A minimal physical model for curvotaxis driven by curved protein complexes at the cell's leading edge.

Cells often migrate on curved surfaces inside the body, such as curved tissues, blood vessels, or highly curved protrusions of other cells. Recent in vitro experiments provide clear evidence that motile cells are affected by the curvature of the substrate on which they migrate, preferring certain curvatures to others, termed "curvotaxis." The origin and underlying mechanism that gives rise to this curvature sensitivity are not well understood. Here, we employ a "minimal cell" model which is composed of a vesicle that contains curved membrane protein complexes, that exert protrusive forces on the membrane (representing the pressure due to actin polymerization). This minimal-cell model gives rise to spontaneous emergence of a motile phenotype, driven by a lamellipodia-like leading edge. By systematically screening the behavior of this model on different types of curved substrates (sinusoidal, cylinder, and tube), we show that minimal ingredients and energy terms capture the experimental data. The model recovers the observed migration on the sinusoidal substrate, where cells move along the grooves (minima), while avoiding motion along the ridges. In addition, the model predicts the tendency of cells to migrate circumferentially on convex substrates and axially on concave ones. Both of these predictions are verified experimentally, on several cell types. Altogether, our results identify the minimization of membrane-substrate adhesion energy and binding energy between the membrane protein complexes as key players of curvotaxis in cell migration.

Tissue fluidification promotes a cGAS-STING cytosolic DNA response in invasive breast cancer.

The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.

CT radiomic predictors of local relapse after SBRT for lung oligometastases from colorectal cancer: a single institute pilot study.

OBJECTIVES: To assess the potential of radiomic features (RFs) extracted from simulation computed tomography (CT) images in discriminating local progression (LP) after stereotactic body radiotherapy (SBRT) in the management of lung oligometastases (LOM) from colorectal cancer (CRC). MATERIALS AND METHODS: Thirty-eight patients with 70 LOM treated with SBRT were analyzed. The largest LOM was considered as most representative for each patient and was manually delineated by two blinded radiation oncologists. In all, 141 RFs were extracted from both contours according to IBSI (International Biomarker Standardization Initiative) recommendations. Based on the agreement between the two observers, 134/141 RFs were found to be robust against delineation (intraclass correlation coefficient [ICC] > 0.80); independent RFs were then assessed by Spearman correlation coefficients. The association between RFs and LP was assessed with Mann-Whitney test and univariate logistic regression (ULR): the discriminative power of the most informative RF was quantified by receiver-operating characteristics (ROC) analysis through area under curve (AUC). RESULTS: In all, 15/38 patients presented LP. Median time to progression was 14.6 months (range 2.4-66 months); 5/141 RFs were significantly associated to LP at ULR analysis (p < 0.05); among them, 4 RFs were selected as robust and independent: Statistical_Variance (AUC = 0.75, p = 0.002), Statistical_Range (AUC = 0.72, p = 0.013), Grey Level Size Zone Matrix (GLSZM) _zoneSizeNonUniformity (AUC = 0.70, p = 0.022), Grey Level Dependence Zone Matrix (GLDZM) _zoneDistanceEntropy (AUC = 0.70, p = 0.026). Importantly, the RF with the best performance (Statisical_Variance) is simply representative of density heterogeneity within LOM. CONCLUSION: Four RFs extracted from planning CT were significantly associated with LP of LOM from CRC treated with SBRT. Results encourage further research on a larger population aiming to define a usable radiomic score combining the most predictive RFs and, possibly, additional clinical features.

Dynamics of prolate spheroids in the vicinity of an air-water interface.

In this article, we present the mobilities of prolate ellipsoidal micrometric particles close to an air-water interface measured by dual wave reflection interference microscopy. Particle's position and orientation with respect to the interface are simultaneously measured as a function of time. From the measured mean square displacement, five particle mobilities (3 translational and 2 rotational) and two translational-rotational cross-correlations are extracted. The fluid dynamics governing equations are solved by the finite element method to numerically evaluate the same mobilities, imposing either slip and no-slip boundary conditions to the flow at the air-water interface. The comparison between experiments and simulations reveals an agreement with no-slip boundary conditions prediction for the translation normal to the interface and the out-of-plane rotation, and with slip ones for parallel translations and in-plane rotation. We rationalize these evidences in the framework of surface incompressibility at the interface.

