Long-term patient outcome is affected by deep venous thrombosis after Achilles tendon rupture repair.

PURPOSE: The aim of the study was to examine the impact of a deep venous thrombosis (DVT) on patient outcomes 3 years after Achilles tendon rupture (ATR) repair and if there were continued improvements between 1 and 3 years after surgery. A secondary aim was to determine risk factors associated with impaired patient outcomes in the long term. METHODS: This cohort study consisted of 181 ATR-repaired patients, from two large randomized clinical trials, who attended a 3-year follow-up evaluation. Patients were postoperatively randomized to two different weight-bearing interventions compared with immobilization in a below-knee plaster cast for 2 weeks. During immobilization, screening for DVT was performed with Doppler ultrasound. At 1 and 3 years postoperatively, functional- and patient-reported outcomes were evaluated by the validated heel-rise test and self-reported questionnaire, Achilles tendon Total Rupture Score (ATRS). RESULTS: In total, 76 out of 181 (42%) patients exhibited a DVT at the 2- or 6-week screening after ATR surgery. Suffering from a DVT during immobilization resulted at 3 years in a worse limb symmetry index (LSI) of heel-rise total work compared to patients without DVT, adjusted for age (DVT mean LSI 68% vs. no DVT 78%, p = 0.027). At 3 years, patients with a DVT during immobilization displayed lower ATRS (DVT median 88 vs. no DVT 93, p = 0.046), which was not significant after adjustment for age. However, patients with DVT exhibited an improvement in ATRS, LSI total work, and LSI maximum height between 1 and 3 years, which was not seen among patients without DVT. Independent risk factors for reduced patient functional outcomes at 3 years were older age, greater calf muscle hypotrophy, and suffering a DVT. CONCLUSIONS: DVT during immobilization affects patients' long-term functional outcomes 3 years after ATR repair. Clinicians should adequately address risk factors contributing to impaired patient outcomes in the long term, including calf muscle hypotrophy, DVT, and older age. LEVEL OF EVIDENCE: Level Ⅲ.

The effect of neuromuscular electrical stimulation on the human skeletal muscle transcriptome.

AIM: The influence on acute skeletal muscle transcriptomics of neuromuscular electrical stimulation (NMES), as compared to established exercises, is poorly understood. We aimed to investigate the effects on global mRNA-expression in the quadriceps muscle early after a single NMES-session, compared to the effects of voluntary knee extension exercise (EX), and to explore the discomfort level. METHODS: Global vastus lateralis muscle gene expression was assessed (RNA-sequencing) in 30 healthy participants, before and 3 h after a 30-min session of NMES and/or EX. The NMES-treatment was applied using textile electrodes integrated in pants and set to 20% of each participant's pre-tested MVC mean (±SD) 200 (±80) Nm. Discomfort was assessed using Visual Analogue Scale (VAS, 0-10). The EX-protocol was performed at 80% of 1-repetition-maximum. RESULTS: NMES at 20% of MVC resulted in VAS below 4 and induced 4448 differentially expressed genes (DEGs) with 80%-overlap of the 2571 DEGs of EX. Genes well-known to be up-regulated following exercise, for example, PPARGC1A, ABRA, VEGFA, and GDNF, were also up-regulated by NMES. Gene set enrichment analysis demonstrated many common pathways after EX and NMES. Also, some pathways were exclusive to either EX, for example, muscle tissue proliferation, or to NMES, for example, neurite outgrowth and connective tissue proliferation. CONCLUSION: A 30-min NMES-session at 20% of MVC with NMES-pants, which can be applied with an acceptable level of discomfort, induces over 4000 DEGs, of which 80%-overlap with DEGs of EX. NMES can induce exercise-like molecular effects, that potentially can lead to health and performance benefits in individuals who are unable to perform resistance exercise.

Optimizing tendon repair and regeneration: how does the in vivo environment shape outcomes following rupture of a tendon such as the Achilles tendon?

