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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).

Purpose To investigate whether Neuromuscular Electrical Stimulation (NMES) simultaneously applied on the quadriceps (Q) and gluteal (G) muscles, as compared to single Q-stimulation alters the knee extensor force production and discomfort. Methods A total of 11 healthy participants (6 females), with normal weight and age between 19 and 54 years were included. The unilateral, isometric maximal voluntary contraction (MVC) was assessed for each participant in an isokinetic dynamometer (Biodex, system 3). NMES was, in a randomized order, applied only on the Q-muscle and on the Q- and G-muscles (QG) simultaneously. NMES-intensity was increased stepwise until the maximal tolerable level was reached regarding discomfort, graded according to the visual analogue scale (VAS). VAS and the % of MVC produced by NMES, were registered for each level, expressed as median (inter-quartile range). Results The maximum tolerated NMES-intensity applied on Q compared to QG resulted in equally high discomfort, 8.0 (6.0–9.0) vs 8.0 (6.3–9.0), and in equivalent knee extensor force production, 36.7 (29.9–47.5) and 36.2 (28.9–49.3), respectively, in % of MVC. At 20% of MVC, NMES applied on Q compared to QG resulted in equal acceptable discomfort, 3.0 (2.0–4.5) vs 3.0 (3–5.5), and comparable intensity levels, 41.5 (38.0–45.8) vs 43.5 (37.0–48.8), respectively. Conclusions Simultaneous QG-NMES, as compared to single Q-NMES, does not seem to affect the knee extensor force production or discomfort. Q-NMES, without voluntary muscle contraction, can with an acceptable level of discomfort result in at least 20% of MVC.

Purpose To compare fixed transverse textile electrodes (TTE) knitted into a sock versus motor point placed standard gel electrodes (MPE) on peak venous velocity (PVV) and discomfort, during calf neuromuscular electrical stimulation (calf-NMES). Methods Ten healthy participants received calf-NMES with increasing intensity until plantar flexion (measurement level I = ML I), and an additional mean 4 mA intensity (ML II), utilizing TTE and MPE. PVV was measured with Doppler ultrasound in the popliteal and femoral veins at baseline, ML I and II. Discomfort was assessed with a numerical rating scale (NRS, 0–10). Significance was set to p Results TTE and MPE both induced significant increases in PVV from baseline to ML I and significantly higher increases to ML II, in both the popliteal and femoral veins (all p p p p = 0.005) while NRS was not significantly different. Conclusion TTE integrated in a sock produces intensity-dependent increases of popliteal and femoral hemodynamics comparable to MPE, but results in more discomfort at plantar flexion due to higher current required. TTE exhibits in the popliteal vein higher increases of PVV compared to MPE. Trial registration Trial_ID: ISRCTN49260430. Date: 11/01/2022. Retrospectively registered.

Purpose Physical inactivity is associated with muscle atrophy and venous thromboembolism, which may be prevented by neuromuscular electrical stimulation (NMES). This study aimed to investigate the effect on discomfort, current amplitude and energy consumption when varying the frequency and phase duration of low-intensity NMES (LI-NMES) via a sock with knitting-integrated transverse textile electrodes (TTE). Methods On eleven healthy participants (four females), calf-NMES via a TTE sock was applied with increasing intensity (mA) until ankle-plantar flexion at which point outcomes were compared when testing frequencies 1, 3, 10 and 36 Hz and phase durations 75, 150, 200, 300 and 400 µs. Discomfort was assessed with a numerical rating scale (NRS, 0–10) and energy consumption was calculated and expressed in milli-Joule (mJ). Significance set to p ≤ 0.05. Results 1 Hz yielded a median (inter-quartile range) NRS of 2.4 (1.0–3.4), significantly lower than both 3 Hz with NRS 2.8 (1.8–4.2), and 10 Hz with NRS 3.4 (1.4–5.4) (both p ≤ .014). Each increase in tested frequency resulted in significantly higher energy consumption, e.g. 0.6 mJ (0.5–0.8) for 1 Hz vs 14.9 mJ (12.3–21.2) for 36 Hz (p = .003). Longer phase durations had no significant effect on discomfort despite generally requiring significantly lower current amplitudes. Phase durations 150, 200 and 400 µs required significantly lower energy consumption compared to 75 µs (all p ≤ .037). Conclusion LI-NMES applied via a TTE sock produces a relevant plantar flexion of the ankle with the best comfort and lowest energy consumption using 1 Hz and phase durations 150, 200 or 400 µs.

