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Introducción: el desarrollo de nuevas tecnologías de diagnóstico molecular ha permitido la detección de numerosas alteraciones del genoma involucradas en el inicio y progresión del cáncer. Desempeña un rol importante la identificación de variantes de utilidad clínica o mutaciones accionables, entendidas como aquellas alteraciones puntuales que permiten guiar las decisiones terapéuticas con inhibidores dirigidos a estos blancos moleculares. El éxito de estos agentes ha llevado a un cambio de paradigma, a tal punto de reemplazar la quimioterapia convencional en un grupo selecto de pacientes que se benefician de terapia dirigida. La secuenciación de nueva generación (NGS, por sus siglas en inglés) es la base de las plataformas genómicas con las que se puede realizar un perfil genómico completo (CGP, por sus siglas en inglés), con el objetivo de identificar las mutaciones accionables sobre las cuales ejercerán su efecto los fármacos dirigidos, permitiendo así la medicina personalizada y oncología de precisión, sin embargo, la utilidad clínica de CGP en pacientes colombianos es desconocida. Objetivos: el objetivo principal de este estudio fue evaluar la utilidad clínica del perfil genómico integral en tumores sólidos durante la práctica clínica habitual en Colombia como recomendación de tratamiento.

The announcement of the China-EU Comprehensive Agreement on Investment (CAI) at the end of December 2020 triggered an intense debate. The deal has found many supporters inside Europe and in China—but also opposition coming from some European quarters and the USA. It is thus crucial to examine the pros and cons of CAI—an accord that if ratified would boost trade and investment relations between the EU and China as well as have profound implications for the USA which is actively working to create a common front with the European allies to counter Beijing’s increased self-confidence and assertiveness.

In osteoarthritis (OA), articular chondrocytes display phenotypic and functional changes associated with epigenomic alterations. These changes contribute to the disease progression, which is characterized by dysregulated reparative processes and abnormal extracellular matrix remodeling leading to cartilage degradation. Recent studies using a murine model of posttraumatic OA highlighted the contribution of changes in DNA hydroxymethylation (5hmC) to OA progression. Here, we integrated transcriptomic and epigenomic analyses in cartilage after induction of OA to show that the structural progression of OA is accompanied by early transcriptomic and pronounced DNA methylation (5mC) changes in chondrocytes. These changes accumulate over time and are associated with recapitulation of developmental processes, including cartilage development, chondrocyte hypertrophy, and ossification. Our integrative analyses also uncovered that Lrrc15 is differentially methylated and expressed in OA cartilage, and that it may contribute to the functional and phenotypic alterations of chondrocytes, likely coordinating stress responses and dysregulated extracellular matrix remodeling.

A scalable procedure with minimum energy requirements, MSAT (Medium Scale Ambient Temperature), in combination with solvents generally recognized as safe (GRAS), has been optimized to obtain polyphenolic extracts from white grape (Vitis vinifera) marc. The solvents considered were propylene glycol (Pg), ethanol (Et), and ethyl lactate (Lc), as well as their respective hydro-organic mixtures. In a first approach, the operating parameters were optimized through a response surface matrix: extraction solvent volume (range 10–150 mL), marc mass (range 20–200 g) and marc/dispersant mass ratio (range 0.5–2 g⋅g–1), using the total polyphenol content (TPC) and the antioxidant activity (AA) of the extracts as response parameters. The highest TPC (5,918 mgGAE⋅L–1) and AA (44 mmolTE⋅L–1) values were obtained using 200 g marc and 100 mL solvent. Regarding the type of solvent, a better response was reached with Lc > Et > Pg > H2O obtaining a polyphenol concentration of 252 mg⋅L–1for the hydro-organic isovolumetric ratio of ethyl lactate. In addition, the stability of the extracts was studied for 62 days. The effect of factors such as temperature, light exposure, and oxidative reactivity was evaluated. The bioactivity indices showed no changes with the storage conditions of the extracts in the first month of analysis, after which 75% of the antioxidant activity as the concentration of the polyphenolic profile (204 mg⋅L–1) remains. The absence of reactive oxygen and the cooling of the extract (4°C) were the most determining factors (p< 0.05) in modulating the stability of the total polyphenolic profile.

