Apheresis as novel treatment for refractory angina with raised lipoprotein(a): a randomized controlled cross-over trial.

AIMS: To determine the clinical impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a) > 500 mg/L on the primary end point of quantitative myocardial perfusion, as well as secondary end points including atheroma burden, exercise capacity, symptoms, and quality of life. METHODS: We conducted a single-blinded randomized controlled trial in 20 patients with refractory angina and raised lipoprotein(a) > 500 mg/L, with 3 months of blinded weekly lipoprotein apheresis or sham, followed by crossover. The primary endpoint was change in quantitative myocardial perfusion reserve (MPR) assessed by cardiovascular magnetic resonance. Secondary endpoints included measures of atheroma burden, exercise capacity, symptoms and quality of life. RESULTS: The primary endpoint, namely MPR, increased following apheresis (0.47; 95% CI 0.31-0.63) compared with sham (-0.16; 95% CI - 0.33-0.02) yielding a net treatment increase of 0.63 (95% CI 0.37-0.89; P < 0.001 between groups). Improvements with apheresis compared with sham also occurred in atherosclerotic burden as assessed by total carotid wall volume (P < 0.001), exercise capacity by the 6 min walk test (P = 0.001), 4 of 5 domains of the Seattle angina questionnaire (all P < 0.02) and quality of life physical component summary by the short form 36 survey (P = 0.001). CONCLUSION: Lipoprotein apheresis may represent an effective novel treatment for patients with refractory angina and raised lipoprotein(a) improving myocardial perfusion, atheroma burden, exercise capacity and symptoms.

The Sprint Mechanics Assessment Score: A Qualitative Screening Tool for the In-field Assessment of Sprint Running Mechanics.

BACKGROUND: Qualitative movement screening tools provide a practical method of assessing mechanical patterns associated with potential injury development. Biomechanics play a role in hamstring strain injury and are recommended as a consideration within injury screening and rehabilitation programs. However, no methods are available for the in-field assessment of sprint running mechanics associated with hamstring strain injuries. PURPOSE: To investigate the intra- and interrater reliability of a novel screening tool assessing in-field sprint running mechanics titled the Sprint Mechanics Assessment Score (S-MAS) and present normative S-MAS data to facilitate the interpretation of performance standards for future assessment uses. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Maximal sprint running trials (35 m) were recorded from 136 elite soccer players using a slow-motion camera. All videos were scored using the S-MAS by a single assessor. Videos from 36 players (18 men and 18 women) were rated by 2 independent assessors blinded to each other's results to establish interrater reliability. One assessor scored all videos in a randomized order 1 week later to establish intrarater reliability. Intraclass correlation coefficients (ICCs) based on single measures using a 2-way mixed-effects model, with absolute agreement with 95% CI and kappa coefficients with percentage agreements, were used to assess the reliability of the overall score and individual score items, respectively. T-scores were calculated from the means and standard deviations of the male and female groups to present normative data values. The Mann-Whitney U test and the Wilcoxon signed-rank test were used to assess between-sex differences and between-limb differences, respectively. RESULTS: The S-MAS showed good intrarater (ICC, 0.828 [95% CI, 0.688-0.908]) and interrater (ICC, 0.799 [95% CI, 0.642-0.892]) reliability, with a standard error of measurement of 1 point. Kappa coefficients for individual score items demonstrated moderate to substantial intra- and interrater agreement for most parameters, with percentage agreements ranging from 75% to 88.8% for intrarater and 66.6% to 88.8% for interrater reliability. No significant sex differences were observed for overall scores, with mean values of 4.2 and 3.8 for men and women, respectively (P = .27). CONCLUSION: The S-MAS is a new tool developed for assessing sprint running mechanics associated with lower limb injuries in male and female soccer players. The reliable and easy-to-use nature of the S-MAS means that this method can be integrated into practice, potentially aiding future injury screening and research looking to identify athletes who may demonstrate mechanical patterns potentially associated with hamstring strain injuries.

Inflammasome modulation with P2X7 inhibitor A438079-loaded dressings for diabetic wound healing.

