Convalescent or standard plasma versus standard of care in the treatment of COVID-19 patients with respiratory impairment: short and long-term effects. A three-arm randomized controlled clinical trial.

BACKGROUND: The efficacy of early treatment with convalescent plasma in patients with COVID-19 is debated. Nothing is known about the potential effect of other plasma components other than anti-SARS-CoV-2 antibodies. METHODS: To determine whether convalescent or standard plasma would improve outcomes for adults in early phase of Covid19 respiratory impairment we designed this randomized, three-arms, clinical trial (PLACO COVID) blinded on interventional arms that was conducted from June 2020 to August 2021. It was a multicentric trial at 19 Italian hospitals. We enrolled 180 hospitalized adult patients with COVID-19 pneumonia within 5 days from the onset of respiratory distress. Patients were randomly assigned in a 1:1:1 ratio to standard of care (n = 60) or standard of care + three units of standard plasma (n = 60) or standard of care + three units of high-titre convalescent plasma (n = 60) administered on days 1, 3, 5 after randomization. Primary outcome was 30-days mortality. Secondary outcomes were: incidence of mechanical ventilation or death at day 30, 6-month mortality, proportion of days with mechanical ventilation on total length of hospital stay, IgG anti-SARS-CoV-2 seroconversion, viral clearance from plasma and respiratory tract samples, and variations in Sequential Organ Failure Assessment score. The trial was analysed according to the intention-to-treat principle. RESULTS: 180 patients (133/180 [73.9%] males, mean age 66.6 years [IQR 57-73]) were enrolled a median of 8 days from onset of symptoms. At enrollment, 88.9% of patients showed moderate/severe respiratory failure. 30-days mortality was 20% in Control arm, 23% in Convalescent (risk ratio [RR] 1.13; 95% confidence interval [CI], 0.61-2.13, P = 0.694) and 25% in Standard plasma (RR 1.23; 95%CI, 0.63-2.37, P = 0.544). Time to viral clearance from respiratory tract was 21 days for Convalescent, 28 for Standard plasma and 23 in Control arm but differences were not statistically significant. No differences for other secondary endpoints were seen in the three arms. Serious adverse events were reported in 1.7%, 3.3% and 5% of patients in Control, Standard and Convalescent plasma arms respectively. CONCLUSIONS: Neither high-titer Convalescent nor Standard plasma improve outcomes of COVID-19 patients with acute respiratory failure. Trial Registration Clinicaltrials.gov Identifier: NCT04428021. First posted: 11/06/2020.

NMES superimposed on movement is equally effective as heavy slow resistance training in patellar tendinopathy.

OBJECTIVE: This study aimed at investigating the effectiveness of an 8-week training protocol, based on neuromuscular electrical stimulation of the quadriceps, which was superimposed onto voluntary exercise (NMES+), in comparison to a traditional heavy slow resistance training (HSRT), in individuals with patellar tendinopathy. METHODS: Thirty-two physically active participants, aged: 33.6±10.2 years, were divided into two groups: NMES+ or HSRT. Maximal voluntary isometric contraction (MVIC) of knee extensor and flexor muscles, power during a countermovement jump (CMJ), and VISA-p questionnaire scores were recorded at the start(T0), 2-weeks(T1), 4-weeks(T2), 6-weeks(T3), 8-weeks(T4) and 4-months post-training (T5). Knee pain and rate of perceived exertion (RPE) were recorded at each training session with a 0-10 scale. RESULTS: Knee pain was significantly lower in NMES+ compared to HSRT during all training sessions. No significant between-group differences were found for VISA-p scores and forces recorded during MVICs at T0,T1,T2,T3,T4 and T5. A significant increase of VISA-p and peak forces during MVIC was recorded across-time in both groups. No significant between-group or across-time differences were found for RPE and CMJ parameters. CONCLUSIONS: NMES+ and HSRT were equally effective in decreasing tendinopathy symptoms and increasing strength, with NMES+ having the advantage to be a pain-free resistance training modality.

A New Human Platelet Lysate for Mesenchymal Stem Cell Production Compliant with Good Manufacturing Practice Conditions Preserves the Chemical Characteristics and Biological Activity of Lyo-Secretome Isolated by Ultrafiltration.

