression of the disease. This study presents a novel numerical procedure for the identification of sit-to-walk strategies and differences in movement habits between control adults and persons with knee osteoarthritis. Ten control and 12 participants with osteoarthritis performed the sit-to-walk task in a motion capture laboratory. Participants sat on a stool with the height adjusted to 100% of their knee height, then stood and walked to pick up an object from a table in front of them. Different movement strategies were identified by means of hierarchical clustering. Trials were also classified as to whether the left and right extremities used a bilateral or an asymmetrical strategy. Participants with osteoarthritis used significantly more asymmetrical arm strategies (P = .03) while adopting the pushing through the chair strategy more often than the control subjects (P = .02). The results demonstrated that the 2 groups favor different sit-to-walk strategies. Asymmetrical arm behavior possibly indicates a compensation for the weakness of the affected leg. The proposed procedure may be useful to rapidly assess postoperative outcomes and developing rehabilitation strategies.

Autoantibodies to Osteoprotegerin are Associated with Low Hip Bone Mineral Density and History of Fractures in Axial Spondyloarthritis: A Cross-Sectional Observational Study.

Osteoporosis is a recognised complication of axial spondyloarthritis (axSpA) and is thought to be due to functional impairment and the osteoclast-activating effects of proinflammatory cytokines. The development of autoantibodies to OPG (OPG-Ab) has been associated with severe osteoporosis and increased bone resorption in rheumatoid arthritis. In this study, we screened for the presence of OPG-Ab in axSpA and reviewed their clinical significance. We studied 134 patients, recruited from two centres in the United Kingdom. Their mean age was 47.5 years and 75% were male. Concentrations of OPG-Ab were related to bone mineral density (BMD) and fracture history using linear and logistic regression models adjusting for age, gender, disease duration and activity, body mass index and bisphosphonate use. We detected OPG-Ab in 11/134 patients (8.2%). Femoral neck and total hip BMD were significantly reduced in OPG-Ab positive patients (0.827 vs. 0.967 g/cm2, p = 0.008 and 0.868 vs. 1.028 g/cm2, p = 0.002, respectively). Regression analysis showed that the presence of OPG-Ab was independently associated with total hip osteopenia (ORadj 24.2; 95% CI 2.57, 228) and history of fractures (ORadj 10.5; 95% CI 2.07, 53.3). OPG-Ab concentration was associated with total hip BMD in g/cm2 (ß = -1.15; 95% CI -0.25, -0.04). There were no associations between OPG-Ab concentration and bone turnover markers, but free sRANKL concentrations were lower in OPG-Ab-positive patients (median 0.04 vs. 0.11 pmol/L, p = 0.050). We conclude that OPG-Ab are associated with hip BMD and fractures in axSpA suggesting that they may contribute to the pathogenesis of bone loss in some patients with this condition.

Replication of association of the apolipoprotein A1-C3-A4 gene cluster with the risk of gout.

OBJECTIVE: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. METHODS: We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Maori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). RESULTS: In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10). CONCLUSION: Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.

Thermal Damage Done to Bone by Burring and Sawing With and Without Irrigation in Knee Arthroplasty.

BACKGROUND: Heat from bone resecting tools used in knee surgery can induce thermal osteonecrosis, potentially causing aseptic implant loosening. This study compared oscillating saws to burrs in terms of temperature generation and histologic damage. Use of irrigation to reduce bone temperature was also investigated. METHODS: Temperatures were recorded during sawing and burring with or without irrigation (uncooled or cooled). Histologic analyses were then carried out. Differences between groups were tested statistically (α = 0.05). RESULTS: On average, burring produced higher temperatures than sawing (P < .001). When uncooled irrigation was used, bone temperatures were significantly lower in sawed bone than in burred bone (P < .001). Irrigation lowered temperatures and thermal damage depths and increased osteocyte viability (P < .001). CONCLUSION: These results suggest that irrigating bone during resection could prevent osteonecrosis onset.

Patient rated outcomes study into the surgical interventions available for the rheumatoid hand and wrist.