Formalin-fixed and paraffin-embedded (FFPE) biospecimens are a valuable and widely-available resource for diagnostic and research applications. With biobanks of tissue samples available in many institutions, FFPE tissues could prove to be a valuable resource for translational orthopaedic research. The purpose of this study was to characterize the molecular profiles and degree of histologic degeneration on archival fragments of FFPE human menisci obtained during arthroscopic partial meniscectomy. We used FFPE menisci for multiplexed gene expression analysis using the NanoString nCounter® platform, and for histological assessment using a quantitative scoring system. In total, 17 archival specimens were utilized for integrated histologic and molecular analyses. The median patient age was 22 years (range: 14-62). We found that the genes with the highest normalized counts were those typically expressed in meniscal fibrocartilage. Gene expression differences were identified in patient cohorts based on age (≤40 years), including genes associated with the extracellular matrix and tissue repair. The majority of samples showed mild to moderate histologic degeneration. Based on these data, we conclude that FFPE human menisci can be effectively utilized for molecular evaluation following a storage time as long as 11 years. Statement of Clinical Significance: The integration of histological and transcriptomic analyses described in this study will be useful for future studies investigating the basis for biological classification of meniscus specimens in patients. Further exploration into the genes and pathways uncovered by this study may suggest targets for biomarker discovery and identify patients at greater risk for osteoarthritis once the meniscus is torn.

Purpose Greater attention should be paid to the emotional aspects of the service experience. In this context, this paper aims to propose that emotions will have a different impact on customers’ complaint behavior and satisfaction depending on the hedonic or utilitarian nature of the service and for this purpose a valence-based approach is followed. Design/methodology/approach A sample of 809 service users was analyzed through multi-group structural equation modeling, including both hedonic (bars and cafeterias, n = 210) and utilitarian services (bank and public transportation services, n = 599). Findings Research findings show the different influence of emotions on customers’ complaint behavior and satisfaction depending on the service nature. Further, the negative affect does not influence behavioral outcomes in hedonic services, whereas positive affect exerts a slight lower influence in utilitarian services. Finally, the service nature plays a moderating role in the emotions–satisfaction and emotions–complaint behavior relationship. Originality/value This research shows the important role of the service nature, reporting different results for hedonic and utilitarian services in the influence of emotions in behavioral outcomes.