Recently, we proposed a Good Manufacturing Practice (GMP)-compliant production process for freeze-dried mesenchymal stem cell (MSC)-secretome (lyo-secretome): after serum starvation, the cell supernatant was collected, and the secretome was concentrated by ultrafiltration and freeze-dried, obtaining a standardized ready-to-use and stable powder. In this work, we modified the type of human platelet lysate (HPL) used as an MSC culture supplement during the lyo-secretome production process: the aim was to verify whether this change had an impact on product quality and also whether this new procedure could be validated according to GMP, proving the process robustness. MSCs were cultured with two HPLs: the standard previously validated one (HPL-E) and the new one (HPL-S). From the same pool of platelets, two batches of HPL were obtained: HPL-E (by repeated freezing and thawing cycles) and HPL-S (by adding Ca-gluconate to form a clot and its subsequent mechanical wringing). Bone marrow MSCs from three donors were separately cultured with the two HPLs until the third passage and then employed to produce lyo-secretome. The following indicators were selected to evaluate the process performance: (i) the lyo-secretome quantitative composition (in lipids and proteins), (ii) the EVs size distribution, and (iii) anti-elastase and (iv) immunomodulant activity as potency tests. The new HPL supplementation for MSCs culture induced only a few minimal changes in protein/lipid content and EVs size distribution; despite this, it did not significantly influence biological activity. The donor intrinsic MSCs variability in secretome secretion instead strongly affected the quality of the finished product and could be mitigated by concentrating the final product to reach a determined protein (and lipid) concentration. In conclusion, the modification of the type of HPL in the MSCs culture during lyo-secretome production induces only minimal changes in the composition but not in the potency, and therefore, the new procedure can be validated according to GMP.

A New Human Platelet Lysate for Mesenchymal Stem Cell Production Compliant with Good Manufacturing Practice Conditions.

Mesenchymal stem cells (MSCs) are classified as advanced therapy medicinal products, a new category of GMP (good manufacturing practice)-compliant medicines for clinical use. We isolated MSCs from 5 bone marrow (BM) samples using human platelet lysate (HPL) instead of foetal bovine serum (FBS). We used a new method of HPL production consisting of treating platelet (PLTs) pools with Ca-Gluconate to form a gel clot, then mechanically squeezing to release growth factors. We compared the new HPL (HPL-S) with the standard (HPL-E) obtained by freezing/thawing cycles and by adding heparin. HPL-S had not PLTs and fibrinogen but the quantity of proteins and growth factors was comparable to HPL-E. Therefore, HPL-S needed fewer production steps to be in compliance with GMP conditions. The number of colonies forming unit-fibroblasts (CFU-F) and the maintenance of stem markers showed no significant differences between MSCs with HPL-E and HPL-S. The cumulative population doubling was higher in MSCs with HPL-E in the earlier passages, but we observed an inverted trend of cell growth at the fourth passage. Immunophenotypic analysis showed a significant lower expression of HLA-DR in the MSCs with HPL-S (1.30%) than HPL-E (14.10%). In conclusion, we demonstrated that HPL-S is an effective alternative for MSC production under GMP conditions.

Early Superimposed NMES Training is Effective to Improve Strength and Function Following ACL Reconstruction with Hamstring Graft regardless of Tendon Regeneration.

The study aimed at investigating the effects of neuromuscular electrical stimulation superimposed on functional exercises (NMES+) early after anterior cruciate ligament reconstruction (ACLr) with hamstring graft, on muscle strength, knee function, and morphology of thigh muscles and harvested tendons. Thirty-four participants were randomly allocated to either NMES+ group, who received standard rehabilitation with additional NMES of knee flexor and extensor muscles, superimposed on functional movements, or to a control group, who received no additional training (NAT) to traditional rehabilitation. Participants were assessed 15 (T1), 30 (T2), 60 (T3), 90 (T4) and at a mean of 380 days (T5) after ACLr. Knee strength of flexors and extensors was measured at T3, T4 and T5. Lower limb loading asymmetry was measured during a sit-to-stand-to-sit movement at T1, T2, T3, T4 and T5, and a countermovement-jump at T4 and T5. An MRI was performed at T5 to assess morphology of thigh muscles and regeneration of the harvested tendons. NMES+ showed higher muscle strength for the hamstrings (T4, T5) and the quadriceps (T3, T4, T5), higher loading symmetry during stand-to-sit (T2, T3, T4, T5), sit-to-stand (T3, T4) and countermovement-jump (T5) than NAT. No differences were found between-groups for morphology of muscles and tendons, nor in regeneration of harvested tendons. NMES+ early after ACLr with hamstring graft improves muscle strength and knee function in the short- and long-term after surgery, regardless of tendon regeneration.

