The extracellular matrix (ECM) provides physical support and imparts significant biochemical and mechanical cues to cells. Matrix stiffening is a hallmark of liver fibrosis and is associated with many hepatic diseases, especially liver cirrhosis and carcinoma. Increased matrix stiffness is not only a consequence of liver fibrosis but is also recognized as an active driver in the progression of fibrotic hepatic disease. In this article, we provide a comprehensive view of the role of matrix stiffness in the pathological progression of hepatic disease. The regulators that modulate matrix stiffness including ECM components, MMPs, and crosslinking modifications are discussed. The latest advances of the research on the matrix mechanics in regulating intercellular signaling and cell phenotype are classified, especially for hepatic stellate cells, hepatocytes, and immunocytes. The molecular mechanism that sensing and transducing mechanical signaling is highlighted. The current progress of ECM stiffness’s role in hepatic cirrhosis and liver cancer is introduced and summarized. Finally, the recent trials targeting ECM stiffness for the treatment of liver disease are detailed. The extracellular matrix (ECM) is a cell-secreted extracellular microenvironment containing various components, such as collagen, fibronectin, laminin, and hyaluronic acid . This exHere we aim to present an overview of the role of ECM stiffness in liver disease. We will start with summarizing the regulators of ECM stiffness in the liver mainly including ECM components, matrix metalloproteinase (MMPs), enzymatic or non-enzymatic crosslinking, and cell properties. We discuss the effects of matrix stiffness on cellular behavior and phenotype in various liver cell types, and the activity of key biomolecules (TGF-β). We review how cells sense ECM mechanical signals and the intercellular mechanotransduction pathways. Finally, we summarize the role of matrix stiffness in liver cirrhosis and hepatic cancer, and potential mechanotherapy. Collectively, this review reinforces the importance of matrix mechanics in hepatic fibrosis, and hopes to provide novel research directions and targets for hepatic disease.Many factors participate in promoting stiffness of the ECM in the pathological liver tissues , includiDuring the fibrotic process, ECM components present an obvious change as the advanced fibrotic hepatic tissue contains approximately 6 times more ECM than the normal, including collagen type I, III, and IV, fibronectin, undulin, elastin, laminin, hyaluronan, and proteoglycans . CollageElastic fiber is a compound consisted of amorphous elastin and fibrous fibrillin, which both are mainly made of smaller amino acids including glycine, valine, alanine, and proline . It is aFibronectin (Fn), mainly secreted and synthesized by endothelial cells, Kupffer cells, and hepatocytes, is a large dimeric glycoprotein existing in its insoluble form as a part of the ECM. The livProteoglycans (PGs) are formed by glycosaminoglycans (GAGs) bound to a core protein, which can be a part of the ECM . PGs havvia preventing collagen degradation through inhibition of MMPs  are normally in a dynamic balance to keep the expression and deposition levels of the ECM in the liver. While fibrosis occurs, their balance will be interrupted and the profibrogenic effects of TIMP-1 are thought to be mediated  of MMPs , which c of MMPs . The imb of MMPs . These fIn addition to the promotion of matrix stiffness by the change of ECM components, the degree of cross-linking of the ECM affects the mechanical characteristics of the matrix.Enzymatic cross-linking is major mediated by LOX, which increases the cross-linking of collagens and subsequently elevate matrix stiffness . The LOX8. The inhibition of TG has been demonstrated to ameliorate liver fibrogenesis in animal models (Transglutaminase (TGs) are calcium-dependent enzymes that catalyze covalent crosslinking between the γ-carboxy-amine group of glutamine residues and the ε-amino group of lysine residues, generating ε-(γ-glutamyl)lysine isopeptide crosslinks . The expl models .Advanced glycation end products (AGEs) are non-enzymatic modifications of protein crosslinking. It differs from enzymatic process as AGEs can form crosslinks throughout the collagen molecule not only at the N- and C-terminal ends of the molecule . Accumulin vitro model for liver cirrhosis, the stiffness of human hepatoma-derived HepG2 cells was significant increased after treatment with three known induction factors   . The lunnd CCl4) . These end CCl4) . Rocky end CCl4) . FurtherHepatic stellate cells (HSCs)are major cellular sources of myofibroblasts driving liver fibrogenesis. In the fibrogenic liver, quiescent HSCs transdifferentiate into proliferative, migratory, and contractile myofibroblasts, manifesting pro-fibrogenic transcriptional and secretory properties, and secrete ECM molecules . HSC becHepatocytes are the main parenchymal cells and functional units of the liver. Previous studies have shown that hepatocytes contributed to the process of liver fibrosis through changing migratory behavior and biological functions. Hepatocytes are sensitive to substrate stiffness . Tingtinin vitro study confirmed that a stiff matrix could strengthen the M2 polarization and induce LOXL2 expression through integrin β5-FAK-MEK1/2-ERK1/2 pathway (In hepatocellular carcinoma (HCC) tissues, macrophage showed an M2 polarization, and the  pathway . This st pathway . All theTGF-β1, a 25-kDa homodimeric protein, has been involved in hepatic fibrogenesis, regulation of liver cell growth, tumor development, and induction of hepatocellular apoptosis . The TGFIntegrin-based focal adhesion (FA) complexes are the major cellular components responsible for detecting mechanical signals produced by the ECM. In mousThe small Rho GTPase RhoA/Rho kinase (ROCK)-mediated mechanotransduction pathway is activated by matrix stiffness . The subAREG and CTGF to promote liver fibrogenesis (Yes-associated protein (YAP) and its close paralog transcriptional coactivator with PDZ-binding motif (TAZ) are activated in HSCs in response to matrix stiffening . Immunohogenesis .AREG and CTGF, and the overexpression of the two genes promotes the liver cirrhosis process  offer valuable alternatives to detect and monitor portal hypertension. The thresholds of liver stiffness>15 kPa is highly suggestive of advanced chronic liver disease, and>20–25 kPa indicates a high likelihood of clinically significant portal hypertension . MoreoveIncreased matrix stiffness is a mechanical feature of solid tumors, including liver cancer. HCC cells cultured on stiff matrix showed a significantly higher proliferative index than that on soft matrix . A rigidActivated HSCs in the liver microenvironment regulate HCC growth by paracrine mechanisms, including secreting growth factors, ECM, and cytokines . The mecMatrix mechanical properties are typically reported as elastic modulus  or shear modulus (G). There is an equation between elastic modulus and shear modulus, and the elastic modulus is approximately three times the shear modulus for isotropic and incompressible materials. Several mechanical test methods have been used to measure the matrix stiffness, including elastography and atomic force microscopy (AFM) methodology .Ultrasound elastography (USE) is an imaging technology sensitive to organ mechanical property that was first introduced in the 1990s . Shear wMagnetic resonance elastography (MRE) uses a modified phase-contrast imaging sequence to detect propagating shear waves within the liver. It provides parameters with high sensitivity to elasticity, viscosity, and poroelastic properties for the evaluation of structural variations in livers at multiple scales . MRE hasin vitro to determine the stiffness of cells and extracellular protein scaffolds (One of the major drawbacks of common liver stiffness measurements including USE and MRE is that they do not provide cellular-level resolution of stiffness heterogeneity in the liver . During caffolds .As the importance of matrix stiffness in mediating the liver fibrotic process, targeting the liver mechanics is a promising therapy to prevent or even reverse liver fibrosis. There are two main methods to interrupt the pathogenesis including decreasing the matrix stiffness directly and inhibiting the mechanotransduction pathways.To reduce the matrix stiffness, targeting the LOXL2-induced crosslinking through anti-LOXL2 antibody AB0023 has been demonstrated effective in reliving liver fibrosis in animal models . AnotherFasudil is a clinically approved small-molecule inhibitor of ROCK. Treatment with Fasudil significantly attenuated the activation of ROCK and alleviates hepatic fibrosis in diabetic rats . Other sin vitro and can alleviate the fibrogenesis in an animal model with liver fibrosis (YAP/TAZ pathway is activated in liver fibrosis, and the suppression of YAP levels by transfecting siRNAs or pharmacological inhibition of YAP by verteporfin can effectively decrease the activation of HSCs fibrosis . Omega-3fibrosis . These fin vitro or animal models, there is still a lot of work to do to further verify their efficacy.The mechanical property of the ECM affects the phenotype and function of various liver cell types and is associated with hepatic disease including cirrhosis and carcinoma. Currently, the knowledge of mechanosensing and intercellular mechanotransduction mechanisms remains limited. A better understanding of how hepatic cells sense matrix stiffness and translate matrix mechanical cues into the cellular responses can provide us with more opportunities to develop accurate drugs or inhibitors targeting altered ECM mechanics in liver diseases. Though some intervention of matrix stiffness has achieved initial effects