Risk for rupture of the Achilles tendon, and other tendons increases with age. Such injuries of tissues that function in high load environments generally are believed to heal with variable outcome. However, in many cases, the healing does not lead to a good outcome and the patient cannot return to the previous level of participation in active living activities, including sports. In the past few years, using proteomic approaches and other biological techniques, reports have appeared that identify biomarkers that are prognostic of good outcomes from healing, and others that are destined for poor outcomes using validated criteria at 1-year post injury. This review will discuss some of these recent findings and their potential implications for improving outcomes following connective tissue injuries, as well as implications for how clinical research and clinical trials may be conducted in the future where the goal is to assess the impact of specific interventions on the healing process, as well as focusing the emphasis on regeneration and not just repair.

Early Tendon Morphology as a Biomarker of Long-term Patient Outcomes After Surgical Repair of Achilles Tendon Rupture: A Prospective Cohort Study.

Background: Patient outcome after acute Achilles tendon rupture (ATR) varies and is difficult to predict. Whether early variations in healing, visualized with ultrasonography, can predict long-term patient outcome is unclear. Purpose: To (1) examine the associations of Achilles tendon cross-sectional area (CSA) and elongation (TE) during healing of ATR repair with patient outcomes at 12 months postoperatively and (2) investigate the predictive or diagnostic capacity of the morphological biomarkers. Study Design: Cohort study; Level of evidence, 2. Methods: This study was based on previously collected data from 86 patients who underwent acute standardized ATR repair between 2013 and 2018 and who were included in a prior randomized trial investigating early functional mobilization (EFM). In the EFM group, loading was allowed immediately after surgery, while in the comparison group, loading was allowed first at 2 weeks postoperatively. Achilles tendon CSA and length were measured with ultrasound at 6 weeks, 6 months, and 12 months postoperatively. CSA ratio and absolute difference in the length of the healthy and injured tendons were calculated. Patient-reported outcome was registered with the validated Achilles tendon Total Rupture Score and functional outcome with the heel-rise endurance test at 12 months postoperatively. The limb symmetry index (LSI) was calculated for maximum heel-rise height (HRHmax) and total concentric work. Multiple linear regression adjusted for age was used, and the area under the receiver operating characteristic curve (AUC) was calculated to evaluate predictive capacity. Results: A larger CSA ratio at 6 weeks was associated with higher LSI HRHmax at 12 months (R2, 0.35; P < .001) and exhibited good predictive capacity (AUC, 0.82). More TE at 12 months was associated with lower LSI total concentric work at 12 months (R2, 0.21; P = .001) and exhibited acceptable predictive capacity (AUC, 0.71). Conclusion: Greater Achilles tendon CSA seen on ultrasound 6 weeks after surgical repair had good clinical prediction for long-term functional outcome. TE at 12 months was predictive of inferior functional outcome. Registration: NCT02318472 (ClinicalTrials.gov identifier).

Complement factor D regulates collagen type I expression and fibroblast migration to enhance human tendon repair and healing outcomes.

Introduction: Dense connective tissues (DCTs) such as tendon, ligament, and cartilage are important stabilizers and force transmitters in the musculoskeletal system. The healing processes after DCT injuries are highly variable, often leading to degenerative changes and poor clinical outcome. Biomarkers in relation to repair quality for human DCTs, especially tendon are lacking. This study expands our previous findings and aimed to characterize the mechanisms by which a potential biomarker of good outcomes, complement factor D (CFD), regulates tendon healing. Methods: Quantitative mass spectrometry (QMS) profiling of tissue biopsies from the inflammatory phase of healing (n = 40 patients) and microdialysates from the proliferative phase of healing (n = 28 patients) were used to identify specific biomarkers for tendon healing. Further bioinformatic and experimental investigations based on primary fibroblasts and fibroblast cell line were used to confirm the identified biomarkers. Results: The QMS profiling of tissue biopsies from the inflammatory phase of healing identified 769 unique proteins, and microdialysates from the proliferative phase of healing identified 1423 unique proteins in Achilles tendon rupture patients. QMS-profiling showed that CFD expression was higher during the inflammatory- and lower during the proliferative healing phase in the good outcome patients. Further bioinformatic and experimental explorations based on both inflammatory and proliferative fibroblast models demonstrated that CFD potentially improved repair by regulating cell migration and modulating collagen type I (Col1a1) expression. Moreover, it was shown that the enhanced Col1a1 expression, through increased fibroblast migration, was correlated with the validated clinical outcome. Discussion: The results of the current studies characterized underlying inflammatory- and proliferative healing mechanisms by which CFD potentially improved tendon repair. These findings may lead to improved individualized treatment options, as well the development of effective therapies to promote good long-term clinical outcomes after tendon and other DCT injuries. Trial registration: http://clinicaltrials.gov, identifiers NCT02318472, NCT01317160.