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.

Background:Early functional mobilization (EFM) may improve patient outcome after Achilles tendon rupture (ATR). However, whether EFM affects patient outcome via changes in tendon elongation, thickening, or calf muscle atrophy is unknown.Purpose:To analyze differences in tendon and muscle morphology recovery over time between groups treated with EFM or standard treatment after ATR repair.Study Design:Cohort study; Level of evidence, 2.Methods:This prospective cohort study included 86 patients (20 women) with ATR repair who had a mean (SD) age of 39.3 (8.2) years and were part of a larger prospective randomized controlled trial. Patients were postoperatively randomized to immediate postoperative weightbearing and ankle motion (EFM group) or to immobilization in a below-knee plaster cast for 2 weeks (control group). Patient-reported and functional outcomes were assessed at 6 and 12 months with the Achilles Tendon Total Rupture Score and the heel-rise test for endurance. At 2 and 6 weeks and 6 and 12 months postoperatively, B-mode ultrasound imaging was performed to assess the length and cross-sectional area (CSA) of the Achilles tendon, the gastrocnemius CSA, as well as the thickness of soleus.Results:The Achilles Tendon Total Rupture Score for the EFM and control groups were 65.8 (18.7) and 56.8 (20.1; P = .045), respectively, at 6 months and 79.6 (15.8) and 78.9 (17.2; P = .87), respectively, at 12 months. At 2 weeks, tendon elongation was significantly more pronounced in the EFM group as compared with the control group (mean side-to-side difference, 1.88 cm vs 0.71 cm; P = .005). Subsequently, tendon elongation increased in the control group while it decreased in the EFM group so that at 6 and 12 months no significant differences between groups were found. Mean Achilles tendon elongation at 1 year was 1.73 (1.07) cm for the EFM group (n = 55) and 1.67 (0.92) cm for the control group (n = 27), with a mean difference of 0.06 cm (95% CI, 0.54 to –0.42; P = .80). Achilles tendon CSA and calf muscle atrophy displayed no significant differences between the groups; however, significant changes were demonstrated over time ( P ≤ .001) in both groups.Conclusion:EFM results in more Achilles tendon elongation at early healing, but this difference subsides over time. EFM does not seem to affect patient outcome via changes in tendon elongation, thickening, or calf muscle atrophy.Registration:NCT02318472 (ClinicalTrials.gov identifier).

C8α-γ deficiency was examined in four unrelated African Americans. Two individuals were compound heterozygotes for a previously reported point mutation in exon 9. mRNA from the remaining six C8A alleles contained a 10 nt insertion between nt 992 and 993 corresponding to the junction between exons 6 and 7. This suggested that C8α-γ deficiency in these individuals was caused by a splicing defect. Genomic sequencing revealed a G→A point mutation in intron 6, upstream of the exon 7 acceptor site. This mutation converts a GG to an AG, generates a consensus 3′ splice site that shifts the reading frame, and creates a premature stop codon downstream. To verify that the point mutation caused a splicing defect, we tested wild-type and mutant mRNA substrates, containing 333 nt of the C8α intron 6/exon 7 boundary, in an in vitro splicing assay. This assay generated spliced RNA containing the 10 bp insertion observed in the C8α mRNA of affected patients. In addition, in mutant RNA substrates, the new 3′ splice site was preferentially recognized compared with wild-type. Preferential selection of the mutant splice site likely reflects its positioning adjacent to a polypyrimidine tract that is stronger than that adjacent to the wild-type site. In summary, we have identified a G→A mutation in intron 6 of C8A as a predominant cause of C8α-γ deficiency in African Americans. This mutation creates a new and preferred 3′ splice site, results in a 10 nt insertion in mRNA, shifts the reading frame, and produces a premature stop codon downstream.