The inflammasome is a multiprotein complex critical for the innate immune response to injury. Inflammasome activation initiates healthy wound healing, but comorbidities with poor healing, including diabetes, exhibit pathologic, sustained activation with delayed resolution that prevents healing progression. In prior work, we reported the allosteric P2X7 antagonist A438079 inhibits extracellular ATP-evoked NLRP3 signaling by preventing ion flux, mitochondrial reactive oxygen species generation, NLRP3 assembly, mature IL-1ß release, and pyroptosis. However, the short half-life in vivo limits clinical translation of this promising molecule. Here, we develop a controlled release scaffold to deliver A438079 as an inflammasome-modulating wound dressing for applications in poorly healing wounds. We fabricated and characterized tunable thickness, long-lasting silk fibroin dressings and evaluated A438079 loading and release kinetics. We characterized A438079-loaded silk dressings in vitro by measuring IL-1ß release and inflammasome assembly by perinuclear ASC speck formation. We further evaluated the performance of A438079-loaded silk dressings in a full-thickness model of wound healing in genetically diabetic mice and observed acceleration of wound closure by 10 days post-wounding with reduced levels of IL-1ß at the wound edge. This work provides a proof-of-principle for translating pharmacologic inhibition of ATP-induced inflammation in diabetic wounds and represents a novel approach to therapeutically targeting a dysregulated mechanism in diabetic wound impairment.

Should iterative spinal surgeries be performed? A case report.

The number of spinal surgeries performed is increasing. Along with this comes an increase in iterative surgeries. Each surgery that a patient undergoes has an increased risk of complication and a decreased success rate compared to the last. We present a case of a 51-year-old female who continues to experience debilitating low back pain following three double fusions performed over four years. The patient describes that she is in more pain now than before any previous surgical intervention. Following these surgeries, the patient has been forced to take early retirement, frequently uses a wheelchair and requires assistance with daily activities. The role of iterative surgery in healthcare needs to be re-assessed. The poor outcomes, especially following tertiary and quaternary surgery, question the use of iterative surgery entirely.

Unnecessary Cervical Discectomy - A simple test to differentiate between Cervical and Shoulder Pathology: A Case Report.

Background: Diagnostic dilemma exists in differentiating between neck and shoulder pathology, as both can give a rise to shoulder and arm symptoms. In addition, the hypersensitivity of magnetic resonance imaging (MRI) scans may wrongly highlight non-clinically significant changes as potential targets for surgical intervention. The arm- squeeze test is a recognised recognized method used to help differentiate pathology arising from the shoulder or the neck. Performing this test preoperatively may prevent needless surgical intervention when diagnostic difficulties exist, even when MRI scans are not helpful. Case Presentation: We report the case of a 41-year-old male who initially presented with numbness and pins and needles in both arms. Following clinical review and an MRI scan of the cervical spine, the patient underwent an Anterior Cervical Discectomy and Fusion. Unfortunately, there was no relief of symptoms following surgery. A post- operative clinical review identified the shoulder as a potential cause of the symptoms. Conclusion: The arm- squeeze test is not popular and is not routinely used in shoulder and cervical spine examinations. However, it is recommended by National Institute for health and care excellence to help differentiate between neck and shoulder pathology, and, hence, dissemination of this information is vital.

Does orthotics use improve comfort, speed and injury rate during running? Preliminary analysis of a randomised control trial.

BACKGROUND: Evidence regarding the effectiveness of using orthotics in improving comfort, increasing running speed and helping to reduce injury rate during running is limited and mixed. Alongside the increasing popularity of running is the increasing rate of running-related injuries (RRIs). Further research into whether orthotics could be used to help reduce RRIs would be highly beneficial for those affected. Additionally, there is a need to clarify whether orthotics use increases comfort during running and helps improve running speed. AIM: To investigate whether running with Aetrex Orthotics improves comfort and performance and reduces injury whilst running. METHODS: Runners were recruited on a voluntary basis if they were 18 or older with no serious health conditions, ongoing foot pain or deformity, previous foot surgery in their lifetime or any surgery in the past 6 mo. Participants were randomly assigned to either an intervention group or a control group. All participants were asked to complete runs and provide quantitative data regarding comfort during running, running time and distance, and any RRIs over an 8-wk study period. Participants in the intervention group ran with Aetrex L700 Speed Orthotics, whilst participants in the control group ran without orthotics. Other than the addition of orthotics for participants in the intervention group, all participants were asked to run as they usually would. This report presents preliminary data from the first 47 participants recruited for this study. Running speed was calculated from running distance and time and given in miles per hour. For each outcome variable, the mean for each group, effect size and 95% confidence interval were calculated, and a t-test was performed to determine if between-group differences were statistically significant. RESULTS: Data for all three primary outcomes was provided from a total of 254 runs by the 23 participants in the intervention group and a total of 289 runs by the 24 participants in the control group. Participants in the intervention group reported higher comfort scores (8.00 ± 1.41 vs 6.96 ± 2.03, P ≤ 0.0001), faster running speeds (6.27 ± 1.03 vs 6.00 ± 1.54, P = 0.013), and lower RRI rates (0.70 ± 1.01 vs 1.21 ± 1.53, P = 0.18) than those in the control group. These findings were statistically significant for comfort and running speed but not for RRI rate, with statistical significance considered if P < 0.05. No adjustments were made for group differences in age, gender, tendency for RRIs or usual running speed. CONCLUSION: This preliminary report provides evidence for orthotics use in increasing comfort levels and running speed, but no significant difference in RRI rate.