Wearable Neuromuscular Electrical Stimulation on Quadriceps Muscle Can Increase Venous Flow.

Neuromuscular electrical stimulation (NMES) of the quadriceps (Q) may increase venous blood flow to reduce the risk of venous thromboembolism. This study assessed whether Q-NMES pants could increase peak venous velocity (PVV) in the femoral vein using Doppler ultrasound and minimize discomfort. On 15 healthy subjects, Q-NMES using textile electrodes integrated in pants was applied with increasing intensity (mA) until the first visible muscle contraction [measurement level (ML)-I] and with an additional increase of six NMES levels (ML II). Discomfort using a numeric rating scale (NRS, 0-10) and PVV were used to assess different NMES parameters: frequency (1, 36, 66 Hz), ramp-up/-down time (RUD) (0, 1 s), plateau time (1.5, 4, and 6 s), and on:off duty cycle (1:1, 1:2, 1:3, 1:4). Q-NMES pants significantly increased PVV from baseline with 93% at ML I and 173% at ML II. Frequencies 36 Hz and 66 Hz and no RUD resulted in significantly higher PVV at both MLs compared to 1 Hz and 1 s RUD, respectively. Plateau time, and duty cycle did not significantly change PVV. Discomfort was only significantly higher with increasing intensity and frequency. Q-NMES pants produces intensity-dependent 2-3-fold increases of venous blood flow with minimal discomfort. The superior NMES parameters were a frequency of 36 Hz, 0 s RUD, and intensity at ML II. Textile-based NMES wearables are promising for non-episodic venous thromboembolism prevention.

Network proteomic analysis identifies inter-alpha-trypsin inhibitor heavy chain 4 during early human Achilles tendon healing as a prognostic biomarker of good long-term outcomes.

The suboptimal or protracted regeneration of injured connective tissues often results in significant dysfunction, pain, and functional disability. Despite the prevalence of the condition, few studies have been conducted which focused on biomarkers or key molecules involved in processes governing healing outcomes. To gain insight into injured connective tissue repair, and using the Achilles tendon as a model system, we utilized quantitative proteomic and weighted co-expression network analysis of tissues acquired from Achilles tendon rupture (ATR) patients with different outcomes at 1-year postoperatively. Two modules were detected to be associated with prognosis. The initial analysis identified inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) as a biomarker or hub protein positively associated with better healing outcomes. Additional analysis identified the beneficial role of ITIH4 in inflammation, cell viability, apoptosis, proliferation, wound healing, and for the synthesis of type I collagen in cultured fibroblasts. Functionally, the effects of ITIH4 were found to be mediated by peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways. Taken together, these findings suggest that ITIH4 plays an important role in processes of connective tissue repair and advocate for the potential of ITIH4 as a therapeutic target for injured connective tissue repair. Trial registration: http://clinicaltrials.gov, identifiers NCT02318472, NCT01317160.

eEF2 improves dense connective tissue repair and healing outcome by regulating cellular death, autophagy, apoptosis, proliferation and migration.