Background: It is still unclear whether optimal medical therapy (OMT) after percutaneous coronary intervention (PCI) has beneficial effects on long-term clinical outcomes in patients aged ≥80 years with coronary artery disease (CAD). Methods: This study analyzed the time to the first major adverse clinical event including death or nonfatal myocardial infarction (MI), for up to 3 years after PCI using multicenter registry data. Data for 1056 patients aged > 80 years successfully treated with PCI were included in the analysis. OMT was defined as a combination of antiplatelet drug, statin, beta-blocker, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Results: In total, 204 (19%) patients in this study received OMT and 852 (81%)　received sub-OMT. During a median follow-up of 725 days, adverse clinical events occurred in 183 patients . Kaplan-Meier analysis showed that patients who received OMT had a lower probability of adverse clinical events than those who received sub-OMT . Propensity score matching yielded 202 patient-pairs treated with OMT or sub-OMT, in whom 64 adverse clinical events  occurred during follow-up. OMT remained significant in the reduction of the risk of adverse clinical events in a multivariate Cox proportional hazards model . Conclusions: OMT after PCI was associated with significantly fewer adverse clinical events, including all-cause death and nonfatal MI, in patients aged ≥ 80 years with CAD. OMT might be safe and effective for these very elderly patients. The aEach of the components of optimal medical therapy (OMT), namely, an antiplatelet agent, statin, beta-blocker, and angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin II receptor blocker (ARB), has been associated with a significant reduction in the risk of cardiovascular events . MoreoveTherefore, in this study, we sought to determine whether OMT is associated with a reduction in adverse clinical events, including all-cause death and nonfatal myocardial infarction (MI), among patients aged ≥80 years with CAD treated by PCI using propensity-score matched data from the Japanese multicenter observational PCI registry.22.1The FUJISUN registry is a multicenter prospective observational registry containing data collected at the University of Yamanashi Hospital and 5 collaborating hospitals in Yamanashi and Shizuoka prefectures in Japan. This registry was designed to record clinical characteristics, PCI-related data, and outcomes after PCI. All prescribed medications and PCI procedures were at the discretion of the patients’ primary physicians. A data manager at each hospital is responsible for collecting clinical and PCI-related data. The FUJISUN registry contains data for 7173 patients who underwent PCI for CAD at any of the attending hospitals from May 2008 to December 2018. This registry is registered in the UMIN Clinical Trials Registry (unique identifier UMIN000047369). The protocol used to collect the FUJISUN data are approved by the ethics committees at all attending hospitals and performed in accordance with the principles outlined in the 1975 Declaration of Helsinki.2.2This study was a sub-analysis of the FUJISUN registry data. Patient data were analyzed according to whether OMT was administered (OMT group) or sub-OMT was provided (sub-OMT group) at discharge. OMT was defined as use of all four medications, namely, an antiplatelet agent, a statin, a beta-blocker, and an ACE-I/ARB. Sub-OMT was defined as omission of any of these four medications. We retrospectively investigated the time to the first major adverse clinical event for up to 3 years after enrollment. Adverse clinical events were defined as all-cause death and nonfatal MI. If the first hospitalization for MI culminated in death from progressive pump failure or sudden cardiac death during the follow-up period, the event was registered as death. Nonfatal MI was diagnosed by typical ischemic chest pain with a creatine kinase-MB level at least twice the upper limit of normal, a troponin T level >0.1 ng/ml, or characteristic ischemic changes on the electrocardiogram at the time of the event. Follow-up data were obtained by the patients’ primary physicians and collected by the data managers at each hospital. All endpoint data were strictly checked for accuracy, consistency, and completeness of follow-up by the investigators. Two of the investigators (T.N. and T.K.) checked all the data, carried out the analyses, and maintained the security of the data files. The need for written informed consent was waived because of the retrospective observational study design. Patients who died within 30 days after PCI and those receiving hemodialysis were excluded.2.3t-test and frequencies using the chi-squared test. Kaplan-Meier survival analyses were performed according to number of OMT medications used and whether the patients received OMT or sub-OMT. The ability of the clinical parameters and use of OMT were assessed using univariate and multivariate Cox proportional hazard models. The univariate Cox hazards analyses included age, male sex, history of MI, history of stroke, prior PCI, prior CABG, peripheral arterial disease (PAD), body mass index, New York Heart Association (NYHA) class II–IV, number of diseased vessels, left main coronary artery disease, left ventricular ejection fraction (LVEF) < 40%, current smoking, diabetes mellitus, hypertension, estimated glomerular filtration rate (eGFR), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, HbA1c, ST-elevation myocardial infarction (STEMI), and use of OMT. Variables with p-values <0.10 were selected in a stepwise multivariate Cox proportional hazards analysis with backward elimination. The hazard ratio (HR) and 95% confidence interval (CI) were estimated by 10 years for age, 10 mg/dL for LDL cholesterol and HDL cholesterol, and 10 ml/min/1.73 m2 for eGFR. Dichotomous variables were coded 1 for the presence of the factor and 0 for its absence. All probability values presented are two-tailed, with statistical significance being inferred at p < 0.05. The use of OMT were at the discretion of the primary physicians. Therefore, we calculated propensity scores to reduce selection bias with regard to patients treated with OMT. The propensity scores for each patient were calculated from a logistic regression model to predict the probability of being treated with OMT. In this logistic model, 20 covariates  were used to calculate the propensity score. We matched patients using the nearest neighbor method with a 1:1 matching procedure without replacement and a caliper width of 0.05, calculated by 0.2 × standard deviation of the logit of the propensity score. Most of the statistical analyses were performed using STATA 16.0 software .All descriptive data are expressed as the mean ± standard deviation or as the frequency (percentage). Mean values were compared between the two groups using the unpaired 33.1This study initially included 1387 patients aged ≥80 years with CAD who were successfully treated with PCI during the study period. Based on our exclusion criteria, data for 96 patients who died within 30 days after PCI and 42 who received hemodialysis were excluded. Data for a further 193 patients who had been lost to follow-up were also excluded. Data for the remaining 1056 patients were included in the analysis. Two hundred and four (19%) of these patients received OMT and 852 (81%) received sub-OMT . The bas3.2The baseline clinical characteristics are compared in 3.3Adverse clinical events occurred in 183 patients  during 30–1095 days of follow-up . Kaplan-Meier analysis showed that the probability of adverse clinical events was significantly lower in patients treated with OMT than in those treated with three, two, or one of the components of OMT  than in the sub-OMT group (n = 202), which is similar to the results obtained for all the study patients  from the Japan Society for the Promotion of Science, Japan.This study was supported by a Takamitsu Nakamura: Conceptualization, Methodology, Writing- Original draft preparation. Takeo Horikoshi: Data analysis, Writing- Original draft preparation. Tsuyoshi Kobayashi: Investigation, Toru Yoshizaki: Investigation, Data curation, Manabu Uematsu: Investigation, Writing- Reviewing and Editing, Yosuke Watanabe: Investigation, Writing- Reviewing and Editing, Jun Nakamura: Investigation, Aritaka Makino: Investigation, Yukio Saito: Investigation, Jun-ei Obata: Investigation, Takao Sawanobori: Investigation, Hajime Takano: Investigation, Ken Umetani: Investigation, Akinori Watanabe: Investigation, Tetsuya Asakawa: Investigation, Akira Sato: Supervision.