Deficit in knee extension strength following anterior cruciate ligament reconstruction is explained by a reduced neural drive to the vasti muscles.

The persistence of quadriceps weakness represents a major concern following anterior cruciate ligament reconstruction (ACLR). The underlying adaptations occurring in the activity of spinal motoneurons are still unexplored. This study examined the discharge patterns of large populations of motor units (MUs) in the vastus lateralis (VL) and vastus medialis muscles following ACLR. Nine ACLR individuals and 10 controls performed unilateral trapezoidal contractions of the knee extensor muscles at 35%, 50% and 70% of the maximal voluntary isometric force (MVIF). High-density surface electromyography (HDsEMG) was used to record the myoelectrical activity of the vasti muscles in both limbs. HDsEMG signals were decomposed with a convolutive blind source separation method and MU properties were extracted and compared between sides and groups. The ACLR group showed a lower MVIF on the reconstructed side compared to the contralateral side (28.1%; P < 0.001). This force deficit was accompanied by reduced MU discharge rates (∼21%; P < 0.05), lower absolute MU recruitment and derecruitment thresholds (∼22% and ∼22.5%, respectively; P < 0.05) and lower input-output gain of motoneurons (27.3%; P = 0.009). Deficits in MU discharge rates of the VL and in absolute recruitment and derecruitment thresholds of both vasti MUs were associated with deficits in MVIF (P < 0.05). A strong between-side correlation was found for MU discharge rates of the VL of ACLR individuals (P < 0.01). There were no significant between-group differences (P > 0.05). These results indicate that mid- to long-term strength deficits following ACLR may be attributable to a reduced neural drive to vasti muscles, with potential changes in excitatory and inhibitory synaptic inputs. KEY POINTS: Impaired expression and control of knee extension forces is common after anterior cruciate ligament reconstruction and is related to high risk of a second injury. To provide novel insights into the neural basis of this impairment, the discharge patterns of motor units in the vastus lateralis and vastus medialis were investigated during voluntary force contractions. There was lower knee extensor strength on the reconstructed side with respect to the contralateral side, which was explained by deficits in motor unit discharge rate and an altered motoneuronal input-output gain. Insufficient excitatory inputs to motoneurons and increased inhibitory afferent signals potentially contributed to these alterations. These results further our understanding of the neural underpinnings of quadriceps weakness following anterior cruciate ligament reconstruction and can help to develop effective rehabilitation protocols to regain muscle strength and reduce the risk of a second injury.

Balance and proprioception impairment, assessment tools, and rehabilitation training in patients with total hip arthroplasty: a systematic review.

BACKGROUND: Osteoarthritis and subsequent total hip arthroplasty (THA) lead to damages to hip joint mechanoceptors, which in turns lead to impairments in proprioception. One of the abilities mainly affected by an altered joint proprioception is balance. The aim of this work was to investigate the balance and proprioception impairments, current assessment tools, and rehabilitation training after THA. METHODS: A systematic literature revision was conducted on PubMed, Web of Science and Cochrane databases. Articles reporting balance and proprioception impairments, current assessment tools, or rehabilitation interventions were included. Methodological quality was assessed using the Downs and Black checklist. A total of 41 articles were included, 33 discussing balance and proprioception assessment, and 8 dealing with training. Data related to type of surgical approach, type and timing of assessment protocols, assessment instrumentation, and type, volume and duration of the rehabilitation training were extracted from each study. RESULTS: Thirty-one studies were of high quality, 2 of moderate quality and 8 of low-quality. Literature review showed an improvement in balance following THA in comparison with the pre-operative performance, although balance abnormalities persist up to 5 years after surgery, with THA patients showing an increased risk for falls. Balance training is effective in all the rehabilitation phases if specifically structured for balance enhancement and consistent in training volume. It remains unclear which assessments are more appropriate for the different rehabilitation phases, and if differences exist between the different surgical procedures used for THA. Only two studies assessed proprioception. CONCLUSION: Balance and proprioception show impairments up to 5 years after THA, increasing the risk of falls. However, patients with THA may benefit of an adequate balance training. Further research is needed to investigate the gaps in balance and proprioception assessment and training following THA surgery.

Muscle fiber conduction velocity in the vastus lateralis and medialis muscles of soccer players after ACL reconstruction.