Outcomes following human dense connective tissue (DCT) repair are often variable and suboptimal, resulting in compromised function and development of chronic painful degenerative diseases. Moreover, biomarkers and mechanisms that guide good clinical outcomes after DCT injuries are mostly unknown. Here, we characterize the proteomic landscape of DCT repair following human Achilles tendon rupture and its association with long-term patient-reported outcomes. Moreover, the potential regulatory mechanisms of relevant biomarkers were assessed partly by gene silencing experiments. A mass-spectrometry based proteomic approach quantified a large number (769) of proteins, including 51 differentially expressed proteins among 20 good versus 20 poor outcome patients. A novel biomarker, elongation factor-2 (eEF2) was identified as being strongly prognostic of the 1-year clinical outcome. Further bioinformatic and experimental investigation revealed that eEF2 positively regulated autophagy, cell proliferation and migration, as well as reduced cell death and apoptosis, leading to improved DCT repair and outcomes. Findings of eEF2 as novel prognostic biomarker could pave the way for new targeted treatments to improve healing outcomes after DCT injuries.Trial registration: NCT02318472 registered 17 December 2014 and NCT01317160 registered 17 March 2011, with URL http://clinicaltrials.gov/ct2/show/NCT02318472 and http://clinicaltrials.gov/ct2/show/study/NCT01317160 .

Motor point heatmap of the calf.

BACKGROUND: Contractions of muscles in the calf induced by neuromuscular electrical stimulation (NMES) may prevent venous thromboembolism, help rehabilitation and optimize strength training, among other uses. However, compliance to NMES-treatment is limited by the use of suboptimal stimulation points which may cause discomfort and less effectivity. Knowledge of where one is most likely to find muscle motor points (MP) could improve NMES comfort and compliance. AIMS: To anatomically map the MPs of the calf as well as to calculate the probability of finding a MP in different areas of the calf. MATERIAL AND METHODS: On 30 healthy participants (mean age 37 years) anatomical landmarks on the lower limbs were defined. The location of the four most responsive MPs on respectively the medial and lateral head of gastrocnemius were determined in relation to these anatomical landmarks using a MP search pen and a pre-set MP search program with 3 Hz continuous stimulation (Search range:4.0-17.5 mA). The anatomy of the calves was normalized and subdivided into a matrix of 48 (6 × 8) smaller areas (3 × 3 cm), from upper medial to lower lateral, in order to calculate the probability of finding a MP in one of these areas. The probability of finding a MP was then calculated for each area and presented with a 95% confidence interval. RESULTS: The MP heatmap displayed a higher concentration of MPs proximally and centrally on the calf. However, there were wide inter-individual differences in the location of the MPs. The highest probability of finding a MP was in area 4, located centrally and medially, and in area 29, located centrolaterally and around the maximum circumference, both with 50% probability (95% CI: 0.31-0.69). The second highest probability of finding MPs was in areas 9, 10, 16, proximally and medially, all with 47% probability (95% CI: 0.28-0.66). These areas 4, 9, 10, 16 and 29 exhibited significantly higher probability of finding motor points than all areas with a mean probability of 27% and lower (p < 0.05) The lateral and distal outskirts exhibited almost zero probability of finding MPs. CONCLUSIONS: This MP heatmap of the calf could be used to expedite electrode placement and to improve compliance in order to receive consistent and enhanced results of NMES treatments.

Tendon pain - what are the mechanisms behind it?