The stiffness of lower limb joints is a critical characteristic of walking. To investigate the potential of establishing a simple and universal model to describe the characteristics related to vertical vibration during human walking, vertical stiffness is introduced at the knee and hip. A multi-mass-spring model of the human body is established in the vertical direction. In the Fourier form, results of experiments on 14 healthy adults show that the vertical displacements of joints are a function of the leg length and walking cadence, while the ground reaction force is a function of the body weight and walking cadence. The obtained universal equations of vertical displacement and ground reaction force are employed as the input parameters to the proposed multi-mass-spring model. Thus, the vertical stiffness in the knee and hip can then be estimated simultaneously by the subject’s weight, leg length, and walking cadence. The variation of vertical stiffness shows different time-varying trends in different gait phases across the entire gait cycle. Finally, the proposed model for vertical stiffness estimation is validated by the vertical oscillation of the pelvis. The average error across three gait cycles for all subjects is 20.48%, with a standard deviation of 5.44%. These results display that the vertical stiffness of knee and hip across the entire gait cycle can be directly estimated by individual parameters that are easy to measure. It provides a different view of human walking analysis and may be applied in future pathological gait recognition, bipedal robots, and lower limb exoskeletons. Walking is one of the most common daily activities of humans, and a large number of engineered locomotion systems are designed to emulate human walking, such as bipedal walkers ,2, bioloAt times, vertical stiffness and leg stiffness were used interchangeably for jumping activities, but it is actually vertical stiffness rather than leg stiffness . MoreoveAs reviewed in , loadingFrom the above studies, it can be summarized that the vertical characteristic is crucial for assessing the walking ability of humans. However, the vertical characteristic of joints has not been studied since the reported ‘vertical stiffness’ was at the whole-body level and the joint stiffness was focused on the moment and angle applied to them. In addition, all kinds of the mentioned ‘stiffness’ were calculated only at the stance phase and based on the measured GRF, displacement, angle, and moment, which are expensive to measure.Therefore, the objective of this study is twofold: (i) to establish a universal gait dynamic model that can estimate both the immeasurable stiffness and measurable displacement, and (ii) to estimate the vertical stiffness of the knee and hip during walking by the individual parameters. Based on these concepts, the vertical stiffness of lower limb joints is hypothesized to be directly estimated by individual parameters like leg length, body weight, and walking cadence.To evaluate the vertical stiffness of lower limb joints continuously and completely, a multi-mass-spring model of the lower limbs is established. Then the vertical displacements of the lower limb during walking are collected and summarized into a uniform equation. Moreover, the vertical stiffness of the hip and knee is derived. The entire process is displayed in This study was developed according to the Declaration of Helsinki, and all the subjects signed an approved informed consent. Lower limb displacement was measured in 14 young healthy subjects . Subjects were free of any lower-limb musculoskeletal-related injury for at least 3 years before testing.In a gait laboratory, subjects walked at their preferred speed while wearing 16 retroreflective markers, as shown in A simple model that can characterize the dynamic behaviors of the lower limbs during walking is the foundation for understanding human motion. To describe the kinematics and kinetics in the vertical direction of both the left and right lower limbs, a multi-mass-spring model that includes both the knee and hip joints of the lower limbs is proposed as shown in m is the mass of the trunk, upper limbs, and head in total, tm and sm are the masses of the thighs and shanks, respectively, based on the relationship of the segment mass to body mass ‘M’ given by Leva [ltx and rtx denote the vertical displacements of the left and right thigh, respectively; lsx and rsx refer to the vertical displacements of the left and right shanks, respectively; lF and rF are the left and right GRF in vertical, respectively; lhk and rhk indicate the vertical stiffness of left and right hip, respectively; and lkk and rkk correspond to the vertical stiffness of left and right knee, respectively.The analytical formula can then be written as: by Leva , mmale=0Then the vertical stiffness of the hip and knee are derived as follows:The solution to vertical stiffness in the knee is as follows:Moreover, the pelvis displacement can be derived as:The stiffness of the hip can be described as:The collected gait signals in Because the collected gait signals begin and end with standing, the initial and final effects should be eliminated by selecting data points from the median segment. Firstly, the starting point of stable walking and 2 entire gait cycles are selected for analysis. Then the fast Fourier transformation (FFT) is used to transform the signal into the frequency domain since gait is quasiperiodic. The frequency and amplitude of major harmonics are then recognized from the frequency domain, as displayed in N is the number of the harmonic order. The amplitude is assumed to be proportional to the leg length; therefore, the amplitude of each harmonic in the series is then divided by the leg length of the subject, and thus the ratio of amplitude to leg length is obtained. Then the mean of the ratio and the initial phase of all the subjects are calculated for a general description of lower limb displacements. Finally, the change in vertical displacement can then be derived as:l is the leg length of the subject, f refers to the real walking cadence, and it is the number of strides in one second; thus, it can also be calculated by the gait cycle time T since It can be observed in t in Equation (8) becomes , which means F refers to the VGRF of one foot and rF is the VGRF of the other foot, M is the mass of the body, and The measured VGRF is also a quasiperiodic signal, as displayed in Walking is commonly studied as a repetitively periodic activity using the “gait cycle” . The gaiF indicates VGRF, s refers to the shank, and t corresponds to the thigh. Other theoretical equations, like the vertical stiffness of the right knee and hip, are obtained with the same process as Equation (12).The vertical oscillation of both the left and right thighs and shanks, as well as the VGRF, are represented in Equations (8)–(11) by individual parameters in a universal form. Therefore, by substituting Equations (8)–(11) into Equations (3)–(5), the vertical stiffness of the hip and knee can then be theoretically derived. Here, an equation of vertical stiffness for the left knee is displayed as:p > 0.05) [The distributions of individual parameters such as body weight and height are near normal since they were tested using the Shapiro–Wilk test ( > 0.05) . To obtaAs obtained from This unification of the quantitative description of human lower limb oscillation during overground walking helps to establish a general representation of the dynamic characteristics such as stiffness.The vertical displacements of the thigh and shank can be represented by the leg length and walking cadence, as illustrated in Equation (12). As shown in 6 N/m, and its fluctuation accounts for half of the gait cycle. The stiffness in another half cycle is approaching zero, which seems unchanged. To study the unchanged section, the highly fluctuating section is hidden, as shown in The empirical coefficients and initial phases of thighs and shanks shown in The vertical stiffness of the hip is extremely high when its corresponding leg goes from the mid-stance phase to the mid-swing phase. From the mid-swing phase to the mid-stance phase, the vertical stiffness of the hip is rather small at about 5 N/m but with a regular shape like ‘w’. There is a discontinuity of the first kind at the mid-stance phase and the mid-swing phase. Furthermore, the vertical stiffness between the right and left hips, like the knee, has a time delay for half of the gait cycle. During walking, the vertical stiffness of the knee and hip varies with the gait phase (time).t’ in Equation (8) is set to 3.5 s in order to include three strides. With the empirical coefficients and phases in It is reasonable to validate the model by evaluating the pelvis displacement estimated by the model because the vertical stiffness has been difficult, if not impossible, to measure during walking until now. Errors between the model solution and the measured displacement of the pelvis are calculated. The measured displacement was collected in the experiment in t equals 3.5 s as mentioned before, sF equals the sampling frequency of the motion capture system, which is 100, and subscript nt refers to the number of time points. The errors for all the subjects are shown in It can be observed that the model solution of the pelvis displacement is approximately consistent with the measured displacement. This proved that the proposed model could characterize walking characteristics such as vertical stiffness and pelvis oscillation by leg length, body weight, and walking cadence. Moreover, to illustrate the universality and stability of the identification process, the model error is calculated from the solved pelvis displacement and the measured pelvis displacement as follows:The primary aim of this study is to estimate the vertical stiffness of the knee and hip using individual parameters that are easy to measure during walking. To achieve this aim, a multi-mass-spring model was established. Furthermore, the Fourier series was used to fit the vertical displacements of lower limb segments and VGRF required in the established model with individual parameters such as leg length and walking cadence. According to the established model, the vertical stiffness of the knee and hip was estimated by leg length, body weight, and walking cadence across the entire gait cycle. Furthermore, the established lower limb model was validated by its solution of pelvic displacement and real measurement.3 to 1 × 105 N/m) of the leg stiffness achieved the closest GRF profile [Firstly, our results implied that the established multi-spring model is effective at characterizing walking characteristics. There were different dynamic models for stiffness calculation, as shown in  profile . This su profile ,20. They profile  and to pAside from the ability of the proposed model in our study to be consistent across the entire gait cycle, the vertical stiffness of joints in our study was a different concept from traditional joint stiffness. Traditionally, the stiffness of the knee and hip was calculated as the quotient of the moment and joint angle change in the sagittal plane, and the moment was calculated by the trajectory data and the GRF . This joDuring the model solution, the vertical oscillations of lower limb segments and VGR were utilized. The vertical oscillation of lower limb segments was fitted by the Fourier series with leg length and walking cadence, while the VGRF was represented with body weight and walking cadence. The amplitude coefficient and initial phases shown in Since the vertical stiffness of the knee and hip was obtained solely by individual parameters such as body weight, leg length, and walking cadence, which are all easy and cheap to measure, it implies that VGRF, body weight, and vertical oscillation of body segments have inherent relationships. This is similar to the previous research. The body weight influenced the GRF, and the vertical displacement of the body for a given individual was determined by the effective leg length . FurtherMoreover, when compared to previous studies, our study illustrates the time-varying process of vertical stiffness corresponding to the gait phase across the entire gait cycle. In vertical, knee stiffness is near zero in the midstance and high in the terminal stance and initial swing. These findings are consistent with previous research, which found that the knee stiffness determined by the slope of the knee moment-angle curve is approximately zero at the start of the stance and increases in the late stance . In addiThe contributions of this study are as follows: (1) the uniform equation to depict the vertical oscillations and VGRF of different people is obtained with individual walking cadences as well as leg length and body weight, respectively; (2) the multi-mass-spring model is established to identify the vertical stiffness of hip and knee simultaneously, and this stiffness can be represented by the body weight, leg length, and walking cadences; and (3) the obtained vertical stiffness is validated by the comparison between the estimated displacement and the measured displacement of the pelvis.There are also some limitations that need to be considered. The main limitation is the size of the subject. Fourteen subjects walked at their preferred speed, obtaining a homogeneous sample. The analyses could be generalized only to the range of age, height, and walking cadence that the statistical significance supports. Similar estimations could be carried out for other groups, such as older adults and children. Another limitation is that several simplifications were employed. Both the mass and length of the left and right lower limbs were regarded as the same, and the ankle and foot were ignored. A more sophisticated model could be considered to take the asymmetrical factors and eliminated terms into account.In summary, the vertical stiffness of the knee and hip can be simultaneously estimated by a multi-mass-spring model. It has been found that the vertical oscillations of lower limb segments were universally expressed by walking cadence and leg length, while vertical ground reaction force was represented by walking cadence and body weight. Moreover, the vertical stiffness of the knee and hip were finally estimated by the walking cadence, leg length, and body weight. The variation of the estimated vertical stiffness across the entire gait cycle displayed different trends toward different gait phases. Additionally, the proposed model was validated efficiently by the estimated vertical oscillation of the pelvis across three gait cycles for the 14 different subjects. The remarkable results obtained in this study represent a different view for future studies on human walking analysis. In the near future, more sophisticated models that consider ankle and damping will be constructed and extended to more human groups.