To examine healing adaptations over 17 weeks post Achilles tendon (AT) rupture in the injured region (IR) compared to an uninjured region (UIR) of the AT. Twenty-four rats were subjected to a complete right-sided AT rupture, while the left side served as a control. ATs were harvested at 1, 2, 8 and 17 weeks post-rupture and stained with antibodies specific to Collagen type I (Col I) and II (Col II) as well as Alcian Blue and Picrosirius Red staining techniques. Histopathological changes, proteoglycan content, collagen alignment and immunoexpression were assessed. Both regions examined, IR and UIR, exhibited over weeks 1–17 similar healing adaptations of increasing collagen alignment, decreasing Col I immunoexpression, as well as increasing proteoglycan content and Col II occurrence. Increased proteoglycan content was found already at week 2 in the UIR, while it first increased at week 8 in the IR. The area positive to Col II was increased compared to controls at week 8 in the UIR, whereas it first raised at week 17 in the IR. Collagen disorganization successively declined to reach control levels at week 17 in the UIR, but was still higher in the IR. This study demonstrated that uninjured areas of the AT remote from the rupture site also undergo pronounced remodeling, although with time-span differences relative to injured AT portions. These changes including the pathologic heterotopic mineralization and chondrogenic differentiation observed in both regions may have implications in the choice of rehabilitation regimes in order to prevent secondary rupture.

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

Purpose Achilles tendon rupture (ATR) is a common injury. The knowledge of seasonal factors´ impact is incomplete, but may provide means for preventive approaches for Achilles tendon related morbidity. The aim of this study was to investigate seasonal variations in ATR incidence in relation to injury mechanism, adverse events including risk of re-rupture, and patient-reported outcome in adults in Stockholm, Sweden. Methods In total, 349 patients with unilateral acute Achilles tendon rupture, prospectively treated with standardized surgical techniques, were retrospectively assessed. Date of injury was assigned to one of the four internationally defined meteorological seasons in the northern hemisphere. Injury mechanism and the rate of adverse events; deep venous thrombosis, infection and re-rupture in relation to per-operative complications. Patient-reported outcome at 1 year was assessed with the validated Achilles tendon Total Rupture Score. Results ATR incidence was significantly highest during winter and spring, and lowest during summer (p 50%). The rate of soccer-related ATR was highest during summer (p p p Conclusion Winter and spring are the high risk seasons for sports-related ATR and the risk sports are badminton, soccer and floorball. The reason for the higher risk of re-rupture after ATR repair during summer should be further investigated. Level of evidence III.

Purpose The aim of this study was to investigate whether patient subjective and functional outcomes after Achilles tendon rupture (ATR) are related to deep venous thrombosis (DVT) during leg immobilization. Methods A cohort study with prospectively collected randomized data was conducted between 2010 and 2017. Two-hundred and fifty-one Patients with an Achilles tendon rupture (mean age = 41 ± 8), treated with uniform surgical techniques, were retrospectively analyzed. DVT incidence at 2 and 6 weeks was assessed using compression duplex ultrasound. At 12 months patient-reported outcomes were assessed using the Achilles tendon Total Rupture Score (ATRS), Foot- and Ankle Outcome Score (FAOS), Physical Activity Scale (PAS) and functional outcome with the calf-muscle endurance test. ANOVA analyses were used and adjusted for assumed confounding factors (patient age, sex, BMI and rehabilitation). Results The total DVT incidence was 122 out of 251 (49%). Patients suffering a DVT exhibited significantly lower ATRS at 1 year compared to patients without DVT (mean 76 vs 83, 95% CI 71–79 vs 80–87; p 80) compared to 51% (95% CI 41–61%) of the patients sustaining a DVT (p p p Conclusion Sustaining a DVT during leg immobilization significantly impairs patient-reported outcome at 1 year after surgical repair of ATR. Level of evidence III.