INTRODUCTION: A multitude of surgical interventions are recognised for the treatment of the rheumatoid hand and wrist, however there seems to be a distinct lack of patient rated outcome measures (PROMs) studies reporting on the efficacy of these procedures. The aim of this study was to assess the PROMs related to hand and wrist surgery in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: A single surgeon series identified 94 patients (133 hands) with RA who had undergone one of eight surgical procedures (Swanson's arthroplasty, finger joint or wrist arthrodesis, carpal tunnel decompression, posterior interosseous nerve denervation, RA nodule excision, synovectomy/tenosynovectomy and tendon repair/release) with a mean follow-up period of 3 years. The primary outcome measures were the same for all patients and comprised the validated modified score for the assessment and quantification of chronic rheumatoid affections of the hand (M-SACRAH) and a separate satisfaction questionnaire. RESULTS: Highly significant improvements in both function and pain scores are reported across the cohort as a whole following hand surgery, with this pattern replicated within all of the operative subgroups. In keeping with these favourable results very high levels of overall satisfaction were reported with 93 % of patients reporting themselves to be very or fairly satisfied with their procedure. CONCLUSIONS: Overall, patient reported outcomes in functional, stiffness and pain domains of the M-SACRAH questionnaire appear very favourable across the range of surgical procedures that can be performed in the rheumatoid hand. We believe this data supports the use of all the procedures explored, and will be helpful in patient guidance.

Characterisation of osteoprotegerin autoantibodies in coeliac disease.

Autoantibodies neutralising the effect of the bone regulatory cytokine osteoprotegerin (OPG) have been described in a patient with severe osteoporosis and coeliac disease. This study aimed to determine the prevalence and epitope specificity of autoantibodies to OPG in patients with coeliac disease, and correlate their presence with bone mineral density. A direct enzyme-linked immunosorbent assay was developed and used to screen patients with coeliac disease for autoantibodies to OPG. Recombinant fragments of OPG were made to evaluate the epitope specificity and affinity of these antibodies. Phenotype information of the patients was obtained by case note review. Raised titres of antibodies to OPG were found in 7/71 (9.8 %) patients with coeliac disease, compared with 1/72 (1.4 %) non-coeliac osteoporosis clinic control patients (p < 0.05). Our results suggest that a polyclonal antibody response to OPG is raised in these patients capable of recognising different epitopes of OPG with varying affinity. The titre of OPG antibodies was associated with lower bone mineral density Z-score of the hip in coeliac patients on univariate (p < 0.05) and multivariate analysis including age, sex height and weight as covariates (p < 0.01). Polyclonal antibodies to OPG are more common in patients with coeliac disease and are independently associated with lower bone mineral density Z-scores of the hip. Further work is required to establish the clinical utility of testing for OPG antibodies.

High degree of accuracy of a novel image-free handheld robot for unicondylar knee arthroplasty in a cadaveric study.

BACKGROUND: Surgical robotics has been shown to improve the accuracy of bone preparation and soft tissue balance in unicondylar knee arthroplasty (UKA). However, although extensive data have emerged with regard to a CT scan-based haptically constrained robotic arm, little is known about the accuracy of a newer alternative, an imageless robotic system. QUESTIONS/PURPOSES: We assessed the accuracy of a novel imageless semiautonomous freehand robotic sculpting system in performing bone resection and preparation in UKA using cadaveric specimens. METHODS: In this controlled study, we compared the planned and final implant placement in 25 cadaveric specimens undergoing UKA using the new tool. A quantitative analysis was performed to determine the translational, angular, and rotational differences between the planned and achieved positions of the implants. RESULTS: The femoral implant rotational mean error was 1.04° to 1.88° and mean translational error was 0.72 to 1.29 mm across the three planes. The tibial implant rotational mean error was 1.48° to 1.98° and the mean translational error was 0.79 to 1.27 mm across the three planes. CONCLUSIONS: The image-free robotic sculpting tool achieved accurate implementation of the surgical plan with small errors in implant placement. The next step will be to determine whether accurate implant placement translates into a clinical and functional benefit for the patient.

Prevalence and clinical prediction of osteoporosis in a contemporary cohort of patients with rheumatoid arthritis.