Magnetic resonance imaging (MRI) has allowed the early detection of PCa to evolve towards clinically significant PCa (csPCa), decreasing unnecessary prostate biopsies and overdetection of insignificant tumours. MRI identifies suspicious lesions of csPCa, predicting the semi-quantitative risk through the prostate imaging report and data system (PI-RADS), and enables guided biopsies, increasing the sensitivity of csPCa. Predictive models that individualise the risk of csPCa have also evolved adding PI-RADS score (MRI-PMs), improving the selection of candidates for prostate biopsy beyond the PI-RADS category. During the last five years, many MRI-PMs have been developed. Our objective is to analyse the current developed MRI-PMs and define their clinical usefulness through a systematic review. We have found high heterogeneity between MRI technique, PI-RADS versions, biopsy schemes and approaches, and csPCa definitions. MRI-PMs outperform the selection of candidates for prostate biopsy beyond MRI alone and PMs based on clinical predictors. However, few developed MRI-PMs are externally validated or have available risk calculators (RCs), which constitute the appropriate requirements used in routine clinical practice.MRI can identify suspicious lesions, providing the semi-quantitative risk of csPCa through the Prostate Imaging-Report and Data System (PI-RADS). Predictive models of clinical variables that individualise the risk of csPCa have been developed by adding PI-RADS score (MRI-PMs). Our objective is to analyse the current developed MRI-PMs and define their clinical usefulness. A systematic review was performed after a literature search performed by two independent investigators in PubMed, Cochrane, and Web of Science databases, with the Medical Subjects Headings (MESH): predictive model, nomogram, risk model, magnetic resonance imaging, PI-RADS, prostate cancer, and prostate biopsy. This review was made following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria and studied eligibility based on the Participants, Intervention, Comparator, and Outcomes (PICO) strategy. Among 723 initial identified registers, 18 studies were finally selected. Warp analysis of selected studies was performed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Clinical predictors in addition to the PI-RADS score in developed MRI-PMs were age, PCa family history, digital rectal examination, biopsy status , ethnicity, serum PSA, prostate volume measured by MRI, or calculated PSA density. All MRI-PMs improved the prediction of csPCa made by clinical predictors or imaging alone and achieved most areas under the curve between 0.78 and 0.92. Among 18 developed MRI-PMs, 7 had any external validation, and two RCs were available. The updated PI-RADS version 2 was exclusively used in 11 MRI-PMs. The performance of MRI-PMs according to PI-RADS was only analysed in a single study. We conclude that MRI-PMs improve the selection of candidates for prostate biopsy beyond the PI-RADS category. However, few developed MRI-PMs meet the appropriate requirements in routine clinical practice. Prostate cancer (PCa) suspicion, based on elevated serum prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE), followed by systematic prostate biopsy, has been the classic strategy for early detection of PCa . HoweverMost relevant progress in the early detection of csPCa has come from pre-biopsy multiparametric magnetic resonance imaging (mpMRI), which can identify suspicious lesions, providing the semi-quantitative risk of csPCa through the Prostate Imaging-Report and Data System (PI-RADS) . AdditioPredictive models (PMs) are the only tool providing the individual risk of csPCa. These PMs have usually been presented through nomograms ; howeverTwo independent reviewers (M.T. and J.M.) searched the literature to retrieve all relevant studies published before 31 March 2022. This search was conducted in PubMed, Cochrane, and Web of Science databases, using the Medical Subject Headings (MeSH): nomogram, risk model, magnetic resonance imaging, PI-RADS, prostate cancer, and prostate biopsy. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria  were folThe study eligibility was based on the Participants, Intervention, Comparator, and Outcomes (PICO) strategy . The incThe flow diagram of study selection is illustrated in Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was used as an evidence-based quality assessment tool . QUADAS-The characteristics of development cohorts of each MRI-PM regarding size, prostate biopsy status , MRI characteristics and reporting methods, prostate biopsy scheme and approach, types of guided biopsies, and the definition of csPCa are summarised in In addition, the specificity corresponded to 95% sensitivity of each MRI-PM and avoided prostate biopsies are summarised in > 3+4) detection was 24.4%. Age, DRE, serum PSA, and prostate volume (PV) assessed from the transrectal ultrasound (TRUS) just before prostate biopsy, were the clinical predictors, in addition to the retrospective review of PI-RADS v1 as grade 0 (PI-RADS 1 and 2), grade 1 (PI-RADS 3), and grade 3 (PI-RADS 4 and 5). The AUROC of MRI-PM compared to that of the baseline model of clinical predictors were 0.87 and 0.85, respectively (p = 0.001). DCAs suggested the net benefit of MRI-PM over MRI and biopsy of all men from the risk threshold of 5%. At 95% sensitivity, the specificity was 38%, and the percentage of avoided biopsies was 19.8%. This model was not externally validated, and no RC was designed. Also in 2016, Kim et al. [p = 0.06). At 95% sensitivity, the specificity was 20% and the rate of avoided biopsies was 15.1%. This MRI-PM was not externally validated and the current available PCPT-RC v.2.0 does not incorporate the MRI findings.In 2016, Fang et al.  developem et al.  incorpor> 7 or maximal core cancer length > 6 mm) in a cohort of 615 suspected. PCa men (21.3% with prior negative prostate biopsy) subjected to transperineal template biopsy (24–40 cores) and 2- to 5-core cognitive-guided biopsies in Essex, UK, between 2012 and 2015. The rate of detected csPCa was 38.5%. The AUROC of MRI improved from 0.87 to 0.92. With the 30% csPCa risk threshold, 34.6% of prostate biopsies were avoided, and 2.5% of csPCa were missed. No external validations were made, and no RC was designed. Niu et al. [> 3+4) among 151 biopsy-naïve men with serum PSA between 4 and 10 ng/mL. After mpMRI, a transrectal 1 or more-core cognitive-guided biopsy of suspicious lesions and/or a 12-core systematic biopsy were performed between 2014 and 2015 in Chengdu, China. The detection rate of csPCa was 21%, and the predictors of the model were age, PSAD, and PI-RADS v2. The AUROC of MRI increased from 0.76 to 0.85 when the model included the age and PSAD. The MRI-PM with 87.3% sensitivity obtained from the 36% csPCa threshold avoided 64.9% of prostate biopsies. The model was internally validated in a subsequent series of 74 men in the same centre; however, it was not externally validated, and no RC was designed. Radtke et al. [> 3+4) after sharing the same clinical predictors used by the Rotterdam RC-3 and RC-4 among 1159 consecutive suspected PCa men subjected to mpMRI reported by PI-RADS v1, and transperineal 24-core template biopsies and 2 to 4 additional cognitive-guided biopsies to suspicious lesions, between 2012 and 2015, in Heidelberg, Germany. The rates of detected csPCa were not provided; however, the model developed from 660 biopsy-naïve men reached an AUC of 0.83 compared to the 0.81 obtained from 335 men with previous negative prostate biopsy. Both models presented a net benefit over mpMRI from 16 and 12% risk of csPCa, respectively. Additionally, their specificities were 35% and 25.5%, respectively, at 95% sensitivity. The rates of avoided biopsies and missed csPCa were not provided. These models have not been externally validated and no RC has been designed. Truong et al. [> 3+4) was detected. The predictors shared in the model were age, serum PSA, PV, and PI-RADS v2. The AUROC to discriminate csPCa was 0.83; with a 40% threshold, 36.5% of prostate biopsies were avoided while missing 6.3% of csPCa. The model exhibited a net benefit over MRI from the 3% risk threshold. External validation of the Truong’s MRI-PM was carried out by Bjurlin et al. [> 7 and >5% of G 4, and maximal core cancer length > 20% or 7 mm) was 37.9%. The baseline model with clinical predictors presented an AUROC of 0.80, increasing to 0.88 when the MRI was shared (p < 0.001). A threshold of 12.5% of csPCa avoided 34.3% of prostate biopsies while missing 6.1% of csPCa. The MRI-PM exhibited a net benefit over MRI and biopsy of all men from the csPCa risk of 3%. This model was externally validated in a cohort of 198 men, from another hospital in Sidney, with an AUROC of 0.86. No RC was designed.In 2017, six MRI-PMs were developed. Bjurlin et al.  developeu et al.  developee et al.  developeg et al.  developen et al.  also rep> 3+4) was 25.5%. The AUROC of MRI-PM increased to 0.92 from the 0.88 of the baseline model of clinical predictors. DCA showed a net benefit of MRI-PM over the baseline model from the csPCa risk threshold of 10%. At 95% sensitivity of the MRI-PM, the specificity was 63%, and 48% of prostate biopsies were avoided. No external