Introduction The ACHOCC‐19 study was performed to characterize COVID‐19 infection in a Colombian oncological population. Methodology Analytical cohort study of patients with cancer and COVID‐19 infection in Colombia. From April 1 to October 31, 2020. Demographic and clinical variables related to cancer and COVID‐19 infection were collected. The primary outcome was 30‐day mortality from all causes. The association between the outcome and the prognostic variables was analyzed using logistic regression models and survival analysis with Cox regression. Results The study included 742 patients; 72% were >51 years. The most prevalent neoplasms were breast (132, 17.77%), colorectal (92, 12.34%), and prostate (81, 10.9%). Two hundred twenty (29.6%) patients were asymptomatic and 96 (26.3%) died. In the bivariate descriptive analysis, higher mortality occurred in patients who were >70 years, patients with lung cancer, ≥2 comorbidities, former smokers, receiving antibiotics, corticosteroids, and anticoagulants, residents of rural areas, low socioeconomic status, and increased acute‐phase reactants. In the logistic regression analysis, higher mortality was associated with Eastern Cooperative Oncology Group performance status (ECOG PS) 3 (odds ratio [OR] 28.67; 95% confidence interval [CI], 8.2–99.6); ECOG PS 4 (OR 20.89; 95% CI, 3.36–129.7); two complications from COVID‐19 (OR 5.3; 95% CI, 1.50–18.1); and cancer in progression (OR 2.08; 95% CI, 1.01–4.27). In the Cox regression analysis, the statistically significant hazard ratios (HR) were metastatic disease (HR 1.58; 95% CI, 1.16–2.16), cancer in progression (HR 1.08; 95% CI, 1.24–2.61) cancer in partial response (HR 0.31; 95% CI, 0.11–0.88), use of steroids (HR 1.44; 95% CI, 1.01–2.06), and use of antibiotics (HR 2.11; 95% CI, 1.47–2.95). Conclusion In our study, patients with cancer have higher mortality due to COVID‐19 infection if they have active cancer, metastatic or progressive cancer, ECOG PS >2, and low socioeconomic status. Implications for Practice This study's findings raise the need to carefully evaluate patients with metastatic cancer, in progression, and with impaired Eastern Cooperative Oncology Group status to define the relevance of cancer treatment during the pandemic, consider the risk/benefit of the interventions, and establish clear and complete communication with the patients and their families about the risk of complications. There is also the importance of offering additional support to patients with low income and residence in rural areas so that they can have more support during cancer treatment., Considering the absence of data on the impact of COVID‐19 infection in cancer patients, the ACHOCC‐19 study was started in Colombia. Results are reported here.

Dissatisfaction occurs in nearly 20% of patients after total knee arthroplasty (TKA); however, there remains only limited understanding of the biologic mechanisms that may contribute to suboptimal postoperative outcomes requiring revision surgery. Expansion of effector T and B cells, could promote an abnormal healing response via local or peripheral immune system mechanisms and contribute to inferior outcomes necessitating revision TKA. In this pilot study, we hypothesized that patients suffering from complications of arthrofibrosis or instability may exhibit differences in adaptive immune function. Patients (n = 31) undergoing revision TKA for an indication of arthrofibrosis or instability were prospectively enrolled. Whole blood and synovial fluid (SF) from the operative knee were collected at time of surgery. Peripheral blood mononuclear cells were isolated and analyzed by flow cytometry. Serum and SF were assessed for immunoglobulin levels by Luminex and antiphospholipid antibodies by enzyme-linked immunoassay. No significant differences were observed in peripheral blood T/B cell populations or serum immunoglobulins levels between groups. SF analysis demonstrated significant differences between the two groups, with higher levels of immunoglobulin G1 (IgG1) (p = 0.0184), IgG3 (p = 0.0084) and antiphosphatidyl serine IgG (p = 0.034) in arthrofibrosis relative to instability patients. Increased levels of both IgG subclasses and antiphospholipid antibodies in the SF suggest that intra-articular T-B cell interactions, potentially triggered by exposure to apoptotic components generated during post-op healing, could be functioning as a source of immune complexes that fuel fibrous tissue growth in arthrofibrotic patients.

The importance of a local tissue immune response in healing injured tissues such as skin and lung is well established. Little is known about whether sterile wounds elicit lymph node (LN) responses and inflammatory responses after injury of musculoskeletal tissues that are mechanically loaded during the repair response. We investigated LN and tissue immune responses in a tibial implant model of joint replacement surgery where wounded tissue is subjected to movement and mechanical loading postoperatively. Draining inguinal and iliac LNs expanded postoperatively, including increases in regulatory T cells and activation of a subset of T cells. Thus, tissue injury was actively sensed in secondary lymphoid organs, with the potential to activate adaptive immunity. Joint tissues exhibited three temporally distinct immune response components, including a novel interferon (IFN) response with activation of signal transducer and activator of transcription (STAT) and interferon regulatory factor (IRF) pathways. Fibrovascular tissue formation was not associated with a macrophage type 2 (M2) reparative immune response, but instead with delayed induction of interleukin-1 family (IL-1β, IL-33, IL-36), IL-17, and prostaglandin pathway genes concomitant with transforming growth factor (TGF)-β and growth factor signaling, fibroblast activation, and tissue formation. Tissue remodeling was associated with activity of the HOX antisense intergenic RNA (HOTAIR) pathway. These results provide insights into immune responses and regulation of tissue healing after knee arthroplasty that potentially can be used to develop therapeutic strategies to improve healing, prevent arthrofibrosis, and improve surgical outcomes. © 2021 American Society for Bone and Mineral Research (ASBMR).