OBJECTIVES: Management of chronic tendon pain is difficult and controversial. This is due to poor knowledge of the underlying pathophysiology of chronic tendon pain, priorly known as tendinitis but now termed tendinopathy. The objective of this topical review was to synthesize evolving information of mechanisms in tendon pain, using a comprehensive search of the available literature on this topic. CONTENT: This review found no correlations between tendon degeneration, collagen separation or neovascularization and chronic tendon pain. The synthesis demonstrated that chronic tendon pain, however, is characterized by excessive nerve sprouting with ingrowth in the tendon proper, which corresponds to alterations oberserved also in other connective tissues of chronic pain conditions. Healthy, painfree tendons are devoid of nerve fibers in the tendon proper, while innervation is confined to tendon surrounding structures, such as sheaths. Chronic painful tendons exhibit elevated amounts of pain neuromediators, such as glutamate and substance p as well as up-regulated expression and excitability of pain receptors, such as the glutamate receptor NMDAR1 and the SP receptor NK1, found on ingrown nerves and immune cells. Increasing evidence indicates that mast cells serve as an important link between the peripheral nervous system and the immune systems resulting in so called neurogenic inflammation. SUMMARY: Chronic painful tendons exhibit (1) protracted ingrowth of sensory nerves (2) elevated pain mediator levels and (3) up-regulated expression and excitability of pain receptors, participating in (4) neuro-immune pathways involved in pain regulation. Current treatments that entail the highest scientific evidence to mitigate chronic tendon pain include eccentric exercises and extracorporeal shockwave, which both target peripheral neoinnervation aiming at nerve regeneration. OUTLOOK: Potential mechanism-based pharmacological treatment approaches could be developed by blocking promotors of nerve ingrowth, such as NGF, and promoting inhibitors of nerve ingrowth, like semaphorins, as well as blocking glutamate-NMDA-receptor pathways, which are prominent in chronic tendon pain.

Comparable Recovery and Compensatory Strategies in Heel-Rise Performance After a Surgically Repaired Acute Achilles Tendon Rupture: An In Vivo Kinematic Analysis Comparing Early Functional Mobilization and Standard Treatment.

BACKGROUND: Deficits in calf muscle function and heel-rise performance are common after an Achilles tendon rupture (ATR) and are related to tendon elongation and calf muscle atrophy. Whether early functional mobilization (EFM) can improve calf muscle function compared with standard treatment (ST) with 2 weeks of immobilization and unloading in a plaster cast is unknown. HYPOTHESIS: EFM would lead to superior recovery of heel-rise performance, as demonstrated by more symmetrical side-to-side ankle and knee joint kinematics, compared with ST. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: In total, 47 patients with an ATR were prospectively included and treated with open surgical repair and randomized 2:1 postoperatively to either EFM or ST. Overall, 29 patients were treated with a dynamic orthosis (EFM), and 18 underwent ST. At 8 weeks and 6 months after ATR repair, 3-dimensional motion analysis of heel-rise performance was conducted. At 6 months, tendon length and muscle volume were assessed with ultrasound imaging, calf muscle function with the heel-rise test, and patient-reported outcomes with the Achilles tendon Total Rupture Score. RESULTS: At 8 weeks and 6 months, there were no significant group differences between the EFM and ST groups in heel-rise performance, but significant side-to-side differences in ankle and knee kinematics were detected. At 8 weeks and 6 months, both the EFM and ST groups showed a significantly decreased peak ankle plantarflexion angle and increased knee flexion angle on the injured limb compared with the uninjured limb during bilateral heel raises. Linear regression demonstrated that greater atrophy of the medial gastrocnemius muscle (P = .008) and higher body weight (P < .001) were predictors of a decreased maximum peak ankle plantarflexion angle on the injured limb at 6 months. CONCLUSION: EFM after an ATR repair did not lead to superior recovery of calf muscle function, as assessed by heel-rise performance, compared with ST. Increased knee flexion seemed to be a compensatory strategy for decreased ankle plantarflexion. Medial gastrocnemius atrophy and increased body weight were additional factors associated with a decreased ankle plantarflexion angle. REGISTRATION: NCT02318472 (ClinicalTrials.gov identifier).

Complement factor D as a predictor of Achilles tendon healing and long-term patient outcomes.