Non-invasive measurement of nuclear relative stiffness from quantitative analysis of microscopy data.

The connection between the properties of a cell tissue and those of the single constituent cells remains to be elucidated. At the purely mechanical level, the degree of rigidity of different cellular components, such as the nucleus and the cytoplasm, modulates the interplay between the cell inner processes and the external environment, while simultaneously mediating the mechanical interactions between neighboring cells. Being able to quantify the correlation between single-cell and tissue properties would improve our mechanobiological understanding of cell tissues. Here we develop a methodology to quantitatively extract a set of structural and motility parameters from the analysis of time-lapse movies of nuclei belonging to jammed and flocking cell monolayers. We then study in detail the correlation between the dynamical state of the tissue and the deformation of the nuclei. We observe that the nuclear deformation rate linearly correlates with the local divergence of the velocity field, which leads to a non-invasive estimate of the elastic modulus of the nucleus relative to the one of the cytoplasm. We also find that nuclei belonging to flocking monolayers, subjected to larger mechanical perturbations, are about two time stiffer than nuclei belonging to dynamically arrested monolayers, in agreement with atomic force microscopy results. Our results demonstrate a non-invasive route to the determination of nuclear relative stiffness for cells in a monolayer.

Operations management solutions to improve ED patient flows: evidence from the Italian NHS.

BACKGROUND: Overcrowding occurs when the identified need for emergency services outweighs the available resources in the emergency department (ED). Literature shows that ED overcrowding impacts the overall quality of the entire hospital production system, as confirmed by the recent COVID-19 pandemic. This study aims to identify the most relevant variables that cause ED overcrowding using the input-process-output model with the aim of providing managers and policy makers with useful hints for how to effectively redesign ED operations. METHODS: A mixed-method approach is used, blending qualitative inquiry with quantitative investigation in order to: i) identifying and operationalizing the main components of the model that can be addressed by hospital operation management teams and ii) testing and measuring how these components can influence ED LOS. RESULTS: With a dashboard of indicators developed following the input-process-output model, the analysis identifies the most significant variables that have an impact on ED overcrowding: the type (age and complexity) and volume of patients (input), the actual ED structural capacity (in terms of both people and technology) and the ED physician-to-nurse ratio (process), and the hospital discharging process (output). CONCLUSIONS: The present paper represents an original contribution regarding two different aspects. First, this study combines different research methodologies with the aim of capturing relevant information that by relying on just one research method, may otherwise be missed. Second, this study adopts a hospitalwide approach, adding to our understanding of ED overcrowding, which has thus far focused mainly on single aspects of ED operations.

Disentangling collective motion and local rearrangements in 2D and 3D cell assemblies.

The accurate quantification of cellular motility and of the structural changes occurring in multicellular aggregates is critical in describing and understanding key biological processes, such as wound repair, embryogenesis and cancer invasion. Current methods based on cell tracking or velocimetry either suffer from limited spatial resolution or are challenging and time-consuming, especially for three-dimensional (3D) cell assemblies. Here we propose a conceptually simple, robust and tracking-free approach for the quantification of the dynamical activity of cells via a two-step procedure. We first characterise the global features of the collective cell migration by registering the temporal stack of the acquired images. As a second step, a map of the local cell motility is obtained by performing a mean squared amplitude analysis of the intensity fluctuations occurring when two registered image frames acquired at different times are subtracted. We successfully apply our approach to cell monolayers undergoing a jamming transition, as well as to monolayers and 3D aggregates that exhibit a cooperative unjamming-via-flocking transition. Our approach is capable of disentangling very efficiently and of assessing accurately the global and local contributions to cell motility.

High rate of second ACL injury following ACL reconstruction in male professional footballers: an updated longitudinal analysis from 118 players in the UEFA Elite Club Injury Study.