validation of this MRI-PM was made, and RC was not designed. Also in 2018, Mehralivand et al. [> 3+4) was 48.3%. The MRI-PM, including DRE, biopsy status, ethnicity, PSA, and PI-RADS v2, exhibited an AUROC of 0.84 compared to 0.72 of the baseline model without MRI (p < 0.001). At 96% sensitivity of the MRI-PM, the specificity was 54%, and 30% of prostate biopsies were avoided. DCA showed the net benefit of MRI-PM over the baseline model and MRI alone from the 10% risk threshold of csPCa. This MRI-PM was externally validated in 251 men from two institutions in Chicago, IL and Birmingham, AL, where the incidence of csPCa was 41.6 and 36%, respectively. No RC was designed.In 2018, Huang et al.  developed et al.  develope> 2) including bpMRI, reported by PI-RADS v2 and stratified as negative (score 1–2), equivocal (score 3), and po- sitive (score 4–5), in addition to age, DRE, and PSAD, in 876 biopsy-naïve men from Herlev, Denmark. Suspected PCa men over 75 years or PSA serum levels behind 50 ng/mL were excluded. These men were subjected to transrectal 2-core cognitive-guided biopsies for each suspicious lesion and/or 10-core systematic biopsies between 2015 and 2017. The AUROC of 0.85, obtained from the baseline model with clinical predictors, increased to 0.89 when the MRI was shared (p < 0.001). The net benefit of MRI-PM over MRI alone, baseline model, and biopsy of all men were observed from a 5% risk of csPCa. At 96% sensitivity, the MRI-PM presented a specificity of 60%, and 38% of prostate biopsies were avoided. No external validation was performed, and no RC was designed. Alberts et al. [> 3+4) was detected in 42% and 29% respectively. These two models incorporated prebiopsy MRI, mostly multiparametric and reported by PI-RADS v1. Transrectal cognitive, software, or in bore-guided biopsies and/or 12-core systematic biopsies were performed, between 2012 and 2017, in Düsseldorf and four Dutch cities. The Rotterdam RC-3 improved its AUROC from 0.76 to 0.84 when the MRI was shared, while the RC-4 improved from 0.74 to 0.85. DCAs showed a net benefit of MRI-PM over RC-3 and RC-4 from the respective 10% and 4% csPCa risk thresholds. At 92% sensitivity, 24% of prostate biopsies were avoided in biopsy-naïve men, and at 96% sensitivity, 41% of prostate biopsies were avoided in men with prior negative prostate biopsy. Both MRI-PMs have been incorporated into the current Rotterdam MRI-RC, which has been externally validated in populations from China, Italy, and the UK [> 2) in 346 men with suspected PCa, 52.8% with prior negative prostate biopsy in whom transrectal 2-core cognitive-guided biopsies to suspicious lesions and/or 12-core systematic biopsy were performed between 2015 and 2016 in Barcelona, Spain. The rate of detected csPCa was 32.6%. Age, DRE, PSAD, biopsy status, and PI-RADS v2 were the individual predictors of csPCa included in the model. The AUROC of MRI-PM was 0.88, and CUCs showed at 10% csPCa risk threshold that 30% of prostate biopsies were avoided, while 95% of csPCa were de-tected. This model was not externally validated, and no RC is available.In 2019, Boesen et al.  developes et al.  adjustedd the UK ,38,39. F< 6) and high-grade (GS > 3+4) among 257 newly diagnosed PCa between 2017 and 2019 in Wuhan, China. PCa was diagnosed after prebiopsy mpMRI and no referred type and approach of prostate biopsy. The rate of high-grade PCa was 59.2%. This PM shared serum PSA, PV, and PI-RADS v.2. The AUROC was 0.84, and the sensitivity and specificity of the greatest discriminative threshold were 79.4% and 77.6%, respectively. A median serum PSA of 51 ng/mL was noted in this development cohort. The corresponding sensitivity at 95% specificity of the model was 40%, and 19% of overdetection of low-grade PCa would be avoided. The net benefit of this MRI-PM developed was not analysed, and external validation of the designed nomogram was carried out on 57 patients in Xiangyang, China. The sensitivity to predict high-grade PCa in this validation cohort was 80%, the specificity was 77%, and the correlation between the prediction threshold and high-grade PCa was 57%. Noh et al. [> 3+4), sharing age, PSAD and bpMRI reported with PI-RADS v2 in 300 suspected PCa men, with 28.3% having a previous negative prostate biopsy, from Seoul, Korea. These men were subjected to transperineal up to 10-core software-guided prostate biopsies to PI-RADS > 3 lesions and/or from 14 to 20-core template-prostate biopsy between 2017 and 2019. The csPCa detection rate was 34%. The AUROC of the MRI-PM model was 0.86 compared to 0.79 of the clinical predictors model. The MRI-PM resulted in a net benefit over MRI and the clinical predictors model from a 10% csPCa threshold. The 95% sensitivity threshold provided 52% specificity and avoided 30% of prostate biopsies. External validation of this MRI-PM has not been done, and no RC has been designed.In 2020, Chen et al.  developeh et al. , also in> 4+3 or maximum cancer core length > 6 mm, and 44.3% of csPCa was detected. The AUROC of MRI alone (0.82) increased to 0.86 when MRI and clinical predictors were combined. DCAs showed a net benefit for MRI-PM over MRI from the csPCa risk threshold of 35%. At 95% sensitivity, the MRI-PM presented 73% specificity, and 43% of prostate biopsies were avoided. This model was not externally validated, and no RC was designed.In 2021, Sakaguchi et al.  develope> 2, in the development cohort was 36.9% and 40.8% in the validation cohort. The developed model shared the independent predictors of age, PCa family history, biopsy status, DRE, serum PSA, PV, and PI-RADS v2. Prostate biopsies were performed by transrectal approach with two to four-core cognitive-guided biopsies to suspicious lesions and/or twelve-core systematic biopsy. The AUROC of MRI-PM increased that of MRI from 0.84 to 0.90 (p = 0.01) in development cohort and from 0.74 to 0.86 in validation cohort (p < 0.001). At the 15% csPCa threshold, 40.1% of overall biopsies would be avoided, and 95.7% of csPCa would be detected in the development cohort, while the specificity was 39.9% and 89.5% would be avoided in the validation cohort. This MRI-PM was analysed according to the PI-RADS categories for the first time. The authors concluded after this analysis that the clinical utility and net benefit of the Barcelona MRI-PM in entire developed and validation cohorts did not represent the true usefulness of the model regarding PI-RADS categories. The model’s performance was low for men with PI-RADS >3, especially those with PI-RADS 5. The performance and clinical utility were greater in men with PI-RADS <3; in those men with PI-RADS 3, 61.9% and 62.3% of prostate biopsies would be avoidable in development and validation cohorts while 28.2% and 14% of the csPCa would be missed. In men with negative mpMRI (PI-RADS < 3), 4.3% and 6.5% of biopsies showed that 33.3% and 18.2% of existing csPCa would be detected in development and validation cohorts, respectively.Finally, in 2022 two new MRI-PMs have been reported. Kinnaird et al.  developeMany previous studies have compared baseline PMs based on clinical predictors, MRI alone, and the MRI-PM ,29,32,34Predictive models are the only tools providing the individualised risk of csPCa of men with suspected PCa . These mConsiderations of MRI characteristics are important since it is the weightiest predictor of csPCa . Both 1.Clinical predictors incorporated in developed MRI-PMs are those with significant and independent weight to predict csPCa in logistic regression analysis . AlthougThe biopsy scheme influence csPCa detection rate and its heterogenicity was observed in this systematic review. Between 8 to 14-core systematic prostate biopsy associated to 1 to 4-core guided biopsies was reported in nine developed MRI-PMs ,31,32,35> 2 was the used definition [The definition of csPCa as the main outcome of MRI-PMs also has changed in deve- loped MRI-PMs. In four MRI-PMs an ISUP-GG finition ,16,17,32finition ,31,33,34finition ,28,35. Tfinition . Today, finition .All included MRI-PMs use as a reference standard the histopathological findings of csPCa in the prostate biopsies. Liu et al.  developeExternal validations are the key point for the extensive use of MRI-PMs in the deve- lopment population. However, external validations that guarantee accurate predictions have been made in less than half of developed MRI-PMs ,31,33,34Risk calculators (RCs) are essential for the routine use of MRI-PMs because they avoid the cumbersome and time-consuming use of nomograms . HoweverTo summarise the synthesis of generated evidence from this systematic review, we note that MRI-PMs are the best way to individualise the risk of csPCa among men with suspected PCa. However, available MRI-RCs are essential to predict the individual csPCa risk in routine practice. Although the overall risk of bias of selected articles for this review was low, developed MRI-PMs are heterogeneous regarding the characteristics of development cohorts, the characteristics of MRIs scanners and reporting methods, the clinical predictors included in the models, the types of prostate biopsy schemes and approaches, and the definitions of csPCa. Few external validations were carried out, and recalibrations of the model and adjustment of csPCa risk threshold