The objective of this study was to evaluate histologic and molecular features of meniscus degeneration in cohorts of patients with and without osteoarthritis (OA) of the knee. Menisci were obtained from patients undergoing total knee arthroplasty for OA (TKA) or arthroscopic partial meniscectomy (APM) for a torn knee meniscus. Degenerative meniscal tears were among the most common tear type in the APM group based on the pattern. Using an integrative workflow for molecular evaluation of formalin-fixed and paraffin-embedded tissues, human menisci underwent blinded histologic evaluation and NanoString gene expression analyses. Histology revealed increased proteoglycan content in TKA menisci compared to APM menisci, but otherwise no significant differences in the total pathology score or sub-scores between patients based on age or cohort. NanoString analyses revealed differential expression of genes primarily associated with the PI3K-AKT signaling pathway, cell cycle, and apoptosis. These data provide new insights into histological and molecular features of meniscus degeneration in patients with and without knee OA. Histologic assessment of menisci showed similar severity of overall degeneration between cohorts, but there were differences at the molecular level. The dysregulated pathways identified in this study could contribute to early-onset meniscus degeneration, or to a predisposition to meniscus tears and subsequent knee OA. Further studies that validate genes and pathways uncovered in this study will allow us to evaluate novel approaches to assess and treat meniscal degeneration.

During osteoarthritis (OA), articular chondrocytes undergo phenotypic changes that resemble developmental patterns characteristic of growth plate chondrocytes. These phenotypic alterations lead to a hypertrophy-like phenotype characterized by altered production of extracellular matrix constituents and increased collagenase activity, which, in turn, results in cartilage destruction in OA disease. Recent studies have shown that the phenotypic instability and dysregulated gene expression in OA are associated with changes in DNA methylation patterns. Subsequent efforts have aimed to identify changes in DNA methylation with functional impact in OA disease, to potentially uncover therapeutic targets. Here, we paired an in vitro 3D/pellet culture system that mimics chondrocyte hypertrophy with RNA sequencing (RNA-Seq) and enhanced reduced representation of bisulfite sequencing (ERRBS) to identify transcriptomic and epigenomic changes in murine primary articular chondrocytes undergoing hypertrophy-like differentiation. We identified hypertrophy-associated changes in DNA methylation patterns in vitro. Integration of RNA-Seq and ERRBS datasets identified associations between changes in methylation and gene expression. Our integrative analyses showed that hypertrophic differentiation of articular chondrocytes is accompanied by transcriptomic and epigenomic changes in vitro. We believe that our integrative approaches have the potential to uncover new targets for therapeutic intervention.