The neural factors underlying the persistency of quadriceps weakness after anterior cruciate ligament reconstruction (ACLR) have been only partially explained. This study examined muscle fiber conduction velocity (MFCV) as an indirect parameter of motor unit recruitment strategies in the vastus lateralis (VL) and medialis (VM) muscles of soccer players with ACLR. High-density surface electromyography (HDsEMG) was acquired from VL and VM in nine soccer players (22.7 ± 2.9 years; BMI: 22.08 ± 1.72 kg·m-2 ; 7.7 ± 2.2 months post-surgery). Voluntary muscle force and the relative myoelectrical activity from the reconstructed and contralateral sides were recorded during linearly increasing isometric knee extension contractions up to 70% of maximal voluntary isometric force (MVIF). The relation of MFCV and force was examined by linear regression analysis at the individual subject level. The initial (intercept), peak (MFCV70 ), and rate of change (slope) of MFCV related to force were compared between limbs and muscles. The MVIF was lower in the reconstructed side than in the contralateral side (-%20.5; P < .05). MFCV intercept was similar among limbs and muscles (P > .05). MFCV70 and MFCV slope were lower in the reconstructed side compared to the contralateral for both VL (-28.5% and -10.1%, respectively; P < .001) and VM (-22.6% and -8.1%, respectively; P < .001). The slope of MFCV was lower in the VL than VM, but only in the reconstructed side (-12.4%; P < .001). These results suggest possible impairments in recruitment strategies of high-threshold motor units (HTMUs) as well as deficits in sarcolemmal excitability, fiber diameter, and discharge rate of knee extensor muscles following ACLR.

Modulation of spinal excitability following neuromuscular electrical stimulation superimposed to voluntary contraction.

PURPOSE: Neuromuscular electrical stimulation (NMES) superimposed on voluntary muscle contraction has been recently shown as an innovative training modality within sport and rehabilitation, but its effects on the neuromuscular system are still unclear. The aim of this study was to investigate acute responses in spinal excitability, as measured by the Hoffmann (H) reflex, and in maximal voluntary contraction (MVIC) following NMES superimposed to voluntary isometric contractions (NMES + ISO) compared to passive NMES only and to voluntary isometric contractions only (ISO). METHOD: Fifteen young adults were required to maintain an ankle plantar-flexor torque of 20% MVC for 20 repetitions during each experimental condition (NMES + ISO, NMES and ISO). Surface electromyography was used to record peak-to-peak H-reflex and motor waves following percutaneous stimulation of the posterior tibial nerve in the dominant limb. An isokinetic dynamometer was used to assess maximal voluntary contraction output of the ankle plantar flexor muscles. RESULTS: H-reflex amplitude was increased by 4.5% after the NMES + ISO condition (p < 0.05), while passive NMES and ISO conditions showed a decrease by 7.8% (p < 0.05) and no change in reflex responses, respectively. There was no change in amplitude of maximal motor wave and in MVIC torque during each experimental condition. CONCLUSION: The reported facilitation of spinal excitability following NMES + ISO could be due to a combination of greater motor neuronal and corticospinal excitability, thus suggesting that NMES superimposed onto isometric voluntary contractions may provide a more effective neuromuscular stimulus and, hence, training modality compared to NMES alone.

Innovative rehabilitative bracing with applied resistance improves walking pattern recovery in the early stages of rehabilitation after ACL reconstruction: a preliminary investigation.

BACKGROUND: The use of knee braces early after anterior cruciate ligament (ACL) reconstruction is a controversial issue. The study preliminarily compares the effect of a traditional brace blocked in knee extension and a new functional brace equipped with a spring resistance on walking and strength performance early after ACL reconstruction performed in the acute/subacute stage. METHODS: 14 ACL-reconstructed patients wore either a traditional (Control group: CG, 7 subjects) or a new functional brace (Experimental group: EG 7 subjects) until the 30th post-operative day. All patients were tested before surgery (T0), 15, 30, and 60 days after surgery (T1, T2, and T3, respectively). Knee angular displacement and ground reaction forces (GRF) during the stance phase of the gait cycle were analyzed at each session and, at T3, maximal voluntary isometric contraction (MVIC) for knee flexor/extensor muscles was performed. Limb symmetry indexes (LSI) of GRF and MVIC parameters were calculated. RESULTS: At T3, EG showed greater peak knee flexion angle of injured limb compared to CG (41 ± 2° vs 32 ± 1°, p < 0.001). During weight acceptance, a significant increase of anteroposterior GRF peak and vertical impulse from T1 to T3 was observed in the injured limb in EG (p < 0.05) but not in CG (p > 0.05). EG showed a greater side-to-side LSI of weight acceptance peak of anteroposterior GRF at T2 (113 ± 23% vs 69 ± 11%, p < 0.05) and T3 (112 ± 23% vs 84 ± 10%, p < 0.05). CONCLUSIONS: The preliminary findings from this study indicate that the new functional brace did help in improving gait biomechanical pattern in the first two months after ACL reconstruction compared to a traditional brace locked in knee extension.