BACKGROUND: Studies on subsequent anterior cruciate ligament (ACL) ruptures and career length in male professional football players after ACL reconstruction (ACLR) are scarce. AIM: To investigate the second ACL injury rate, potential predictors of second ACL injury and the career length after ACLR. STUDY DESIGN: Prospective cohort study. SETTING: Men's professional football. METHODS: 118 players with index ACL injury were tracked longitudinally for subsequent ACL injury and career length over 16.9 years. Multivariable Cox regression analysis with HR was carried out to study potential predictors for subsequent ACL injury. RESULTS: Median follow-up was 4.3 (IQR 4.6) years after ACLR. The second ACL injury rate after return to training (RTT) was 17.8% (n=21), with 9.3% (n=11) to the ipsilateral and 8.5% (n=10) to the contralateral knee. Significant predictors for second ACL injury were a non-contact index ACL injury (HR 7.16, 95% CI 1.63 to 31.22) and an isolated index ACL injury (HR 2.73, 95% CI 1.06 to 7.07). In total, 11 of 26 players (42%) with a non-contact isolated index ACL injury suffered a second ACL injury. RTT time was not an independent predictor of second ACL injury, even though there was a tendency for a risk reduction with longer time to RTT. Median career length after ACLR was 4.1 (IQR 4.0) years and 60% of players were still playing at preinjury level 5 years after ACLR. CONCLUSIONS: Almost one out of five top-level professional male football players sustained a second ACL injury following ACLR and return to football, with a considerably increased risk for players with a non-contact or isolated index injury.

Multistable interaction between a spherical Brownian particle and an air-water interface.

We report the measurement of the interaction energy between a charged Brownian polystyrene particle and an air-water interface. The interaction potential is obtained from the Boltzmann equation by tracking particle interface distance with a specifically designed Dual-Wave Reflection Interference Microscopy (DW-RIM) setup. The particle has two equilibrium positions located at few hundreds of nanometers from the interface. The farthest position is well accounted by a DLVO model complemented by gravity. The closest one, not predicted by current models, more frequently appears in water solutions at relatively high ions concentrations, when electrostatic interaction is screened out. It is accompanied by a frozen rotational diffusion dynamics that suggests an interacting potential dependent on particle orientation and stresses the decisive role played by particle surface heterogeneities. Building up on both such experimental results, the important role of air nanobubbles pinned on the particle interface is discussed.

Systematic video analysis of ACL injuries in professional male football (soccer): injury mechanisms, situational patterns and biomechanics study on 134 consecutive cases.

BACKGROUND: A few small studies have reported on the mechanisms of ACL injury in professional male football. AIM: To describe the mechanisms, situational patterns and biomechanics (kinematics) of ACL injuries in professional male football matches. METHODS: We identified 148 consecutive ACL injuries across 10 seasons of professional Italian football. 134 (90%) injury videos were analysed for mechanism and situational pattern, while biomechanical analysis was possible in 107 cases. Three independent reviewers evaluated each video. ACL injury epidemiology (month), timing within the match and pitch location at the time of injury were also reported. RESULTS: 59 (44%) injuries were non-contact, 59 (44%) were indirect contact and 16 (12%) were direct contact. Players were frequently perturbed immediately prior to injury. We identified four main situational patterns for players who suffered a non-contact or an indirect contact injury: (1) pressing and tackling (n=55); (2) tackled (n=24); (3) regaining balance after kicking (n=19); and (4) landing from a jump (n=8). Knee valgus loading (n=83, 81%) was the dominant injury pattern across all four of these situational patterns (86%, 86%, 67% and 50%, respectively). 62% of the injuries occurred in the first half of the matches (p<0.01). Injuries peaked at the beginning of the season (September-October) and were also higher at the end of the season (March-May). CONCLUSIONS: 88% of ACL injuries occurred without direct knee contact, but indirect contact injuries were as frequent as non-contact injuries, underlying the importance of mechanical perturbation. The most common situational patterns were pressing, being tackled and kicking.

Compliance in post-operative rehabilitation is a key factor for return to sport after revision anterior cruciate ligament reconstruction.