Mobile services are expanding rapidly, and in this tremendously dynamic environment, companies should provide value-added services to meet users’ demand. In this context, the study aims to determine whether different user groups exist in this market and profile them.,Based on the information of 568 mobile service users, a research was developed in the context of a mature mobile services market – Spain. A behavior-based cluster analysis is developed by means of confirmatory factor analysis (CFA), followed by two-step clustering. Then, an ANOVA and post hoc Tukey tests are conducted to confirm differences among the obtained clusters.,The study findings show that mobile service users cannot be perceived as a homogenous group, as different users with different behaviors coexist in this market. More specifically, four behavior-based segments emerge in the mobile service sector: “service connoisseurs,” “uninvolved pragmatics,” “potential switchers” and “delighted loyal”; “potential switchers” being the most challenging segment for mobile service companies.,This study reports mobile service users’ heterogeneity; and in turn, mobile service managers should consider customers as four different types, instead of considering them as one single customer.,Los servicios moviles se estan expandiendo rapidamente y en este entorno tremendamente dinamico, las companias de servicios moviles deberian de proporcionar servicios de valor anadido para satisfacer la demanda de sus usuarios. En este contexto, esta investigacion tiene como objetivo determinar si existen diferentes grupo de usuarios en este mercado y aportar su pefil.,Sobre la base de informacion de 568 usuarios de servicios moviles se lleva a cabo una investigacion en el contexto de un mercado de servicios moviles maduro –Espana-. Se lleva a cabo un analisis cluster basado en el comportamiento de los usuarios, mediante un analisis factorial confirmatorio (CFA), seguido de un analisis cluster bi-etapico. A continuacion, se realizan un test Anova y un test pos hoc de Tuckey para confirmar las diferencias entre los grupos obtenidos.,Los resultados de la investigacion muestran que los usuarios de servicios moviles no pueden ser percibidos como un grupo homogeneo, ya que en este mercado coexisten diferentes usuarios con diferentes comportamientos. Mas especificamente, cuatro segmentos de usuarios surgen en el sector de los servicios moviles basados en su comportamiento: “conocedores del servicio”, “pragmaticos no involucrados”, “potenciales cambiadores de servicio” y “leales encantados”, siendo “potenciales cambiadores de servicio” los que presentan un mayor desafio las empresas de servicios moviles.,Este estudio muestra la heterogeneidad de los usuarios de servicios moviles, y por tanto, los gestores de los servicios moviles deben considerar a sus clientes como cuatro tipos diferentes, en lugar de considerarlos como un unico tipo de cliente.

Introducción: el cáncer de pulmón en quienes nunca han fumado es responsable de entre 17.000 y 26.000 muertes anuales en los Estados Unidos y también es la séptima causa principal de mortalidad por cáncer en este país. La incidencia de cáncer de pulmón en personas que nunca han fumado parece estar aumentando. El cáncer de pulmón (CP), es la principal causa de muerte por cáncer en todo el mundo, es una enfermedad compleja y muy heterogénea. Además, una parte de los pacientes con CP no ha fumado nunca, población que estamos comenzando a explorar de forma exhaustiva. Se han relacionado varios factores de riesgo con el CP en personas que nunca han fumado entre los cuales encontramos la exposición al radón, al humo del combustible doméstico, las infecciones por Mycobacterium tuberculosis y el virus del papiloma humano, resaltando el papel importante de estos factores en la carcinogénesis. La coinfección por VPH en el cáncer de pulmón favorece la inclusión de la oncoproteína E5 y, por tanto, altera la señalización mitogénica downstream de RAS, EGFR y proteína quinasa-C (PKC), y la activación constitutiva de AP-1, que a través de c-jun pueden promover la supervivencia de las células tumorales. Aún hace falta conocer la asociación entre el estado de infección por VPH y la respuesta terapéutica.

Histopathology is widely used to analyze clinical biopsy specimens and tissues from pre-clinical models of a variety of musculoskeletal conditions. Histological assessment relies on scoring systems that require expertise, time, and resources, which can lead to an analysis bottleneck. Recent advancements in digital imaging and image processing provide an opportunity to automate histological analyses by implementing advanced statistical models such as machine learning and deep learning, which would greatly benefit the musculoskeletal field. This review provides a high-level overview of machine learning applications, a general pipeline of tissue collection to model selection, and highlights the development of image analysis methods, including some machine learning applications, to solve musculoskeletal problems. We discuss the optimization steps for tissue processing, sectioning, staining, and imaging that are critical for the successful generalizability of an automated image analysis model. We also commenting on the considerations that should be taken into account during model selection and the considerable advances in the field of computer vision outside of histopathology, which can be leveraged for image analysis. Finally, we provide a historic perspective of the previously used histopathological image analysis applications for musculoskeletal diseases, and we contrast it with the advantages of implementing state-of-the-art computational pathology approaches. While some deep learning approaches have been used, there is a significant opportunity to expand the use of such approaches to solve musculoskeletal problems.