were necessary when accurate predictions were made. The analysis of MRI-PMs regarding PI-RADS categories seems reasonable because clinical usefulness in overall populations does not represent the true utility in each PI-RADS. However, this analysis has only been carried out in a single MRI-PM, and, incredibly, only two RCs are currently available.https://pi-cai.grand-challenge.org/) (accessed on 27 September 2022). This available dataset provides clinical information that could also be used for AI-based PM development. The continuous update of an MRI-RC by machine learning algorithms and feedback through the new diagnosed cases will provide the models with the evolution of attended populations, the current diagnostic approaches, and csPCa definition refinements to maintain the effectiveness of csPCa predictions [There is an emerging need for tools to improve the radiologist interpretation of MRI. Radiomics, known as the conversion of digital images into mineable high-dimensional data, which has gradually become a research focus in recent years . uture ddictions .MRI-PMs are the current way to individualise the risk of csPCa and improve the selection of candidates for prostate biopsy. Available RCs are essential to facilitate the routine use of MRI-PMs. External validations are needed to assure accurate predictions of csPCa in any population where a developed MRI-PM is to be accomplished. Among the recently developed MRI-PMs, few meet the appropriate requirements used in routine clinical practice. In addition, only a single MRI-PM has been analysed according to the PI-RADS categories, which seems essential to define the scenarios of clinical usefulness and the appropriate csPCa risk thresholds. Future MRI-PMs should incorporate improved methods of prediction through radiomics, better definition of csPCa through genomics, and the integration of bigdata and the generation of artificial intelligence algorithm. The key point of external validations should be resolved through the integration and feedback of generated algorithms in federated networks.


On February 14, 2022, a panel of the Court of Arbitration for Sport (CAS) announced its decision permitting 15-year-old Russian figure skater Kamila Valieva to compete at the 2022 Olympic Games, despite rules in the World Anti-Doping Code (WADC) that mandated her provisional suspension due to a positive drug test (International Olympic Committee et al., WADA's comments are reminiscent of the criticisms that courts face when they invalidate laws to protect individual rights. More specifically, courts are accused of engaging in judicial activism by exceeding their role to interpret and apply laws and by encroaching on the law-making role of democratically elected legislative branches that represent the “will of the people” (Court of Appeal for Ontario, This paper will explore the CAS panel's decision in the Valieva case by situating it within the legal authority of arbitrators and the necessary institutional role that CAS ought to serve in the international sport system. This institutional role ensures that international sport organizations are held legally accountable for violating athletes' fundamental rights, and that athletes are able to participate in the evolution of sport rules in a manner not otherwise permitted due to the undemocratic and unrepresentative nature of governance structures in international sport organizations.Ad Hoc Division operating at the Olympic Games. Valieva, RUSADA, and the Russian Olympic Committee were named as respondents in the appeals (International Olympic Committee et al., On December 25, 2021, Valieva was selected for an in-competition doping control test at the 2022 Russian National Figure Skating Championships (International Olympic Committee et al., older athletes who are not protected persons, and thus resulted in the different and harsher treatment of protected personsThe CAS panel dismissed the appeals and decided not to reinstate Valieva's provisional suspension, thereby allowing her to compete at the 2022 Olympic Games (International Olympic Committee et al., In reaching the above conclusion, the panel was careful to note that its decision was an exercise in interpreting the WADC and not an example of “rewriting rules or making policies that are better made by sporting bodies exercising proper governance” (International Olympic Committee et al., CAS's intervention in the Valieva case is defensible when one considers the scope of the arbitration panel's authority. Arbitrators obtain their authority from the arbitration agreement entered into between disputing parties and other sources of arbitral powers (Bjorklund, Ad Hoc Division authorize a panel to decide a dispute pursuant to the Olympic Charter, applicable regulations, as well as the general principles of law and rules of law, the application of which the panel deems appropriateAd Hoc Division and attempted to apply the WADC to decide the dispute. It was only after identifying a gap in the WADC that the panel resorted to applying the fundamental legal principle of proportionality found in Swiss law and other systems of law to interpret the WADC in a manner that avoided violating this principle.In the case of Valieva, the arbitration agreement consisted of the entry form that Valieva signed to compete in the Olympic Games and the arbitration clause in rule 61.2 of the IOC's Olympic CharterPrivate International Law Act (Federal Act on Private International Law, A CAS panel's reliance on external legal rules and norms also arises from its inherent powers that are a necessary consequence of its judicial nature and its duty to ensure the administration of justice (Bjorklund, The arbitration panel's reliance on the fundamental principle of proportionality to interpret the WADC in the Valieva case was not only authorized but necessary in light of CAS's institutional role in the international sport system. It is well-established that international sport organizations are neither representative of nor politically accountable to athletes, even though athletes are the ultimate subjects of their regulatory authority (Houlihan, In the context of the international anti-doping system, the absence of political accountability in relation to athletes has several implications for CAS's institutional role. First, without political accountability, athletes must resort to legal means, such as arbitration, to hold international sport organizations accountable Lang, . As LangThe arbitration panel's decision in the Valieva case is a good example of CAS's authority and necessary institutional role to scrutinize the substance of sport rules through the application of external legal rules. Rather than be accused of engaging in arbitral activism and overstepping its role as a judicial body, CAS should be encouraged to exercise these lawful and necessary arbitral activities as it is increasingly being called upon by athletes and other stakeholders to adjudicate human rights disputes in sport. If CAS fails to exercise this authority and assume this role, then it risks weakening its institutional legitimacy and being relegated to a mere enforcer of sport rules made by undemocratic and unrepresentative international sport organizations that often disregard the rights and interests of athletes Foster, , 2021. SThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


IntroductionAnterior cruciate ligament (ACL) reconstruction techniques continue to evolve and the need to address the more anatomical femoral tunnel placement of the graft is critical, and in our study, we assessed the placement of femoral tunnel via transportal and retrograde drilling techniques.Material and methodsSixty patients where n=31 for retrograde, n=29 for transportal were assessed via CT knee for the femoral tunnel aperture on the intercondylar ridge via high low and deep shallow direction ratio and interpreted accordingly.ResultsIn our study, the femoral tunnel done via transportal method (n=29) has a deep shallow ratio range of 22%-47% and mean of 31.9±6.5, and graft is anatomical in 79%. The femoral tunnel done via the retrograde method (n=31) has a deep shallow depth ratio range of 11%-41% with a mean of 27.5±6.5 and graft is anatomical in 77% of the study group and the p-value means the ratio is 0.01 (significant). The femoral tunnel done via transportal method (n=29) has a high low ratio range of 19%-45% and mean of 32.9±6.3 and graft is anatomical in 72%. The femoral tunnel done via the retrograde method (n=31) has a deep shallow depth ratio range of 20%-38% with a mean of 33.9±4.1 and graft is anatomical in 94% of the study group with a p-value mean ratio being 0.51 (insignificant).ConclusionWatch out for the femoral tunnel placement in a deep shallow direction while going for standard transportal technique and high low direction while performing retrograde technique. Anterior cruciate ligament (ACL) reconstruction techniques are evolving, and for the surgeon, technical considerations include graft selection, correct graft tensioning , and correct tunnel placement, as it must provide sufficient stability during knee function without causing graft impingement within the intercondylar notch -3. The sA surgeon will test whether or not the graft placement and