OBJECTIVE: Osteoporosis has previously been reported to be twice as common in patients with RA as in controls, but these studies predate the introduction of aggressive management of RA. The aim of this study was to evaluate the prevalence and clinical predictors of osteoporosis in RA in a contemporary cohort and to develop a clinical tool for the identification of patients at risk. METHODS: The prevalence of osteoporosis was related to clinical and demographic variables in 304 consecutive RA patients undergoing DXA at a single centre between 2009 and 2010 and compared with the frequency of osteoporosis in a population-based cohort of 903 subjects. RESULTS: The RA cohort was predominantly female (81.9%), with an average age of 63.5 years (s.d. 11.8) and a disease duration of 9.6 years (s.d. 10.2). Osteoporosis was present in 91 (29.9%) patients at either the spine or total hip compared with 157/903 (17.4%) of age- and gender-matched controls. In RA patients, osteoporosis was associated with female gender (P = 0.002), age (P < 0.001), time since menopause (P < 0.001), BMI (P < 0.001), ESR (P = 0.006), Larsen score (P = 0.011) and co-morbidities (P = 0.020), but logistic regression analysis showed that only age and BMI were independent predictors. A predictive tool based on age and BMI was developed that had 91.4% sensitivity for the detection of osteoporosis in an independent RA population. CONCLUSION: The prevalence of osteoporosis in RA remains high in the modern era despite aggressive management and the use of biologic therapy. Most RA patients with osteoporosis can be identified by a simple algorithm taking age and BMI into account.

Research synthesis of recommended acetabular cup orientations for total hip arthroplasty.

Total hip arthroplasty (THA) is regarded as one of the most successful surgical procedures of modern times yet continues to be associated with a small but significant complication rate. Many early failures may be associated with poor component positioning with, in particular, acetabular component orientation dependent on the subjective judgement of the surgeon. In this paper, we compare the manufacturers' instructions on acetabular cup orientation with the literature-based recommended safety zones and surgical technique, by transforming them onto a single, clinically-relevant framework in which the different reference systems, safety guidelines and current instrumentation surgical techniques can be evaluated. The observed limited consensus between results reflects ongoing uncertainty regarding the optimum acetabular component positioning. As malpositioning of the acetabular cup increases the risk of revision surgery, any ambiguity over the correct position can have a causal effect. Our analysis highlights the need for a surgical reference system which can be used to describe the position of the acetabular cup intra-operatively.

Functional and patient-reported outcome of partial wrist denervation versus the Mannerfelt wrist arthrodesis in the rheumatoid wrist.

INTRODUCTION: Wrist arthrodesis offers high success rates in patients with rheumatoid arthritis; however, loss of residual mobility may cause unnecessary disability. This makes wrist denervation an appealing alternative. However, there is a distinct lack of patient-reported outcome measure studies comparing these two procedures. The aim of this study was to report any change in function, pain and satisfaction following wrist arthrodesis compared to denervation in a single surgeon series of rheumatoid patients. PATIENTS AND METHODS: The results of 16 wrist arthrodesis in 15 patients and 14 partial (PIN) wrist denervations in 13 patients were compared with a mean follow-up period of 39 and 22 months, respectively. The primary outcome measures were the same for both groups and included the validated patient-rated wrist evaluation questionnaire and a satisfaction questionnaire. RESULTS: Wrist arthrodesis significantly improved the mean total pain and functional outcome scores by 54 and 36 %, respectively, at the time of follow-up. Wrist denervation patients also reported significant improvements of 44 and 42 % in total pain and functional outcomes, respectively; 87 % reported being very satisfied with their wrist arthrodesis procedure compared to 78 % in the denervation group. No statistically significant difference in response between the groups was observed in this series of patients. CONCLUSIONS: Both procedures enjoyed favourable results amongst patients with excellent satisfaction outcomes. PIN denervation is a simple procedure with low complication rates and we therefore consider it a valid alternative to more difficult treatment options, such as partial or total wrist arthrodesis.

Validity and reliability of an alternative method for measuring power output during six-second all-out cycling.