Timing of Muscle Activation Is Altered During Single-Leg Landing Tasks After Anterior Cruciate Ligament Reconstruction at the Time of Return to Sport.

OBJECTIVES: It is well known that alterations in landing mechanics persist for years after anterior cruciate ligament reconstruction (ACL-R). Nevertheless, existing literature is controversial in reporting successful or unsuccessful recovery of prelanding muscle activation timing after ACL-R. The study aimed at comparing myoelectric and kinematic patterns during landing tasks between ACL-R and healthy subjects. DESIGN: Cross-sectional study. SETTING: Institutional research laboratory. PATIENTS AND INTERVENTION: Fifteen male athletes after ACL-R using patellar tendon and 11 using hamstrings autograft at the time of return to sport were recruited. Fifteen healthy athletes served as control group. Participants performed 4 different single-leg landing tasks arriving onto a force plate. MAIN OUTCOME MEASURES: Electromyographic (EMG) activity of knee extensors and flexors, normalized vertical ground reaction force (vGRF), and knee angular displacement were recorded. RESULTS: In all the tasks, preimpact EMG duration was longer in ACL-R (112 ± 28 ms in the knee extensors; 200 ± 34 ms in the knee flexors) compared with healthy participants (74 ± 19 ms in the knee extensors; 153 ± 29 ms in the knee flexors; P < 0.05). Initial contact (IC) and maximum postimpact knee angle were lower in ACL-R (9 ± 7 degrees at IC; 39 ± 12 degrees at maximum flexion) compared with healthy participants (17 ± 9 degrees at IC; 52 ± 15 degrees at maximum flexion; P < 0.05). Normalized vGRF was higher in ACL-R compared with healthy participants (3.4 ± 0.5 and 2.7 ± 0.6; P < 0.05). CONCLUSIONS: At the time of return to sport, ACL-R subjects showed altered motor control strategies of single-leg landings. These alterations may lead to uncoordinated movement, hence increasing the risk of reinjury.

Postural Adjustments Following ACL Rupture and Reconstruction: A Longitudinal Study.

Longitudinal changes in compensatory and anticipatory postural adjustments around the knee were investigated from rupture of ACL until return to play after reconstruction. Twelve ACL-injured participants (ACL-P) were asked to respond to unpredictable and predictable perturbations before (T1), 2 (T2) and 6 months after (T3) reconstruction. Twelve healthy participants served as controls. Compensatory and anticipatory latencies of vastus lateralis (VL) and medialis (VM) were measured with respect to the arrival of perturbations. ACL-P showed delayed compensatory latencies compared to controls at T1 for VL (101±32 ms vs 63±7 ms) and VM (117±36 ms vs 75±17 ms) and at T2 for VL (94±20 ms vs 63±7 ms) and VM (94±27 ms vs 71±11 ms). ACL-P showed earlier anticipatory latencies than controls for VL at T1 (-69±44 ms vs -12±12 ms) and T2 (-46±17 ms vs -16±12 ms). At T3, ACL-P showed delayed compensatory latencies for VL (91±18 ms vs 56±21 ms) and VM (95±13 ms vs 66±4 ms), whilst anticipatory latencies were restored. Rehabilitation should address delayed compensatory responses.

Early compensatory and anticipatory postural adjustments following anterior cruciate ligament reconstruction.