tensioning were adequate, and the patient will be able to observe this when their activity levels increase. Thus, imaging is used in the early postoperative period to rate surgical success as “good” or “poor” depending on the location of the graft tunnels ,7.Many previous studies compared the femoral tunnel placement via transtibial, transportal, and outside-in methods, and many of them have given their own advantages and drawbacks of each technique, as well as radiographic assessment, and transtibial resulted in the more vertical and non-anatomical placement of the graft, while other two possess more or less anatomical placement of the graft when compared to past studies that have done to locate the anatomical landmarks of the ACL footprint -12.Given the limitations of the preceding studies, the current study compares the femoral tunnel placed via standard transportal technique (inside out) and retrograde drilling technique (outside in).The Institutional Ethics Sub-Committee (IESC) of Dr. D. Y. Patil Medical College and Research Centre in Pune approved this prospective study . We conducted this study on 60 patients admitted to the Department of Orthopedics at DPU, Pune, who were diagnosed with primary complete ACL rupture. All 60 patients provided informed written consent. This research was carried out between June 2019 and July 2021. Following pre-anesthesia check-ups, patients who were all medically fit for surgery were scheduled for arthroscopic reconstructive surgery of the ACL rupture.Inclusion criteriaPatients who have been diagnosed with a primary complete ACL tear and are more than 18 years of age but less than 60 years of age were included in this study.Exclusion criteria Patients who were medically unfit for surgery, patients who had failed primary ACL reconstruction surgery, patients who had multi-ligament injuries to the knee joint in addition to the ACL tear.Selection criteriaAll of the surgeries were performed by a single surgeon, with others assisting him at various times, and the randomization of the technique used was determined by paper chits totaling 60, with 30 of each technique written on them, which were chosen following the patient's admission and performed accordingly.Surgical techniqueTransportal (Inside-Out)The ACL impression is depicted on the average surface of the lateral femoral condyle at 90 degrees of knee flexion, and the section point is identified. The entry area is then bored with an aide wire in 120 degrees of knee flexion using a femoral offset aimer inserted through the anteromedial port. Penetrating continues until the aide wire tip appears on the parallel side of the distal thigh near the femur epicondyle. The femoral passage was then created by drilling through both all over cortices with a 4.5 mm endoscopic drill bit. The length of the passage was then determined using a depth gauze. After that, the femoral passage was reamed with a reamer that corresponded to the graft diameter. Reaming was avoided 10-15 mm from the far cortex depending on the length of the graft.Retrograde Technique (Outside-In)The ACL impression can be seen on the average surface of the lateral femoral condyle at 90 degrees of knee flexion. The acufex pinpoint femoral aimer is placed at the near cortex of the lateral femoral condyle, 60 degrees to the sagittal plane and 20 degrees to the coronal plane, over the previous ACL impression. The femoral passage is bored with the acufex trunav until the previous leg tendon impression is reached, at which point the passage length is estimated using a burrow profundity assessment check. After estimating the length with a button flip scope of 5-10mm, retrograde boring is performed with a boring apparatus identical to the graft distance across, ending within 10mm of the far cortex.Tunnel assessmentA 3D-CT scan of their knee will be performed in our institute within three days of surgery using a SIEMENS 128 slice  and 3D reconstructed image slices are isolated. The quadrant approach of Bernard et al  was usedFigure Figure Figure Figure Table The study aims to measure the femoral footprints of ACL reconstruction using the inside-out and outside-in techniques. The study's main finding is that the majority of the measurements are accurate and correspond to normal anatomical footprints of the ACL.The mean age in our study group was 29.7 (9.2) years, with a minimum of 17 and a maximum of 60 years. The interquartile range was 29-35.5 years, and the median age was 29 years. Many patients are young, with approximately 90% of the study group being under the age of 40, with elderly patients mostly presenting with mucoid degeneration of the ACL. In our study group of 60 patients, we had 73% males and 27% females, with a male to female ratio of 2.7:1. The group was nearly evenly divided on the side of the tear, with 52% on the right side and 48% on the left. Sports were the mode of injury in approximately 38% of cases, with trauma accounting for the remaining 62%.The population in the study's mean ratio of high-low graft length ratio with inside-out technique (n=29) was 32.9 (6.3) and outside-in technique (n=31) was 33.9 (4.1). In our study, a femoral tunnel drilled from the inside out (n=29) had a deep shallow ratio range of 22%-47% and a mean of 31.9 (6.5), and the graft was anatomical in 79% of the cases. In contrast, a femoral tunnel done via outside-in drilling method (n=31) has a deep shallow depth ratio range of 11%-41% with a mean of 27.5 (6.5), and the graft is anatomical in 77% of the study group, with a p-value mean ratio of 0.01 (significant). Whereas the femoral tunnel done via inside-out drilling method (n=29) has a high low ratio range of 19%-45% and a mean of 32.9 (6.3), and the graft is anatomical in 72%, the femoral tunnel done via outside-in drilling method (n=31) has a high low depth ratio range of 20%-38% and a mean of 33.9 (4.1), and the graft is anatomical in 94% of the study group with the insignificant p-value.Also, in our study, we found that the outside-in drilling technique has better graft placement in the high-low direction, with 94% being anatomical compared to 72% being anatomical in the inside-out technique with a p-value of 0.03 (significant) as compared to deep-shallow where the graft is anatomical in 79% of the inside-out group and 77% in the outside-in group with a p-value of 0.86 (insignificant).The mean value is statistically significant in the deep-shallow position for the inside-out group, indicating that the graft placement has a higher chance of being anatomically placed, whereas the individual ratios and anatomically placed grafts in both study groups are statistically insignificant. Whereas the mean value of the graft in the high-low position is insignificant, the graft is more anatomically placed in the outside-in group with a significant p-value. The aimer pivot, where the guidewire may exit slightly off-center, is responsible for the above disparity in the deep shallow direction of the femoral tunnel placement.Parkar et al. discovered that when comparing transtibial and anteromedial techniques, the p-values for the overall femoral grid and tibial tunnel, as well as isolated femoral high-low position, are significant and that the high-low direction is an important factor .Nakamura et al.  comparedThis study focuses on current novel techniques and their lack of agreement on which technique of femoral tunnel placement is better, and in our study we aimed at the anatomical placement of femoral tunnel.Additionally, many studies compared the transtibial and anteromedial techniques of femoral tunnel placement and used different methods of assessment, which makes the conclusion and inference different based on the method ,17.Inter-rater agreement was not considered when evaluating the CT scan because previous studies on the subject demonstrated insignificant inter-rater and intra-rater variability ,19.Also, the evaluation of actual tunnel positioning was done after the surgery, and tunnel lengthening and widening were not considered. The sample size was smaller, in a single center, and performed by a single surgeon, and larger groups with multi-center studies are needed to assess the femoral tunnel placement techniques, as both mean values appear to be near normal, except for a few extremes in the outside-in drilling technique, which can be attributed to the newer technique being used by the current surgeon, which is a known complication of ACL reconstruction for surgeons in their early stages of learning .Although equally placed anatomically in both techniques, the femoral tunnel position by outside-in drilling technique is more anatomical in our study group in the high-low direction and has a significant mean ratio in the deep-shallow direction . In a combined femoral grid assessment of both techniques, the outside-in technique is more anatomically placed, despite the extremities of the outside-in technique in the deep-shallow direction, where the extremities can be attributed to the surgeon's newer method. So, both techniques have an equal chance of being anatomically placed, and it is up to the surgeon to decide. While using the inside-out technique, keep an eye on the high-low direction and consider the deep-shallow direction when using the outside-in technique.


