Cumulative patellofemoral force and stress are lower during faster running compared to slower running in recreational runners.

Management strategies for patellofemoral pain often involve modifying running distance or speed. However, the optimal modification strategy to manage patellofemoral joint (PFJ) force and stress accumulated during running warrants further investigation. This study investigated the effect of running speed on peak and cumulative PFJ force and stress in recreational runners. Twenty recreational runners ran on an instrumented treadmill at four speeds (2.5-4.2 m/s). A musculoskeletal model derived peak and cumulative (per 1 km of continuous running) PFJ force and stress for each speed. Cumulative PFJ force and stress decreased with faster speeds (9.3-33.6% reduction for 3.1-4.2 m/s vs. 2.5 m/s). Peak PFJ force and stress significantly increased with faster speeds (9.3-35.6% increase for 3.1-4.2 m/s vs. 2.5 m/s). The largest cumulative PFJ kinetics reductions occurred when speeds increased from 2.5 to 3.1 m/s (13.7-14.2%). Running at faster speeds increases the magnitude of peak PFJ kinetics but conversely results in less accumulated force over a set distance. Selecting moderate running speeds (~3.1 m/s) with reduced training duration or an interval-based approach may be more effective for managing cumulative PFJ kinetics compared to running at slow speeds.

GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy.

Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia.

In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates.

Gene-editing technologies, which include the CRISPR-Cas nucleases1-3 and CRISPR base editors4,5, have the potential to permanently modify disease-causing genes in patients6. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis). We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment. In addition to supporting a 'once-and-done' approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide7), our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs.

Lateral tenodesis procedures increase lateral compartment pressures more than anterolateral ligament reconstruction, when performed in combination with ACL reconstruction: a pilot biomechanical study.

OBJECTIVES: Given the common occurrence of residual laxity and re-injury post anterior cruciate ligament reconstruction (ACLR), additional anterolateral procedures are increasingly used in combination with an ACLR. Despite the perception that there is a risk of over-constraining the lateral tibiofemoral (LTF) compartment, potentially leading to osteoarthritis, assessment on their effect on intra-articular compartment pressures is still lacking. Our objective was therefore, through a pilot biomechanical study, to compare LTF contact pressures after the most commonly used anterolateral procedures. METHODS: A controlled laboratory pilot study was performed using 4 fresh-frozen cadaveric whole lower limbs. Through 0° to 90° of flexion, LTF contact pressures were measured with a Tekscan sensor, located under the lateral meniscus. Knee kinematics were obtained in 3 conditions of rotation (NR: neutral, ER: external and IR: internal rotation) to record the position of the knees for each loading condition. A Motion Analysis system with a coordinate system based on CT scans 3D bone modelling was used. After an ACLR, defined as the reference baseline, 5 anterolateral procedures were compared: anterolateral ligament reconstruction (ALLR), modified Ellison, deep Lemaire, superficial Lemaire and modified MacIntosh procedures. The last 3 procedures were randomised. For each procedure, the graft was fixed in NR at 30° of flexion and with a tension of 20 N. RESULTS: Compared with isolated ACLR, addition of either ALLR or modified Ellison procedure did not increased the overall LTF contact pressure (all p>0.05) through the full range of flexion for the IR condition. Conversely, deep Lemaire, superficial Lemaire and modified MacIntosh procedure (all p<0.05) did increase the overall LTF contact pressure compared with ACLR in IR. No significant difference was observed in ER and NR conditions. CONCLUSION: This pilot study, comparing the main anterolateral procedures, revealed that addition of either ALLR or modified Ellison procedure did not change the overall contact pressure in the LTF compartment through 0° to 90° of knee flexion. In contrast, the deep and superficial Lemaire, and modified MacIntosh procedures significantly increased overall LTF contact pressures when the knee was internally rotated.

Different anterolateral procedures have variable impact on knee kinematics and stability when performed in combination with anterior cruciate ligament reconstruction.