Dense connective tissue healing, such as tendon, is protracted leading to highly variable and unsatisfactory patient outcomes. Biomarkers prognostic of long-term clinical outcomes is, however, unknown. The present study was designed to investigate the proteomic profile of healing, identify potential biomarkers, and assess their association with the patient's long-term outcomes after ATR. Quantitative mass spectrometry analysis demonstrated 1423 proteins in healing and contralateral healthy Achilles tendons of 28 ATR patients. Comparing healing at 2 weeks and healthy protein profiles, we identified 821 overlapping, 390 upregulated, and 17 downregulated proteins. Upregulated proteins are related mainly to extracellular matrix organization and metabolism, while downregulated pathways were associated with exocytosis in immune modulation and thrombosis formation. Further proteomic profiling in relation to validated patient outcomes revealed the downregulated pro-inflammatory complement factor D (CFD) as the most reliable predictive biomarker of successful tendon healing. Our finding showed a comprehensive proteomic landscape and bioinformatics on human connective tissue, indicating subtype-specific and shared biological processes and proteins in healing and healthy Achilles tendons, as well as in tendons related to good and poor patient outcomes. Inflammatory protein CFD and serpin family B member 1 were finally identified as potential predictive biomarkers of effective healing outcomes when combined the proteomic profiles with a validated clinical database. Following the future elucidation of the mechanisms associated with the identified biomarkers as predictors of good outcomes, our findings could lead to improved prognostic accuracy and development of targeted treatments, thus improving the long-term healing outcomes for all patients.

Effect of Surgeon Experience on Long-Term Patient Outcomes in Surgical Repair of Acute Achilles Tendon Rupture.

BACKGROUND: The effect of surgeon experience on patient outcomes after surgical Achilles tendon rupture (ATR) repair has so far been unknown. PURPOSE: To examine whether patient-reported and functional outcomes as well as adverse events after surgical ATR repair differ between orthopaedic specialist surgeons and resident surgeons. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: We retrospectively analyzed data from 295 patients treated with surgical ATR repair with standardized techniques. The level of surgeon experience (specialist vs resident) and number of adverse events (rerupture, infection, and deep venous thrombosis) were recorded. Patient-reported and functional outcomes were assessed 12 months postoperatively using the validated Achilles tendon total rupture score (ATRS) and the heel-rise test, respectively. Analysis of covariance was used to compare differences in outcomes between specialist surgeons and resident surgeons. Pearson chi-square or Fisher exact test was used for analysis of adverse events. RESULTS: The mean ATRS at 12 months for patients operated on by resident surgeons was significantly higher compared with specialist surgeons (85.9 [95% CI, 80.3-91.5] vs 77.8 [95% CI, 73.8-81.9]; P = .028). In addition, the lateral difference (operated vs unoperated side) in mean total concentric work and number of heel-rise repetitions at 12 months was smaller in patients operated on by resident surgeons (P = .011 and 0.015, respectively). The number of adverse events did not differ significantly between the 2 groups. CONCLUSION: Resident surgeons achieved patient-reported and functional outcomes at least as good as those of specialist surgeons in surgical ATR repair, with a similar risk of adverse events.

No effects of early functional mobilization on gait patterns after acute Achilles tendon rupture repair.

This study aimed to compare recovery of gait patterns in patients treated with early functional mobilization (EFM) or standard treatment (ST) after Achilles tendon rupture repair. Second, this study aimed to explore associations between gait patterns and tendon elongation and calf muscle atrophy, respectively. Forty-seven patients (12 females), mean age 38.7 (7.3) years, were included. Patients were postoperatively randomized to EFM (n = 29), including immediate weightbearing and ankle motion for 6 weeks, or ST (n = 18), with 2 weeks of unloading in a plaster cast followed by 4 weeks of weightbearing in an orthosis. Three-dimensional gait analyses were performed at 8 weeks and 6 months postoperatively to evaluate ankle and knee kinematics and kinetics. Ultrasound imaging was performed to assess tendon length and calf muscle atrophy. At 8 weeks, there were no significant group differences in ankle and knee kinematics and kinetics, while side-to-side differences between injured and uninjured side were present within both groups. At 6 months, the ST group exhibited higher generating ankle power and greater peak moments in ankle and knee compared to the EFM group. In both groups, peak ankle dorsiflexion angle was greater on the injured side compared to the uninjured side. No correlations were found between ankle joint gait deviations and degree of tendon elongation or muscle atrophy. Clinical significance: The accelerated rehabilitation regimen with EFM did not result in a more symmetrical gait pattern. The gait pattern deviations in the ankle joint were not related to the degree of muscle atrophy or tendon elongation.