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.

Objectives: An increased frequency of intermittent hypoxemia (IH) is associated with a higher risk for poor developmental outcomes, disability, or death in extremely preterm infants. The objective of the prFesent study is to quantify the effect of hands-on medical and parental interventions on the incidence of IH in extremely preterm infants. Methods: An observational design with intraindividual comparisons was used. Blood oxygen saturation levels (SpO2) and time-lapse video were recorded. Frequency, duration, and time to occurrence of IH (SpO2 Results: The highest proportion of time with IH occurred during NMC (2.49%) and incubator touch (1.32%), the lowest during SSC (0.74%) and health care by parents (0.67%). IH frequency per hour was highest during NMC (2.95, IQR 1.19–4.01) and lowest during SSC (0.88, IQR 0.37–2.32, p < 0.001). While an increase in IH during NMC was expected, the high incidence during incubator touch was surprising. Parental touch in the incubator is intended to be soothing, not stressful. Conclusions: Future studies need to clarify how preterm infants process touch, which attributes of touch are fundamental trigger mechanisms of IH, and which handling strategies are most effective in lowering the incidence of IH during hands-on medical care.

Background: Neuromuscular electrical stimulation (NMES) may improve venous hemodynamics to decrease the risk of venous thromboembolism. However, whether calf-NMES using textile electrodes integrated in socks can improve venous hemodynamics without discomfort is unknown. Aim: The primary aim of this study was to examine whether calf-NMES, using one new textile electrode- compared to an established gel electrode-setup, could induce significant dose-dependent increases in the peak venous velocity (PVV) and non-inferior comfort.Methods: On ten healthy participants, intensity (mA) of calf-NMES (frequency 36 Hz, phase duration 200µs) was increased until a visible plantar flexion (threshold 1), plus an additional six NMES-levels (threshold II), utilizing two different electrode setups. A new transverse textile electrode (TTE) setup consisted of two textile electrodes (2 x 2.5 cm) sewn into the back of a sock placed 2 cm apart at the largest circumference of the calf. The established gel electrodes (3x3cm) were placed on the participants best motor points and designated the motor point electrode (MPE) setup. PVV was measured in v. poplitea and v. femoralis at baseline and at threshold I and II using a Doppler ultrasound machine. Comfort was assessed with a numerical rating scale (NRS, 0-10). Values were expressed as medians and significance was set to pResults: In v. poplitea both TTE and MPE induced significant dose-dependent increases in PVV from baseline to threshold I with 123% and 63% and to threshold II with 319% and 208%, respectively (all pthreshold I with 47% and 55% and to threshold II with 102% and 107%, respectively (all p threshold I (pthreshold II there was no difference in NRS (p=0.836).Conclusion: A new reusable TTE produces non-inferior dose-dependent venous hemodynamics compared to a standard MPE. Further development, however, is needed concerning textile electrode discomfort to improve patient compliance.Trial registration: Retrospectively registered with ISRCTN registry. Trial ID: ISRCTN49260430. Date: 11/01/2022.

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 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.

The effect of surgeon experience on patient outcomes after surgical Achilles tendon rupture (ATR) repair has so far been unknown.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.Cohort study; Level of evidence, 3.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.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];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.