El pseudomixoma peritoneal es una enfermedad infrecuente caracterizada por ascitis mucinosa acompañada de implantes tumorales peritoneales y sobre el epiplón. La etiología de esta entidad es desconocida y, según la histología, se divide en dos grandes grupos: la adenomucinosis y la carcinomatosis mucinosa peritoneal. Tradicionalmente, el tratamiento quirúrgico recomendado es la citorreducción parcial que se repite regularmente para controlar los síntomas hasta que no se encuentre ningún beneficio adicional. A pesar de la controversia, en la actualidad, la evidencia favorece la realización de la peritonectomía radical más quimioterapia intraperitoneal hipertérmica, seguidas de quimioterapia intraperitoneal posoperatoria temprana (en los 7 días siguientes al procedimiento). A continuación se presentan los dos primeros casos tratados con esta técnica en Colombia y se revisa detalladamente la información publicada al respecto.

Posttraumatic osteoarthritis (PTOA) is associated with abnormal and increased subchondral bone remodeling. Inhibiting altered remodeling immediately following joint damage can slow PTOA progression. Clinically, however, inhibiting remodeling when significant joint damage is already present has minimal effects in slowing further disease progression. We sought to determine the treatment window following PTOA initiation in which inhibiting remodeling can attenuate progression of joint damage. We hypothesized that the most effective treatment would be to inhibit remodeling immediately after PTOA initiation. We used an animal model in which a single bout of mechanical loading was applied to the left tibia of 26-week-old male C57Bl/6 mice at a peak load of 9 N to initiate load-induced PTOA development. Following loading, we inhibited bone remodeling using daily alendronate (ALN) treatment administered either immediately or with 1 or 2 weeks' delay up to 3 or 6 weeks post-loading. A vehicle (VEH) treatment group controlled for daily injections. Cartilage and subchondral bone morphology and osteophyte development were analyzed and compared among treatment groups. Inhibiting remodeling using ALN immediately after load-induced PTOA initiation reduced cartilage degeneration, slowed osteophyte formation, and preserved subchondral bone volume compared to VEH treatment. Delaying the inhibition of bone remodeling at 1 or 2 weeks similarly attenuated cartilage degeneration at 6 weeks, but did not slow the development of osteoarthritis (OA)-related changes in the subchondral bone, including osteophyte formation and subchondral bone erosions. Immediate inhibition of subchondral bone remodeling was most effective in slowing PTOA progression across the entire joint, indicating that abnormal bone remodeling within the first week following PTOA initiation played a critical role in subsequent cartilage damage, subchondral bone changes, and overall joint degeneration. These results highlight the potential of anti-resorptive drugs as preemptive therapies for limiting PTOA development after joint injury, rather than as disease-modifying therapies after joint damage is established. © 2021 American Society for Bone and Mineral Research (ASBMR).

Propósito: realizar una revisión de la evidencia acerca del tratamiento del cáncer de pulmón de célula no pequeña (CPCNP). Fuente de los datos: la información se obtuvo a partir de búsquedas practicadas en MEDLINE, CCT R, BIOSIS , EMBASE , LIL ACS y CIN HAL. También se recopilaron las referencias más representativas presentadas durante los últimos cinco años en los congresos ASCO, ESMO y de la IASLC. Extracción de los datos: los datos fueron extraídos por miembros asociados al ONCOLGroup. La recopilación de la información no siguió una estrategia uniforme. Resultados de la síntesis de datos: la terapia que se utiliza para tratar el carcinoma de pulmón de células no pequeñas (CPCNP) mejora la supervivencia global y la calidad de vida; no obstante, la mayoría de los pacientes mueren por la enfermedad antes del segundo año del diagnóstico, evento que ha favorecido la generación de nuevas estrategias que permitirán optimizar este desenlace. En la actualidad, el tratamiento estándar de primera línea implica varias combinaciones con base en algún platino que incrementan la supervivencia en comparación con la monoterapia y el mejor soporte paliativo. Estos regímenes son comparables respecto de su eficacia, pero difieren en el perfil de seguridad. Nuevas alternativas de tratamiento dirigidas contra blancos moleculares benefician a poblaciones específicas, cuando se administran solas o con otros agentes con los que presentan sinergismo. Esta revisión no realizó una evaluación sistemática de la evidencia. Conclusión: la terapia médica utilizada en el CPCNP modifica positivamente los desenlaces principales, incluyendo la calidad de vida