Background and Objectives: Studies analyzing magnetic resonance imaging (MRI) after simultaneously performing lateral meniscal allograft transplantation (MAT) and capsulodesis are currently rare. This study aimed to compare the MRI results between the group that performed lateral MAT alone and the group that performed both lateral MAT and capsulodesis simultaneously. Materials and Methods: A total of 55 patients who underwent lateral MAT with a 1-year follow-up MRI were included. The patients were divided into two groups according to the surgical procedure: group I  and group C . Differences between groups were compared regarding subjective knee scores, graft extrusion, graft signal, articular cartilage loss, and joint space width (JSW). Results: The subjective knee scores improved significantly in both groups , and there were no significant differences in these scores between both groups at the 1-year follow-up. Group C showed less coronal graft extrusion at the 1-year follow-up . Pathologic coronal graft extrusion (≥3 mm) was found in seven (26.9%) patients in group I and three (10.3%) in group C. Concerning the graft signal, group C showed less grade 3 signal intensity in the posterior root of the graft. There were no significant differences in preoperative and postoperative cartilage status between groups. Regarding JSW, there were no significant differences in postoperative JSW between both groups. However, in group C, JSW significantly increased from 3.9 ± 0.4 mm to 4.5 ± 1.4 mm (p = 0.031). Conclusions: In lateral MAT, capsulodesis (open decortication and suture anchor fixation) could reduce graft extrusion without complications. In the future, large-volume and long-term prospective comparative studies are needed to confirm the clinical effects following capsulodesis. Meniscal allograft transplantation (MAT) reduces knee pain, improves knee function, and alleviates the degenerative progression of articular cartilage ,2,3,4,5.The causes of graft extrusion after MAT include graft size mismatch before surgery, malposition of the graft during surgery, overtensioning of the meniscal suture, osteophytes, and overstuffing. Graft size reduction, anatomic placement of the graft, and peripheral osteophyte excision have been performed to overcome graft extrusion ,15,16,17Studies analyzing magnetic resonance images (MRI) after simultaneously performing lateral MAT and capsulodesis are currently rare. It is believed that different results may be shown depending on the method of performing capsulodesis. Therefore, this study aimed to compare the MRI results between the group that performed lateral MAT alone and the group that performed both lateral MAT and capsulodesis (open decortication and suture anchor fixation) simultaneously. It was hypothesized that the group that simultaneously underwent lateral MAT and capsulodesis would show less graft extrusion and osteoarthritis progression on the MRI one year after MAT.A total of 63 patients who underwent lateral MAT in our institute from March 2018 to July 2021 were retrospectively reviewed. The lateral MAT was indicated for patients with failed conservative treatment after subtotal or total meniscectomy for 6 months and with visual analog scale (VAS) scores ≥ 3 for pain. The patients who underwent MRI examination within 2 days postoperatively and were available for follow-up evaluation for ≥1 year were included. Exclusion criteria were axial limb malalignment ≥ 5°, cruciate ligament deficiency, diffuse osteoarthritis categorized as more than grade 3 according to modified Outerbridge grade (MOG), joint obliteration on the Rosenberg view, and medial compartment osteoarthritis ≥ Kellgren-Lawrence grade 2. However, MAT was performed as a salvage operation in cases of localized MOG 3 or 4 lesions in which coverage by the meniscal graft could be expected. Finally, out of 63 patients, 55 were selected. The patients were divided into two groups according to the surgical procedure in a consecutive and non-random manner: group I  with patients from March 2018 to June 2019, and group C  with patients from July 2019 onward . CombineLateral MAT was performed using the keyhole technique with modified instruments by a single experienced surgeon (D.W. Lee) . The allIn patients undergoing capsulodesis, after palpating the lateral epicondyle, an oblique small stab wound was made anteriorly on the iliotibial band, and the articular capsule was exposed by bending the iliotibial band up and down. After exposing the rim of the lateral tibial plateau by longitudinally excising the articular capsule, a part of the cartilage and the cortical bone were removed gently in the 10 mm anterior and 10 mm posterior sections using a small rongeur to expose the cancellous bone. At the rim of the lateral tibial plateau, an all-soft suture anchor  was inserted slightly anterior to the midbody level of the lateral meniscus . Two paiFor postoperative rehabilitation, the same delayed rehabilitation protocol was applied to all patients . The casThe lateral joint space width (JSW) was measured from the Rosenberg. The measurements were performed on a picture archiving and communication system (PACS) workstation . The absolute JSW was calculated from the lateral edge of the femoral condyle to the lateral edge of the tibial plateau ,23,24 F. Our preTo evaluate graft position and the status of the cartilage of the lateral compartment, follow-up MRIs at 2 days and 12 months postoperatively were conducted. All patients signed an informed consent form prior to MRI examinations with a 3.0-T system apparatus . Graft extrusion on the coronal plane at the level of the posterior border of the medial collateral ligament was measured from the lateral margin of the graft to the superolateral aspect of the tibial plateau . PatholoGraft signal was assessed using MRI at 12 months, postoperatively, and graded following Park et al. : grade 0The cartilage status at the lateral compartment was assessed according to the MOG  ,33,34. TRadiological measurements were independently performed by one experienced orthopedic surgeon and one experienced radiologist (D.W. Lee and S.G. Moon). Each examiner measured twice with a 6-week interval, and the mean value was used. In the grading system, if there were different results between the two examiners, the results were determined based on consensus.The clinical outcomes were evaluated using the Lysholm score and International Knee Documentation Committee (IKDC) subjective knee score. Preoperative data and postoperative data at 12 months were compared.p < 0.05. The independent t-test or Mann–Whitney U test was used to compare parametric variables between the two groups. Preoperative and postoperative parametric or non-parametric variables were compared using the paired t-test or Wilcoxon signed-rank test in each group. The intraobserver and interobserver reliabilities of measurements were presented with the intraclass correlation coefficient (ICC) [Statistical analysis was performed using the SPSS software . In all analyses, statistical significance was set at nt (ICC) . To detent (ICC) .p < 0.001). There were no significant differences in these scores between both groups at the 1-year follow-up .Preoperative demographic data showed no statistically significant differences between both groups and are summarized in p < 0.001). Coronal graft extrusion increased significantly from 1.4 ± 1.6 mm to 2.7 ± 1.2 in group I (p < 0.001) and not in group C (p = 0.223)  . Patholo= 0.223) .p = 0.031).There were no significant differences in preoperative and postoperative cartilage status between both groups . RegardiThere were no complications related to the suture anchor. Group C showed no lateral capsular tear, meniscocapsular separation, or lateral tibial plateau bone edema.The main finding of the current study was that combined lateral MAT and capsulodesis (open decortication and suture anchor fixation) showed less coronal graft extrusion and a greater increase of lateral JSW at the 1-year follow-up compared with isolated lateral MAT. Additional capsulodesis also positively affected graft maturation in the posterior root.Various efforts have been implemented to reduce graft extrusion after MAT, and recently, studies have reported positive results by applying a method of stabilizing the stretched lateral capsule during MAT. Masferrer-Pino et al.  found thThe cause of high signal intensity seen in MRI after MAT is believed to be extracellular matrix degeneration or fibrocartilaginous scar formation rather than tear ,37. The We did not apply universal classification such as Kellgren-Lawrence grade to determine joint space narrowing of the lateral edge ,40. Lee Capsulodesis may be an excellent attempt to reduce graft extrusion after MAT, but further biomechanical studies are needed to elucidate how this procedure will affect the physiological meniscal movement. Seo et al.  stated tThe current technique for lateral capsulodesis using an all-soft suture anchor seems to be a simple, reliable, and easy method to prevent graft extrusion. There is also less possibility of complications due to additional procedures. The all-soft suture anchor did not result in significant bone loss in the lateral tibial plateau and allowed for optimal postoperative MRI evaluation.There are several limitations in this study. First, two different surgical methods were not randomly assigned because lateral capsulodesis was started with clinical suspicion that it could be beneficial for graft stabilization. A lateral MAT was not conducted frequently under strict criteria, and the current study had a relatively small sample size and could not perform a prospective randomized trial. However, the inclusion criteria for both groups were the same, and preoperative demography after retrospective analysis revealed that the two groups did not differ significantly. Second, since the result of MRI and clinical examinations in the first year are considered in this study, a longer follow-up is necessary to identify how graft extrusion affects long-term clinical outcomes. Third, it may be necessary to use two suture anchors, depending on the size of the tibia, but this study conducted capsulodesis using only one. Fourth, objective functional tests were not performed. It is necessary to analyze how graft extrusion affects motor function in closed kinetic chain situations as well as subjective function scores. Finally, there was no second-look arthroscopy; thus, the authors could not evaluate intra-articular biological conditions.In lateral MAT, capsulodesis (open decortication and suture anchor fixation) could reduce graft extrusion without complications. In the future, large-volume and long-term prospective comparative studies are needed to confirm the clinical effect following capsulodesis.


Pan American Journal of Public Health draws readers’ attention to an error in the following article, pointed out by the authors.The William H. Herman should read number 5 Department of Epidemiology, University of Michigan, Ann Arbor, United States of AmericaIn page 1, affiliation of