PURPOSE: To assess the rate of return to sport (RTS) following revision Anterior Cruciate Ligament Reconstruction (ACLR) in a rehabilitation-based cohort of patients. A secondary goal of the study was to evaluate the association between compliance in post-operative rehabilitation and RTS rate. METHODS: The study cohort included 79 sport-active patients (62 males, 17 females, 30.0 ± 10.2 years old) who underwent revision ACLR surgery and followed the same functional-oriented rehabilitation protocol. Patients were evaluated using a RTS survey: return to any kind of sport participation, return to the same pre-injury sport, return to the same sport at the same pre-injury level. With regards to compliance in post-operative rehabilitation, patients were then grouped in (1) Fully Compliant (FC), (2) Moderately Compliant (MC), (3) Scarcely Compliant (SC), and (4) Non-Compliant (NC). RESULTS: At an average follow-up of 29 ± 12 months, 86% of the patients returned to some kind of sport activity, 62% returned to the same pre-injury sport activity and 59% returned to the same pre-injury level of sport activity. While no surgical aspects were correlated with RTS, higher BMI was found to have a negative influence (p = 0.033). Regardless of the type of sport, compliance significantly affected RTS at the same pre-injury level (p = 0.006): 86% in FC, 67% in MC, 50% in SC, and 45% in NC. For each compliance goal achieved, the probability of RTS increased by 68% (OR = 1.68; p = 0.027). CONCLUSION: RTS at the same pre-injury level after revision ACLR is challenging. A higher compliance in rehabilitation significantly increases the chances of RTS. LEVEL OF EVIDENCE: IV.

The influence of preoperative dependency on mortality, functional recovery and complications after microsurgical resection of intracranial tumors.

INTRODUCTION: The decision whether to operate on patients with intracranial tumors is complex and influenced by patient-specific factors, including the preoperative functional status. This work assesses the risks for mortality and complications, and post-operative recovery in functionally dependent patients undergoing microsurgical resection of intracranial tumors. METHODS: Observational two-center study, analyzing institutional registry data. Dependency was defined as admission Karnofsky Performance Scale (KPS) of ≤ 50. The primary endpoint was in-hospital mortality. Secondary endpoints were rate and type [Clavien-Dindo grade (CDG)] of complications, as well as postoperative change in KPS until the 3-month follow-up (M3). RESULTS: Of n = 1951 patients, n = 98 (5.0%) were dependent. Mortality rates were 2.0% for dependent and 0.4% for independent patients (p = 0.018). In univariable analysis, dependent patients were more likely than independent patients to die in hospital (OR 5.49, 95% CI 1.12-26.8, p = 0.035). In a multivariable model, the effect was slightly attenuated (OR 4.75, 95% CI 0.91-24.7, p = 0.064). Dependent patients tended to experience more postoperative complications. They were more likely to suffer from a severe complication (CDG 4 and 5; OR 3.55, 95% CI 1.49-8.46, p = 0.004). In 40.8 and 52.4% of cases, dependent patients regained functional independence at discharge and M3, respectively. CONCLUSIONS: In operated patients with intracranial tumors presenting functionally dependent at admission, the risk for in-hospital mortality and complications is elevated. However, if conducted successfully, surgery may lead to regain of independence in every second patient within 3 months.

Health care multidisciplinary teams: The sociotechnical approach for an integrated system-wide perspective.

BACKGROUND: The current literature on the enabling conditions of multidisciplinary teams focuses on the singular dimensions of the organizations (i.e., human resources, clinical pathways, objects) without shedding light on to the way in which these organizational factors interact and mutually influence one another. PURPOSE: Drawing on a system perspective of organizations, the authors analyze the organizational patterns that promote and support multidisciplinary teams and how they interrelate and interact to enforce the organization work system. METHODOLOGY/APPROACH: The authors develop a modified sociotechnical system (STS) model to understand how the two dimensions of technical (devices/tools, layout/organization of space, core process standardization) and social (organizational structure, management of human resources and operations) can facilitate the implementation of multidisciplinary teams in health care. The study conducts an empirical analysis based on a sample of hospital adopters of transcatheter aortic valve implantation using the revised STS model. FINDINGS: The modified STS model applied to the case studies improves our understanding of the critical implementation factors of a multidisciplinary approach and the importance of coordinating radical changes in the technical and the social subsystems of health care organizations. The analysis informs that the multidisciplinary effort is not a sequential process and that the interplay between the two subsystems needs to be managed efficaciously as an integrated organizational whole to deliver the goals set. PRACTICE IMPLICATIONS: Hospital managers must place equal focus on the closely interrelated technical and social dimensions by investing in (a) shared layouts and spaces that cross the boundaries of the specialized health care units, (b) standardization of the core processes through the implementation of local clinical pathways,

Subtemporal approach for distal basilar occlusion for giant aneurysm. Nuances and advantages of the subtemporal approach.