In a laboratory setting where both a mechanically-braked cycling ergometer and a motion analysis (MA) system are available, flywheel angular displacement can be estimated by using MA. The purpose of this investigation was to assess the validity and reliability of a MA method for measuring maximal power output (Pmax) in comparison with a force transducer (FT) method. Eight males and eight females undertook three identical sessions, separated by 4 to 6 days; the first being a familiarization session. Individuals performed three 6-second sprints against 50% of the maximal resistance to complete two pedal revolutions with a 3-minute rest between trials. Power was determined independently using both MA and FT analyses. Validity: MA recorded significantly higher Pmax than FT (P < .05). Bland-Altman plots showed that there was a systematic bias in the difference between the measures of the two systems. This difference increased as power increased. Repeatability: Intraclass correlation coefficients were on average 0.90 ± 0.05 in males and 0.85 ± 0.08 in females. Measuring Pmax by MA, therefore, is as appropriate for use in exercise physiology research as Pmax measured by FT, provided that a bias between these measurements methods is allowed for.

Exploiting light-based 3D-printing for the fabrication of mechanically enhanced, patient-specific aortic grafts.

Despite polyester vascular grafts being routinely used in life-saving aortic aneurysm surgeries, they are less compliant than the healthy, native human aorta. This mismatch in mechanical behaviour has been associated with disruption of haemodynamics contributing to several long-term cardiovascular complications. Moreover, current fabrication approaches mean that opportunities to personalise grafts to the individual anatomical features are limited. Various modifications to graft design have been investigated to overcome such limitations; yet optimal graft functionality remains to be achieved. This study reports on the development and characterisation of an alternative vascular graft material. An alginate:PEGDA (AL:PE) interpenetrating polymer network (IPN) hydrogel has been produced with uniaxial tensile tests revealing similar strength and stiffness (0.39 ± 0.05 MPa and 1.61 ± 0.19 MPa, respectively) to the human aorta. Moreover, AL:PE tubular conduits of similar geometrical dimensions to segments of the aorta were produced, either via conventional moulding methods or stereolithography (SLA) 3D-printing. While both fabrication methods successfully demonstrated AL:PE hydrogel production, SLA 3D-printing was more easily adaptable to the fabrication of complex structures without the need of specific moulds or further post-processing. Additionally, most 3D-printed AL:PE hydrogel tubular conduits sustained, without failure, compression up to 50% their outer diameter and returned to their original shape upon load removal, thereby exhibiting promising behaviour that could withstand pulsatile pressure in vivo. Overall, these results suggest that this AL:PE IPN hydrogel formulation in combination with 3D-printing, has great potential for accelerating progress towards personalised and mechanically-matched aortic grafts.

Is the mechanical function of meniscal tissue altered in osteoarthritic knees?

BACKGROUND: Deteriorating meniscal function is thought to play a role in knee osteoarthritis. Meniscal proteoglycans maintain mechanical stiffness of the tissue through electrostatic effects. This study aimed to investigate whether the mechanical properties of macroscopically intact meniscus are preserved in osteoarthritis. METHODS: Discs of lateral meniscal tissue two millimetres thick and of five millimetres diameter from osteoarthritic knees and from healthy donors were placed within a confined compression chamber, mounted in a materials testing machine and bathed in isotonic 0.14M PBS, hypotonic deionised water or hypertonic 3M PBS. Following equilibrium, a 10% ramp compressive strain was applied followed by a 7200 second hold. Resultant stress relaxation curves were fitted to a nonlinear poroviscoelastic model with strain dependent permeability using finite element modelling to determine mechanical parameters. All samples were assayed for proteoglycan content. Comparison of results was undertaken using multivariate ANOVA. RESULTS: Thirty samples from osteoarthritic knees and 18 samples from healthy donors were tested. No significant differences in mechanical parameters or proteoglycan content was observed between groups. In both groups Young's modulus (E) was significantly greater, and zero-strain permeability significantly reduced, in samples tested in deionised water compared to samples tested in 0.14M or 3M PBS (all p < 0.05). CONCLUSION: Mechanical parameters of intact lateral meniscus in osteoarthritic knees are similar to those found in healthy knees. Proteoglycan concentration and their electrostatic contribution to mechanical stiffness of the meniscus is maintained in menisci derived from osteoarthritic knees. Whilst macroscopic tears in the meniscal ultrastructure may contribute to osteoarthritis, intact meniscal tissue maintains its function.