PURPOSE: Early identification of postoperative neuromuscular deficits has been advocated to prevent muscle weakness and maximize functional outcomes following anterior cruciate ligament reconstruction (ACLR). The purpose of this study was to investigate neuromechanical changes in compensatory and anticipatory postural adjustments, which play a major role in minimizing unpredictable and predictable disturbances, respectively, as early as 2 months after ACLR. METHODS: Nine young male individuals who underwent ACLR with patellar tendon and nine age-matched healthy controls were exposed to two blocks of ten either unexpected or expected loading perturbations of the knee joint, while semi-reclined on a raised plinth. Amplitude and latency of postural responses in the vastus lateralis (VL), rectus femoris (RF) and biceps femoris (BF) muscles were determined by surface electromyography. RESULTS: Latency of compensatory responses was higher in patients with ACLR than in healthy participants for VL (82 ± 15 vs 68 ± 10 ms, P < 0.05) and RF (81 ± 21 vs 63 ± 10 ms, P < 0.05). Amplitude of compensatory responses was 54 % lower in patients with ACLR than in healthy participants for VL (P < 0.05). Onset of anticipatory responses occurred earlier in patients with ACLR than in healthy participants for VL (-83 ± 45 vs -26 ± 21 ms, P < 0.05), RF (-59 ± 48 vs -10 ± 13 ms, P < 0.05) and BF (-72 ± 42 vs -12 ± 14 ms, P < 0.01). CONCLUSION: Patients with ACLR showed early abnormalities in compensatory and anticipatory postural adjustments, which may reflect the inability to quickly detect sudden changes in muscle length or to completely activate muscles surrounding the knee, and may be addressed by specific training interventions.

Inactivated human platelet lysate with psoralen: a new perspective for mesenchymal stromal cell production in Good Manufacturing Practice conditions.

BACKGROUND AIMS: Mesenchymal stromal cells (MSC) are ideal candidates for regenerative and immunomodulatory therapies. The use of xenogeneic protein-free Good Manufacturing Practice-compliant growth media is a prerequisite for clinical MSC isolation and expansion. Human platelet lysate (HPL) has been efficiently implemented into MSC clinical manufacturing as a substitute for fetal bovine serum (FBS). Because the use of human-derived blood materials alleviates immunologic risks but not the transmission of blood-borne viruses, the aim of our study was to test an even safer alternative than HPL to FBS: HPL subjected to pathogen inactivation by psoralen (iHPL). METHODS: Bone marrow samples were plated and expanded in α-minimum essential medium with 10% of three culture supplements: HPL, iHPL and FBS, at the same time. MSC morphology, growth and immunophenotype were analyzed at each passage. Karyotype, tumorigenicity and sterility were analyzed at the third passage. Statistical analyses were performed. RESULTS: The MSCs cultivated in the three different culture conditions showed no significant differences in terms of fibroblast colony-forming unit number, immunophenotype or in their multipotent capacity. Conversely, the HPL/iHPL-MSCs were smaller, more numerous, had a higher proliferative potential and showed a higher Oct-3/4 and NANOG protein expression than did FBS-MSCs. Although HPL/iHPL-MSCs exhibit characteristics that may be attributable to a higher primitive stemness than FBS-MSCs, no tumorigenic mutations or karyotype modifications were observed. CONCLUSIONS: We demonstrated that iHPL is safer than HPL and represents a good, Good Manufacturing Practice-compliant alternative to FBS for MSC clinical production that is even more advantageous in terms of cellular growth and stemness.

Individuals With Chronic Ankle Instability Show Abnormalities in Maximal and Submaximal Isometric Strength of the Knee Extensor and Flexor Muscles.

BACKGROUND: It has been shown that chronic ankle instability (CAI) leads to abnormalities in neuromuscular control of more proximal joints than the ankle. Although strength of the hip and the ankle muscles has been largely investigated providing concordant results, limited evidence with contrasting results has been reported regarding knee extensor and flexor muscles. PURPOSE: To investigate maximal and submaximal isometric muscle strength in individuals with CAI. STUDY DESIGN: Controlled laboratory study. METHODS: Fifteen participants with unilateral CAI and 15 healthy matched controls were recruited. To quantify maximal strength, peak forces were recorded during a maximal isometric voluntary contraction of knee extensor and flexor muscles at 30° and 90° of knee flexion and normalized by the body weight of each participant. At both angles, submaximal isometric contractions at 20%, 50%, and 80% of the maximal voluntary isometric contraction were performed to analyze strength steadiness, in terms of coefficient of variation, and strength accuracy, in terms of absolute error. During all the assessments, knee extensor and flexor muscle activation was recorded by means of surface electromyography. RESULTS: Knee flexor maximal isometric strength was significantly lower in the injured limb of individuals with CAI in comparison with healthy controls at both 30° (0.15 ± 0.05 vs 0.20 ± 0.05; P < .05) and 90° (0.14 ± 0.04 vs 0.18 ± 0.05; P < .05). Knee extensor and flexor steadiness was significantly lower (higher coefficient of variation) in both the injured and the noninjured limbs of individuals with CAI in comparison with healthy individuals at 90° and at 30° for knee flexor steadiness of the injured limb. Knee extensor and flexor accuracy was lower (higher absolute error) in both the injured and noninjured limbs of individuals with CAI in comparison with healthy individuals, mainly at 30°, while at 90° it was lower only in the injured limb. No differences between the 2 groups were found for maximal isometric strength of knee extensor muscles, as well as for muscle activations. CONCLUSION: Individuals with CAI show abnormalities in maximal and submaximal isometric strength of knee flexor muscles, and submaximal strength of the knee extensor muscles. Further studies should deeply investigate mechanisms leading to these abnormalities. CLINICAL RELEVANCE: Rehabilitation interventions should consider abnormalities of neuromuscular control affecting joints more proximal than the ankle in individuals with CAI. REGISTRATION: NCT05273177 (ClinicalTrials.gov identifier).