OBJECTIVE: The optimal anterolateral procedure to control anterolateral rotational laxity of the knee is still unknown. The objective was to compare the ability of five anterolateral procedures performed in combination with anterior cruciate ligament reconstruction (ACLR) to restore native knee kinematics in the setting of a deficient anterior cruciate ligament (ACL) and anterolateral structures. METHODS: A controlled laboratory study was performed using 10 fresh-frozen cadaveric whole lower limbs with intact iliotibial band. Kinematics from 0° to 90° of flexion were recorded using a motion analysis three-dimensional (3D) optoelectronic system, allowing assessment of internal rotation (IR) and anteroposterior (AP) tibial translation at 30° and 90° of flexion. Joint centres and bony landmarks were calculated from 3D bone models obtained from CT scans. Intact knee kinematics were assessed initially, followed by sequential section of the ACL and anterolateral structures (anterolateral ligament, anterolateral capsule and Kaplan fibres). After ACLR, five anterolateral procedures were performed consecutively on the same knee: ALLR, modified Ellison, deep Lemaire, superficial Lemaire and modified MacIntosh. The last three procedures were randomised. For each procedure, the graft was fixed in neutral rotation at 30° of flexion and with a tension of 20 N. RESULTS: Isolated ACLR did not restore normal overall knee kinematics in a combined ACL plus anterolateral-deficient knee, leaving a residual tibial rotational laxity (p=0.034). Only the ALLR (p=0.661) and modified Ellison procedure (p=0.641) restored overall IR kinematics to the normal intact state. Superficial and deep Lemaire and modified MacIntosh tenodeses overconstrained IR, leading to shifted and different kinematics compared with the intact condition (p=0.004, p=0.001 and p=0.045, respectively). Compared with ACLR state, addition of an anterolateral procedure did not induce any additional control on AP translation at 30° and 90° of flexion (all p>0.05), except for the superficial Lemaire procedure at 90° (p=0.032). CONCLUSION: In biomechanical in vitro setting, a comparison of five anterolateral procedures revealed that addition of either ALLR or modified Ellison procedure restored overall native knee kinematics in a combined ACL plus anterolateral-deficient knee. Superficial and deep Lemaire and modified MacIntosh tenodeses achieved excellent rotational control but overconstrained IR, leading to a change from intact knee kinematics. LEVEL OF EVIDENCE: The level-of-evidence statement does not apply for this laboratory experiments study.

The effect of knee prosthesis design on tibiofemoral biomechanics during extension tasks following total knee arthroplasty.

BACKGROUND: Determine whether the tibiofemoral motion and electromyographic activity of the knee differs in patients with a medial pivot implant, compared to those with cruciate-retaining and posterior-stabilised designs, during knee extension after Total Knee Arthroplasty (TKA). METHODS: An observational study was conducted on a cohort of patients that had undergone TKA for a minimum of 12 months prior. Three matched groups (n = 18) were categorised based on implant type: medial-pivot (MP), posterior-stabilised (PS) and cruciate-retaining (CR). Kinematics, with motion analysis (Vicon, USA) and surface electromyography (Delsys, USA) were assessed during step-ascent and walking tasks. RESULTS: All groups displayed a similar amount of knee extension in both tasks. They also paradoxically produced an average mean internal rotation movement during knee extension in both the step-ascent and walking tasks. The only significant difference was found in the step-ascent task, in which the MP group produced a larger absolute amount of rotation than the CR implant group (P = 0.007), but neither group differed from the PS implant group. The groups did not differ in rotation during the walking task (P > 0.05). The MP group displayed significantly (P < 0.01) greater knee extensor activation during the step-ascent than the PS group. CONCLUSION: The MP design was only significantly different to another implant design for the step-ascent task. Patients with either knee implant types were not strictly limited to producing the traditional "screw-home" mechanism, defined by external rotation during extension. Furthermore, comparison with the non-implant contralateral limb suggested that rotation is not necessarily dictated by implant design.

Multiligament Knee Injury: Injury Patterns, Outcomes, and Gait Analysis.

Multiligament knee injuries remain a challenge for the treating surgeon and little is known about the injury patterns and factors determining clinical and gait outcomes after multiligament knee reconstruction (MLKR). This article aims to identify specificities of this complex injury, in terms of demographics, mechanisms of injury, injury pattern, and associated lesions. The time frame between injury and surgery and distribution of repair versus reconstruction procedures have been analyzed. This study reports functional and clinical outcomes, providing an overview of expected results. Using motion capture gait analysis, knee kinematics and gait characteristics of MLKR patients have been assessed.

Medial patellofemoral ligament reconstruction with or without tibial tubercle transfer is an effective treatment for patellofemoral instability.