Summary Objective Mechanical loading and joint health have a unique relationship in osteoarthritis (OA) onset and progression. Although high load levels adversely affect cartilage health, exercise that involves low to moderate load levels can alleviate OA symptoms. We sought to isolate the beneficial effects of mechanical loading using controlled in vivo cyclic tibial compression. We hypothesized that low-level cyclic compression would attenuate post-traumatic OA symptoms induced by destabilization of the medial meniscus (DMM). Methods 10-week-old C57Bl/6J male mice underwent DMM surgery (n = 51). After a 5-day post-operative recovery period, we applied daily cyclic tibial compression to the operated limbs at low (1.0N or 2.0N) or moderate (4.5N) magnitudes for 2 or 6 weeks. At the completion of loading, we compared cartilage and peri-articular bone features of mice that underwent DMM and loading to mice that only underwent DMM. Results Compared to DMM alone, low-level cyclic compression for 6 weeks attenuated DMM-induced cartilage degradation (OARSI score, P = 0.008, 95% confidence interval (CI): 0.093 to 0.949). Low-level loading attenuated DMM-induced osteophyte formation after 2 weeks (osteophyte size, P = 0.033, 95% CI: 3.27–114.45 μm), and moderate loading attenuated subchondral bone sclerosis after 6 weeks (tissue mineral density (TMD), P = 0.011, 95% CI: 6.32–70.60 mg HA/ccm) compared to limbs that only underwent DMM. Finally, loading had subtle beneficial effects on cartilage cellularity and aggrecanase activity after DMM. Conclusion Low-level cyclic compression is beneficial to joint health after an injury. Therefore, the progression of early OA may be attenuated by applying well controlled, low-level loading shortly following joint trauma.

The recent surge in Chinese outbound foreign direct investment in Europe has been met with anxiety often invoking national security concerns. Using the national security framework developed by Moran and Oldenski, we try to ascertain which transactions justify apprehension. Our case study is the acquisition by a subsidiary of wholly state-owned State Grid Corporation of China of a 35% stake in CDP Reti S.p.A. (CDP Reti) that controls Italy’s electricity grid via its subsidiary Terna S.p.A. Although State Grid Corporation of China can nominate two members of CDP Reti’s board of directors, we find that there is no direct threat to national security. We then tackle the geopolitical dimension of investments in electricity grids. Using the ‘thought experiment’ developed by Scholten and Bosman, the contribution we make is that, in a world where the importance of renewable energy increases, a framing power rather than control over the strategic development of a country’s grid is sufficient to exert geopolitical power. Since State Grid Corporation of China’s exponents on CDP Reti’s board can at least partly influence the company’s investment decisions, we conclude that the transaction grants China geopolitical influence over Italy’s grid. Furthermore, in the future this type of geopolitical influence could also lead to indirect security concerns. The interconnection of European electricity flows extends this conclusion to the EU’s electricity grid as a whole.