Optimizing repair of tendon ruptures and chronic tendinopathies: Integrating the use of biomarkers with biological interventions to improve patient outcomes and clinical trial design.

Tendons are dense connective tissues of the musculoskeletal system that link bones with muscles to foster mobility. They have complex structures and exist in varying biomechanical, metabolic and biological environments. In addition, tendon composition and mechanical properties can change over the lifespan as an individual ages. Many tendons function in high stress conditions with a low vascular and neuronal supply, conditions often leading to development of chronic tendinopathies, and in some cases, overt rupture of the tissues. Given their essential nature for human mobility and navigation through the environment, the effective repair and regeneration of different tendons after injury or damage is critical for quality of life, and for elite athletes, the return to sport participation at a high level. However, for mainly unknown reasons, the outcomes following injury are not always successful and lead to functional compromise and risk for re-injury. Thus, there is a need to identify those patients who are at risk for developing tendon problems, as well those at risk for poor outcomes after injury and to design interventions to improve outcomes after injury or rupture to specific tendons. This review will discuss recent advances in the identification of biomarkers prognostic for successful and less successful outcomes after tendon injury, and the mechanistic implications of such biomarkers, as well as the potential for specific biologic interventions to enhance outcomes to improve both quality of life and a return to participation in sports. In addition, the implication of these biomarkers for clinical trial design is discussed, as is the issue of whether such biomarkers for successful healing of one tendon can be extended to all tendons or are valid only for tendons in specific biomechanical and biological environments. As maintaining an active lifestyle is critical for health, the successful implementation of these advances will benefit the large number of individuals at risk.

Textile Electrodes: Influence of Electrode Construction and Pressure on Stimulation Performance in Neuromuscular Electrical Stimulation (NMES).

The major reason for preventable hospital death is venous thromboembolism (VTE). Non-pharmacological treatment options include electrical stimulation or compression therapy to improve blood flow in the extremities. Textile electrodes offer potential to replace bulky devices commonly used in this field, thereby improving the user compliance. In this work, the performance of dry and wet knitted electrodes in combination with pressure application to the electrode was evaluated in neuromuscular electrical stimulation (NMES). A motor point stimulation on the calf was performed on nine healthy subjects to induce a plantarflexion and the required stimulation intensity as well as the perceived pain were assessed. The performance of the different electrode constructions was compared and the influence of the pressure application was analysed. The results show that wet textile electrodes (0.9 % saline solution) perform significantly better than dry electrodes. However, opportunities were found for improving the performance of dry textile electrodes by using an uneven surface topography in combination with an intermediate to high pressure application to the electrode (> 20 mmHg), e.g. by using a compression stocking. Moreover, the smaller of the two tested electrode areas (16 cm2; 32 cm2) appears to be favourable in terms of stimulation comfort and efficiency.

STOP leg clots-Swedish multicentre trial of outpatient prevention of leg clots: study protocol for a randomised controlled trial on the efficacy of intermittent pneumatic compression on venous thromboembolism in lower leg immobilised patients.

INTRODUCTION: Leg immobilisation in a cast or an orthosis after lower limb injuries is associated with a high risk of complications of venous thromboembolism (VTE) and hampered healing. Current pharmacoprophylaxes of VTE are inefficient and associated with adverse events. Intermittent pneumatic compression (IPC) could represent a novel, efficient and safe VTE-prophylactic alternative that may enhance injury healing. The aim of STOP leg clots is to assess the efficacy of adjuvant IPC-therapy on reduction of VTE incidence and improvement of healing in lower leg immobilised outpatients. METHODS AND ANALYSIS: STOP leg clots is a multicentre randomised controlled superiority trial. Eligible patients (700 patients/arm) with either an acute ankle fracture or Achilles tendon rupture will be randomised to either addition of IPC during lower-leg immobilisation or to treatment-as-usual. The primary outcome will be the total VTE incidence, that is, symptomatic and asymptomatic deep venous thrombosis (DVT) or symptomatic pulmonary embolism (PE), during the leg immobilisation period, approximately 6-8 weeks. DVT incidence will be assessed by screening whole leg compression duplex ultrasound at removal of leg immobilisation and/or clinically diagnosed within the time of immobilisation. Symptomatic PE will be verified by CT.Secondary outcomes will include patient-reported outcome using validated questionnaires, healing evaluated by measurements of tendon callus production and changes in VTE-prophylactic mechanisms assessed by blood flow and fibrinolysis. Data analyses will be blinded and based on the intention-to-treat. ETHICS AND DISSEMINATION: Ethical approval was obtained by the ethical review board in Stockholm, Sweden, Dnr 2016/1573-31. The study will be conducted in accordance with the Helsinki declaration. The results of the study will be disseminated in peer-reviewed international journals. TRIAL REGISTRATION: NCT03259204. TIME SCHEDULE: 1 September 2018 to 31 December 2022.