PURPOSE: The hypotheses were that medial patellofemoral ligament reconstruction (MPFLr) would improve the long-term symptoms of patellofemoral Instability (PFI) and control patellar tilt, based on computed tomography (CT), and that the addition of a TT transfer, when it is necessary, would not deteriorate the outcome. The purpose of this study was to evaluate the long-term clinical and radiographic outcomes of a large series of MPFLr, either isolated or associated with a TT transfer. METHODS: From 133 MPFLr with a minimum of 4 years postoperatively, three groups were defined: isolated MPFLr, MPFLr with tibial tubercle (TT) medialisation or MPFLr with TT medialisation and distalisation. IKDC and Kujala scores were evaluated. Patellar tilt was evaluated on the patient's preoperative and the last available radiograph, and on CT scan measurements performed preoperatively and at 6-month postoperatively. RESULTS: The mean follow-up was 6.3 ± 1.7 years [4.1-10.3] and four patients reported recurrent patellar dislocation. Between pre and postoperative at last follow-up a significant improvement in IKDC and Kujala functional scores was observed (P < 0.01), with no difference between the three groups. Regarding patellar tilt, there were significant decreases in Laurin and Merchant angles and an improvement of the Maldague stage (P < 0.01). The CT analysis of patellar tilt also demonstrates a significant improvement of the patella tilt (P < 0.01). The control of the patella tilt was correlated with a good functional result (P < 0.01). CONCLUSION: The MPFLr, whether isolated or associated with a TT transfer, provides good long-term clinical and radiological outcomes with a low rate of recurrence. The addition of a TT transfer, when necessary, results in the same good outcomes. This article provides a guide for surgeons evaluating PFI to choose the most appropriate procedure. LEVEL OF EVIDENCE: IV.

Anterolateral Ligament of the Knee: What we Know About its Anatomy, Histology, Biomechanical Properties and Function.

To better control anterolateral rotational instability (ALRI) after anterior cruciate ligament reconstruction (ACLR), many recent studies have examined the anterolateral ligament (ALL). Although some inconsistencies have been reported, anatomic studies demonstrated that the ALL runs on the lateral side of the knee from the femoral lateral epicondyle area to the proximal tibia, between Gerdy's tubercle and the fibula head. Histologic research has characterized the ALL structure, which is more than a simple capsular thickening; it shows a dense collagen core, typical bony insertions and mechanoreceptor function. An analysis of biomechanical properties suggests that the ALL is weaker than other knee ligaments. While its contributions to tibial anterior translation control and to a high grade on the Pivot-Shift test are still unclear, there is a consensus that the ALL controls tibial internal rotation. Further research will be needed to clarify the significance of ALL injuries and to gauge the value of combined ACL and ALL reconstructions.

The relationship between segmental kinematics and ball spin in Type-2 cricket spin bowling.

The techniques of spin bowling in cricket have been largely formulated from the collective intuitions of past players. A standard model of bowling technique has been generally prescribed for both off-spin and leg-spin bowlers, but there has been no biomechanics research to validate this approach. This study measured 20 Type-2 off-spin and 15 Type-2 leg-spin bowlers using a 3D Cortex motion analysis system. Correlation coefficients between segmental kinematic variables and spin rate in the off-spin and leg-spin bowlers revealed that off-spin bowling was associated with an earlier movement time of the thorax, whereas leg-spin bowling was associated with a greater magnitude and earlier movement time of pelvis rotation, as well as a greater magnitude of pelvis-shoulder separation movement. The maximum velocity of rear hip flexion differentiated between both groups of bowlers. The GLM suggested that for off-spinners, rear hip flexion velocity significantly explained the variance in spin rate (subject to sequential timing constraints), while for leg-spinners, the time of maximum rear hip flexion and maximum arm circumduction velocity significantly explained variance in spin rate. This study supports the notion that off-spinners and leg-spinners have significant differences in their joint kinematics, and should not be coached under a one-size-fits-all technical model.

The kinematic differences between off-spin and leg-spin bowling in cricket.

Spin bowling is generally coached using a standard technical framework, but this practice has not been based upon a comparative biomechanical analysis of leg-spin and off-spin bowling. This study analysed the three-dimensional (3D) kinematics of 23 off-spin and 20 leg-spin bowlers using a Cortex motion analysis system to identify how aspects of the respective techniques differed. A multivariate ANOVA found that certain data tended to validate some of the stated differences in the coaching literature. Off-spin bowlers had a significantly shorter stride length (p = 0.006) and spin rate (p = 0.001), but a greater release height than leg-spinners (p = 0.007). In addition, a number of other kinematic differences were identified that were not previously documented in coaching literature. These included a larger rear knee flexion (p = 0.007), faster approach speed (p < 0.001), and flexing elbow action during the arm acceleration compared with an extension action used by most of the off-spin bowlers. Off-spin and leg-spin bowlers also deviated from the standard coaching model for the shoulder alignment, front knee angle at release, and forearm mechanics. This study suggests that off-spin and leg-spin are distinct bowling techniques, supporting the development of two different coaching models in spin bowling.