Objectives: Anterior cruciate ligament (ACL) injury is one of the leading orthopedic injuries in young individuals and even with surgical repair it is reported that around 50% of patients develop post-traumatic osteoarthritis (PTOA). Although ACL reconstruction improves anterior-posterior knee joint stability and cartilage contact biomechanics, some studies have shown persistent abnormalities in the tibiofemoral kinematics. Extensive rehabilitation work is often required following both ACL tear and ACL reconstruction surgery. New bone formation (osteophyte) and synovial inflammation (synovitis) are often associated with the progression and severity of OA post-injury and surgery, however the effect of mechanical loading stimulus in musculoskeletal repair remains relatively unexplored. The role played by resident synovial stromal cells in the activation of their local inflammatory and regenerative programming is poorly understood. Work in our laboratory has shown that in vivo imaging of activated fibroblasts using 68Ga-FAP radiotracer may be a valuable tool to follow the progression of OA and the bone-tendon interface healing. This study aims to explore the therapeutic effect of exercise following ACL reconstruction on the progression or mitigation of PTOA following an ACL injury, evaluating the mechanism and contribution of synovial fibroblast activation using microPET/CT imaging. Methods: All study procedures were approved by Weill Cornell IACUC (#2019-0034). Thirty, 12 week old male C57BL/6 mice underwent a non-invasive ACL rupture induced by a single axial compressive load of the tibia at a rate of 1mm/s on the right knee (Fig. 1). One week following injury, the animals were allocated into 4 treatment groups (n=6 per group): non-treated (G1); non-treated with sham surgery (G2); treated with ACL reconstruction (G3); treated with ACL reconstruction and treadmill exercise starting 1 week post-operatively (G4). Six mice were used to harvest the ACL tendon graft (allograft) and their knees scanned in the microCT as healthy controls.Treadmill exercise was performed 5 days/week, at 10m/min for 40min. PET/CT (Inveon scanner - Siemens Medical Solutions) imaging was performed pre-injury (baseline) and at 1, 2, 3, 4 and 8 weeks post-injury to measure fibroblast activation in the joint. One hundred μl of a 7% v/v EtOH/saline solution containing our 68Gallium (Ga)68-labeled fibroblast activation protein alpha (FAP-α) inhibitor (3.7-18.5MBq) was administered by tail vein injection and the mice were scanned for 60 minutes under anesthesia. The knee joint was identified as the region of interest (ROI) and the radioactivity concentration (Bq/ml x %ID/g) within the ROI was calculated using the Siemens imaging software. All animals were euthanized at 8 week post-injury. ACL graft healing and OA development were evaluated by micro-CT, X-Ray and routine histology. Statistical analyses were performed by Two-way ANOVA and Tukey’s post hoc test analysis was used to compare means ± SD. Significance level was defined as p ≤ 0.05. Results: PET/CT scans demonstrated accumulation of 68Ga-FAP in the injured and surgical knees compared to the contralateral healthy control knees (Fig. 2). FAP signal intensity peaked at 1 week after injury and continued increasing at 2 weeks in the surgical groups, with significant differences demonstrated in the ACL reconstructed groups (G3 and G4, pConclusions: The intimal layer of the native synovium is composed of 2 main cell types: macrophages and fibroblast-like cells. Recent studies have shown a correlation between activated macrophages and their association with OA severity and joint symptoms; however, the cross-talk between these 2 types of cells and their contribution to PTOA following ACL injury and reconstruction surgery is poorly understood. Our study identified time-dependent changes in FAP activity following ACL reconstruction and mechanical loading stimulus that could be correlated to PTOA development. Our data demonstrates that ACL reconstruction followed by a low intensity exercise regimen leads to a decrease of FAP activity in the ACL injured knee. We also found that the ACL reconstruction groups had less degenerative changes in the posterior medial tibial plateau, which may be due to an improvement of anterior-posterior joint stability, and the exercise group showed a greater amount of bone formed at the tendon-bone interface of the tibia suggesting a superior graft healing process. Immunochemistry for FAP-α is currently being analyzed to confirm the spatial localization of FAP expression. [Figure: see text][Figure: see text][Figure: see text]