FGF gene expression in injured tendons as a prognostic biomarker of 1-year patient outcome after Achilles tendon repair.

PURPOSE: Healing outcome after Achilles Tendon Rupture (ATR) is variable and unsatisfactory. Many ATR patients still exhibit pain, functional deficits and limitations in walking one-year post-surgery. The present study was designed to investigate the association between the expression of healing biomarkers and patient outcome after ATR. METHODS: Tendon biopsies were collected from 25 ATR patients during surgery. At 1-year post surgery, all patients completed questionnaires; Achilles tendon Total Rupture Score (ATRS) and Foot and Ankle Outcome Score (FAOS), and were tested for functional outcomes by heel-rise test. In biopsies, FGF, COL III, FN, COL I and MMP-9 mRNA levels were assessed by quantitative RT-PCR while protein expression was studied by immunohistochemistry (IHC). RESULTS: Our analysis confirmed the presence of FGF, COL III, FN, COL I and MMP-9 at mRNA and protein levels in tendon biopsies. FGF gene expression associated positively with improved total ATRS and better functional outcomes. Additionally, FGF mRNA levels were associated with less pain, less running limitations and less loss in physical activity. In addition, higher COL III mRNA expression was associated with more tendon strength. CONCLUSION: Our findings indicate that FGF gene expression is associated with improved patient-reported outcome. FGF expression in surgical biopsies could potentially be used to assist the prognostic evaluation of patient outcome and may be used as a predictor for healing. However, further studies are needed to evaluate the role of FGF in Achilles tendon healing. LEVEL OF EVIDENCE: II.

Higher pyruvate levels after Achilles tendon rupture surgery could be used as a prognostic biomarker of an improved patient outcome.

PURPOSE: The primary aim of this study was to assess the relationship between the metabolites lactate and pyruvate in the healing tendon after Achilles tendon rupture (ATR) and patient-reported outcome at 6 and 12 months. A secondary aim was to evaluate which underlying factors regulate lactate and pyruvate concentrations. METHODS: Lactate and pyruvate concentrations were measured two weeks post-operatively in both the healing- and healthy Achilles tendon in 109 patients (90 men, 19 women; mean age 40 ± 7.9 years). Patient demographics, degree of physical activity, timing of surgery, operation time, patient-reported loading and step counts were investigated in relation to metabolite concentrations. At 6 and 12 months, the Achilles tendon Total Rupture Score (ATRS) questionnaire was used to assess patient outcome. RESULTS: The mean number of steps taken during the post-operative days 1-10 was the only factor significantly related to the mean concentration of lactate (R2 = 0.34, p = 0.038), and pyruvate (R2 = 0.46, p = 0.006). Pyruvate was demonstrated as the only factor significantly associated with ATRS at both 6 months (R2 = 0.32, p = 0.003) and at 12 months (R2 = 0.37, p = 0.004) using multiple linear regression. CONCLUSION: The mean concentration of pyruvate during early ATR healing may predict patient outcome at 6 and 12 months post-operatively and possibly be used as a biomarker of healing. Early mobilization with an increased number of steps taken is an important clinical strategy to improve the metabolite concentrations during healing. LEVEL OF EVIDENCE: III.