We described the subtemporal approach, which was used for distal basilar artery occlusion in a patient with a symptomatic giant unclippable aneurysm. We discuss issues related to positioning and lumbar drainage. We illustrate the basic steps: identification of the tentorial notch; sharp opening of the arachnoid behind the third nerve; placement of a fixed mechanical retractor to "hold" the brain; identification of the third nerve and mobilization from arachnoid attachments; identification of the course and insertion of the fourth nerve; division and retraction of the tentorial edge to enhance exposure; preparation of the "perforator-free zone"; and final clip application followed by ICG fluorescein angiography. We show some of the areas exposed with this approach. The video can be found here: http://youtu.be/S_NLIjKQL_o .

After revision anterior cruciate ligament reconstruction, who returns to sport? A systematic review and meta-analysis.

BACKGROUND: Return to sport and to pre-injury level represents an important outcome after both primary and revision anterior cruciate ligament (ACL) reconstructions. PURPOSE: The aim of the present meta-analysis was to determine the return to sport rate after revision ACL reconstruction. MATERIAL AND METHODS: A systematic search was performed of the MEDLINE, Embase and the Cochrane Central Register of Controlled Trials Databases. All the studies that reported return to sport, return to pre-injury sport level and return to high level/competitive sport was considered for the meta-analysis. The overall pooled mean of post-operative knee laxity and pooled rate of positive pivot-shift and objective International Knee Documentation Committee (IKDC) categories was calculated as well. RESULTS: Overall, 472 abstracts were identified and screened for inclusion and only 16 studies reported the rate of return to any level of sport activity at the final follow-up of 4.7 years (range 1.0-13.2 years), showing a pooled rate of 85.3% (CI 79.7 to 90.2). The return to pre-injury sport level was achieved in 53.4% (CI 37.8 to 68.7) of cases. Normal or quasi-normal objective IKDC, less than 5 mm of side-to-side difference at arthrometric evaluations and grade I-II pivot-shift test were reported in 84%, 88% and 93% patients, respectively. CONCLUSIONS: In spite of almost 8 patients out of 10 returning to sport after revision ACL reconstruction and showing good stability, only half of the patients returned to the same pre-injury sport level.

Revision anterior cruciate ligament reconstruction: clinical outcome and evidence for return to sport.

PURPOSE: An increasing number of patients undergo revision anterior cruciate ligament (ACL) reconstruction, with the intention of returning to sport being a major indication. The aim of this study is to assess the available evidence for clinical improvement and return to sport, to understand the real potential of this procedure in regaining functional activity, and to facilitate improved counselling of patients regarding the expected outcome after revision ACL reconstruction. METHODS: The search was conducted on the PubMed database. Articles reporting clinical results for revision ACL reconstruction were included. A meta-analysis was performed on return to sport, and results were compared to the literature on primary ACL reconstruction. Other specific clinical outcomes (Lysholm, Tegner, IKDC Objective scores) were also included in the meta-analysis. RESULTS: Of the 503 identified records, a total of 59 studies involving 5365 patients were included in the qualitative data synthesis. Only 31 articles reported the rate of return to sport. Whereas 73 % of good objective results and satisfactory subjective results were documented, 57 % of patients did not return to the same level of sport activity, significantly inferior to that of a primary procedure. CONCLUSION: The real potential of revision ACL reconstruction should not be overestimated due to the low number of patients able to return to their previous activity level, significantly inferior with respect to that reported for primary ACL reconstruction. This finding will help physicians in the clinical practice providing realistic expectations to the patients. Future studies should focus on participation-based outcome measures such as return to sport and in strategies to improve the results in terms of return to previous activities after revision ACL reconstruction. LEVEL OF EVIDENCE: Systematic review and meta-analysis including Level IV studies, Level IV.