Background Acute Achilles tendon rupture (ATR) is a frequently disabling injury, which exhibits unclear variability in long-term functional and patient-reported outcomes. Biomarkers from early healing, which have been shown to be prognostic of long-term outcome would facilitate the development of improved treatment methods. Hypothesis/purpose The aim of this study was to assess essential metabolites pyruvate and its product lactate, as early biomarkers in relation to long-term functional- and patient-reported outcome after ATR. Study design Prospective cohort study. Methods A total of 124 patients (103 men, 21 women; mean age 40 ± 7 years) with ATR, treated with uniform anesthetic and surgical technique, were prospectively assessed. At two weeks post-injury pyruvate and lactate concentrations were assessed in both the injured and uninjured limbs using microdialysis followed by enzymatic quantification. The ratios of the concentration in the injured versus uninjured limb of pyruvate (pyruvate-r) and lactate (lactate-r) were calculated as well as the lactate/pyruvate ratios (L/P-r). At 12 months, patient-reported outcome was examined using self-reported questionnaires; Achilles tendon Total Rupture Score (ATRS), Foot and Ankle Outcome Score (FAOS), and physical activity score. At 12 months, functional outcome was studied using the validated heel-rise test. Results Elevated pyruvate-r, at two weeks, was significantly associated with total ATRS (R = 0.254, P = 0.028), less loss in physical activity (R = 0.241, P = 0.039), less experience of pain in FAOS (R = 0.275, P = 0.032), and a higher number of heel-rise repetitions on injured side (R = 0.230, P = 0.040) at 12 months. Increased lactate-r was related with less strength limitations in the calf (R = 0.283, P = 0.011), while the elevated lactate-pyruvate ratio, notably, was related to more limitations in walking on uneven surface (R = -0,243, P = 0.027). The findings were verified by multiple linear regression taking confounding factors into consideration. Conclusion This study established that the metabolite pyruvate is a good potential biomarker, prognostic of patient outcome at the one-year follow-up after ATR surgery. These novel findings suggest that local biomarkers could be developed at an early-stage screen for new ATR treatments.

Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are two of the most common emergencies of the gastrointestinal tract in preterm infants with very low birth weight (VLBW, birth weight

IntroductionLeg 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 analysisSTOP 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 disseminationEthical 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 registrationNCT03259204.Time schedule1 September 2018 to 31 December 2022

We would like to thank Dr. Vento1 for clarifying the particular issues raised by our commentary2 and for providing helpful additional details. Moreover, we would like to emphasize once more the importance of the given study - being the first large trial evaluating efficacy and safety of a modified IN-SUR-E approach applying high-frequency oscillatory ventilation (HFOV) lung recruitment prior to surfactant (IN-REC-SUR-E) compared to standard IN-SUR-E in very immature preterm infants.3 We read this study with great interest, and we are encouraged by the reported results.

An amendment to this paper has been published and can be accessed via the original article.

Abstract High-frequency ventilation (HFV) has been used as a respiratory support mode for neonates for over 30 years. HFV is characterized by delivering tidal volumes close to or less than the anatomical dead space. Both animal and clinical studies have shown that HFV can effectively restore lung function, and potentially limit ventilator-induced lung injury, which is considered an important risk factor for developing bronchopulmonary dysplasia (BPD). Knowledge of how HFV works, how it influences cardiorespiratory physiology, and how to apply it in daily clinical practice has proven to be essential for its optimal and safe use. We will present important aspects of gas exchange, lung-protective concepts, clinical use, and possible adverse effects of HFV. We also discuss the study results on the use of HFV in respiratory distress syndrome in preterm infants and respiratory failure in term neonates. Impact Knowledge of how HFV works, how it influences cardiorespiratory physiology, and how to apply it in daily clinical practice has proven to be essential for its optimal and safe use. Therefore, we present important aspects of gas exchange, lung-protective concepts, clinical use, and possible adverse effects of HFV. The use of HFV in daily clinical practice in lung recruitment, determination of the optimal continuous distending pressure and frequency, and typical side effects of HFV are discussed. We also present study results on the use of HFV in respiratory distress syndrome in preterm infants and respiratory failure in term neonates.