Towards a comprehensive biomechanical assessment of the elderly combining in vivo data and in silico methods.

The aging process is commonly accompanied by a general or specific loss of muscle mass, force and/or function that inevitably impact on a person's quality of life. To date, various clinical tests and assessments are routinely performed to evaluate the biomechanical status of an individual, to support and inform the clinical management and decision-making process (e.g., to design a tailored rehabilitation program). However, these assessments (e.g., gait analysis or strength measures on a dynamometer) are typically conducted independently from one another or at different time points, providing clinicians with valuable yet fragmented information. We hereby describe a comprehensive protocol that combines both in vivo measurements (maximal voluntary isometric contraction test, superimposed neuromuscular electrical stimulation, electromyography, gait analysis, magnetic resonance imaging, and clinical measures) and in silico methods (musculoskeletal modeling and simulations) to enable the full characterization of an individual from the biomechanical standpoint. The protocol, which requires approximately 4 h and 30 min to be completed in all its parts, was tested on twenty healthy young participants and five elderlies, as a proof of concept. The implemented data processing and elaboration procedures allowing for the extraction of several biomechanical parameters (including muscle volumes and cross-sectional areas, muscle activation and co-contraction levels) are thoroughly described to enable replication. The main parameters extracted are reported as mean and standard deviation across the two populations, to highlight the potential of the proposed approach and show some preliminary findings (which were in agreement with previous literature).

Effects of MLS Laser on pain, function, and disability in chronic non-specific low back pain: A double-blind placebo randomized-controlled trial.

BACKGROUND: Among non-pharmacological interventions, Multiwave Locked System (MLS) Laser therapy has been used in patients with several musculoskeletal pathologies and in combination with other therapeutical interventions. The effects of sole MLS therapy on pain and function in patients with chronic non-specific low-back pain are unknown. OBJECTIVE: The objective of this study was to investigate the effects of MLS Laser therapy on pain, function, and disability in patients with chronic non-specific low back pain in comparison to a placebo treatment group. METHODS: Forty-five patients were randomized into two groups: the MLS Laser group and the Sham Laser group, undergoing 8 sessions of either a MLS Laser therapy or a Sham Laser therapy, respectively. At the beginning of the therapy (T0), at the end of the therapy (T1), and 1 month after the end of therapy (T2) patients were assessed for low back pain (by means of a VAS scale), function (by means of kinematic and electromyographic assessment of a forward bending movement) and self-reported disability (by means of the Roland-Morris and Oswestry Disability questionnaires). RESULTS: There was a significant reduction of pain and disability in both groups at T1 and T2 in comparison with T0. At T2 patients in the MLS group showed a significantly lower pain in comparison with patients in the Sham group (VAS = 2.2 ± 2 vs. 3.6 ± 2.4; p< 0.05). No differences between the two groups were found for function and disability. CONCLUSION: Both MLS Laser and Sham Laser therapies lead to a significant and comparable reduction in pain and disability in patients with chronic non-specific low back pain. However, one month after treatment, MLS Laser therapy has been found to be significantly more effective in reducing pain as compared to sham treatment.

Using Macrophage Polarization in Human Platelet Lysate to Test the Immunomodulatory Potential of Cells for Clinical Use.