Impact of lipoprotein apheresis on thrombotic parameters in patients with refractory angina and raised lipoprotein(a): Findings from a randomized controlled cross-over trial.

BACKGROUND: Raised lipoprotein(a) [Lp(a)] is a cardiovascular risk factor common in patients with refractory angina. The apolipoprotein(a) component of Lp(a) exhibits structural homology with plasminogen and can enhance thrombosis and impair fibrinolysis. OBJECTIVES: The objective of the study was to assess the effect of lipoprotein apheresis on markers of thrombosis and fibrinolysis in patients with high Lp(a). METHODS: In a prospective, single-blind, crossover trial, 20 patients with refractory angina and raised Lp(a) > 50 mg/dL were randomized to three months of weekly lipoprotein apheresis or sham. Blood taken before and after apheresis/sham was assessed using the Global Thrombosis Test, to assess time taken for in vitro thrombus formation (occlusion time) and endogenous fibrinolysis (lysis time), as well as von Willebrand Factor, fibrinogen, D-dimer, thrombin/anti-thrombin III complex, prothrombin fragments 1 + 2, and thrombin generation assays. RESULTS: Lp(a) was significantly reduced by apheresis (100.2 [interquartile range {IQR}, 69.6143.0] vs 24.8 [17.2,34.0] mg/dL, P = .0001) but not by sham (P = .0001 between treatment arms). Apheresis prolonged occlusion time (576 ± 116 s vs 723 ± 142 s, P < .0001) reflecting reduced platelet reactivity and reduced lysis time (1340 [1128, 1682] s vs 847 [685,1302] s, P = .0006) reflecting enhanced fibrinolysis, without corresponding changes with sham. Apheresis, but not sham, reduced von Willebrand Factor (149 [89.0, 164] vs 64.2 [48.5, 89.8] IU/dL, P = .0001), and fibrinogen (3.12 ± 0.68 vs 2.20 ± 0.53 g/L, P < .0001), and increased prothrombin fragments 1 + 2 (158.16 [128.77, 232.09] vs 795.12 [272.55, 1201.00] pmol/L, P = .0006). There was no change in D-dimer, thrombin/anti-thrombin III complex, or thrombin generation assay with apheresis or sham. CONCLUSION: Lipoprotein apheresis reduces Lp(a) and improves some thrombotic and fibrinolytic parameters in patients with refractory angina.

High prevalence of raised lipoprotein(a) in patients with refractory angina.

BACKGROUND: Angina that is refractory to conventional medical therapy and revascularisation, remains challenging to manage and poses significant burden to patients. Elevated lipoprotein(a) [Lp(a)] has emerged as an important independent cardiovascular risk factor and predictor of adverse outcomes in atherosclerotic disease. The prevalence of raised Lp(a) amongst patients with refractory angina has not yet been defined. OBJECTIVE: To establish the prevalence of raised [Lp(a)] >500 mg/L in patients with refractory angina. METHODS: We conducted an epidemiological screening pilot study in 75 patients with refractory angina from a UK tertiary cardiac centre. We determined the proportion of the cohort with raised Lp(a) >500 mg/L using an isoform-insensitive method. In addition, a full fasting lipid profile (including: LDL cholesterol, HDL cholesterol, total cholesterol to HDL ratio and triglycerides) was obtained. Patients were also asked about the presence of conventional cardiovascular risk factors. RESULTS: Our study demonstrated that 60% of the 75 patients with refractory angina had raised Lp(a) levels of >500 mg/L. The median and inter-quartile range of Lp(a) values were 771 mg/L (162 mg/L,1260 mg/L) respectively. CONCLUSIONS: This high prevalence of raised Lp(a) detected in our cohort with refractory angina may suggest a causal role. Further research is necessary to confirm this association and prospective studies are needed to explore the potential therapeutic benefit of Lp(a) reduction in patients with refractory angina.