Macrophage-based co-cultures are used to test the immunomodulatory function of candidate cells for clinical use. This study aimed to characterize a macrophage polarization model using human platelet lysate (hPL) as a GMP-compliant alternative to Fetal Bovine Serum (FBS). Primary human monocytes were differentiated into unpolarized (M0) or polarized (M1, M2a, and M2c) macrophages in an hPL- or FBS-based medium. The protein secretion profiles and expression of phenotypic markers (CD80 for M1, CD206 for M2a, and CD163 for M2c) were analyzed. Subsequently, chondrocytes were tested in an hPL-based co-culture model to assess their immunomodulatory function in view of their possible use in patients with osteoarthritis. The results showed similar marker regulation between hPL and FBS cultures, but lower basal levels of CD206 and CD163 in hPL-cultured macrophages. Functional co-culture experiments with chondrocytes revealed increased CD206 expression both in hPL and in FBS, indicating an interaction between macrophages and chondrocytes. While markers in FBS-cultured macrophages were confirmed in hPL-cultured cells, the interpretation of marker modulation in immunomodulatory assays with hPL-based cultures should be carried out cautiously due to the observed differences in the basal marker levels for CD206 and CD163. This research underscores the utility of hPL as a GMP-compliant alternative to FBS for macrophage-based co-cultures and highlights the importance of understanding marker expressions in different culture conditions.

Neuroplastic alterations in common synaptic inputs and synergistic motor unit clusters controlling the vastii muscles of individuals with ACL reconstruction.

This cross-sectional study aims to elucidate the neural mechanisms underlying the control of knee extension forces in individuals with anterior cruciate ligament reconstructions (ACLR). Eleven soccer players with ACLR and nine control players performed unilateral isometric knee extensions at 10% and 30% of their maximum voluntary force (MVF). Simultaneous recordings of high-density surface electromyography (HDEMG) and force output were conducted for each lower limb, and HDEMG data from the vastus lateralis (VL) and vastus medialis (VM) muscles were decomposed into individual motor unit spike trains. Force steadiness was estimated using the coefficient of variation of force. An intramuscular coherence analysis was adopted to estimate the common synaptic input (CSI) converging to each muscle. A factor analysis was applied to investigate the neural strategies underlying the control of synergistic motor neuron clusters, referred to as motor unit modes. Force steadiness was similar between lower limbs. However, motor neurons innervating the VL on the reconstructed side received a lower proportion of CSI at low-frequency bandwidths (< 5 Hz) in comparison to unaffected lower limbs (P < 0.01). Furthermore, the reconstructed side demonstrated a higher proportion of motor units associated with the neural input common to the synergistic muscle, as compared to unaffected lower limbs (P < 0.01). These findings indicate that the VL muscle of reconstructed lower limbs contribute marginally to force steadiness and that a plastic rearrangement in synergistic clusters of motor units involved in the control of knee extension forces is evident following ACLR.

Superimposing neuromuscular electrical stimulation onto voluntary contractions to improve muscle strength and mass: A systematic review.

Training and rehabilitation programmes involving neuromuscular electrical stimulation superimposed onto voluntary contractions (NMES+) have gained popularity in the last decades. Yet, there is no clear consensus on the effectiveness of such intervention. The aim of this review was to evaluate the effect of chronic exposure to NMES+ on muscle strength and mass compared to conventional volitional training or passive electrical stimulation alone. Two authors conducted an electronic search to identify randomized controlled trials that investigated the effect of NMES+ training, involved healthy participants or orthopaedic patients, detailed a well-defined NMES training protocol, and provided outcomes related to muscle strength and/or mass. The authors extracted data on participants, intervention characteristics, muscle-related outcomes, and assessed the methodological quality of the studies. A total of twenty-four studies were included in the review. The majority of these reported an increase in muscle strength following NMES+ training compared to an equivalent voluntary or passive NMES training. The highest improvements were found when NMES was superimposed on sub-maximal exercises involving both concentric and eccentric contractions. Two studies reported an increase in muscle mass after NMES+, while two other studies exhibited no differences. This review indicated that chronic exposure to NMES+ determines muscle strength improvements greater or equal compared to volitional training alone. However, differences in the methodological characteristics of the stimulation and the type of exercise associated with NMES+ revealed significant discrepancies in the results. A deeper understanding of the neurophysiological adaptations to NMES+ is crucial to fully explain the muscle-related enhancement resulting from such intervention.HighlightsNMES+ consists of simultaneously applying neuromuscular electrical stimulation while voluntarily contracting the stimulated muscle.Although a growing number of studies have suggested that intervention based on NMES+ have a strong potential in enhancing as well as preserving muscle function, there is still no clear consensus on the effectiveness of such technique.This review revealed that training based on NMES+ can induce a significant improvement of muscle strength in both healthy and orthopaedic individuals.