Nanomechanical Mapping of Hard Tissues by Atomic Force Microscopy: An Application to Cortical Bone

Force mapping of biological tissues via atomic force microscopy (AFM) probes the mechanical properties of samples within a given topography, revealing the interplay between tissue organization and nanometer-level composition. Despite considerable attention to soft biological samples, constructing elasticity maps on hard tissues is not routine for standard AFM equipment due to the difficulty of interpreting nanoindentation data in light of the available models of surface deformation. To tackle this issue, we proposed a protocol to construct elasticity maps of surfaces up to several GPa in moduli by AFM nanoindentation using standard experimental conditions (air operation, nanometrically sharp spherical tips, and cantilever stiffness below 30 N/m). We showed how to process both elastic and inelastic sample deformations simultaneously and independently and quantify the degree of elasticity of the sample to decide which regime is more suitable for moduli calculation. Afterwards, we used the frequency distributions of Young’s moduli to quantitatively assess differences between sample regions different for structure and composition, and to evaluate the presence of mechanical inhomogeneities. We tested our method on histological sections of sheep cortical bone, measuring the mechanical response of different osseous districts, and mapped the surface down to the single collagen fibril level

NSCLC Biomarkers to Predict Response to Immunotherapy with Checkpoint Inhibitors (ICI): From the Cells to In Vivo Images

SIMPLE SUMMARY: Lung cancer and in particular non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death. The development of new therapeutic approaches, including immunotherapy, has led to substantial improvement in survival time and quality of life. However, the clinical benefit of immunotherapy-based strategies is still limited to a minority of patients, reflecting the need to identify predictive biomarkers of response, which are any substance, structure, or process or its products that can be measured in the body and that can influence or predict clinical response. In this work, we provide an overview of the approved and the most promising investigational biomarkers, which have been assessed in vitro/ex vivo and in vivo, to identify patients who could benefit the most from immunotherapy-based treatment. ABSTRACT: Lung cancer remains the leading cause of cancer-related death, and it is usually diagnosed in advanced stages (stage III or IV). Recently, the availability of targeted strategies and of immunotherapy with checkpoint inhibitors (ICI) has favorably changed patient prognosis. Treatment outcome is closely related to tumor biology and interaction with the tumor immune microenvironment (TME). While the response in molecular targeted therapies relies on the presence of specific genetic alterations in tumor cells, accurate ICI biomarkers of response are lacking, and clinical outcome likely depends on multiple factors that are both host and tumor-related. This paper is an overview of the ongoing research on predictive factors both from in vitro/ex vivo analysis (ranging from conventional pathology to molecular biology) and in vivo analysis, where molecular imaging is showing an exponential growth and use due to technological advancements and to the new bioinformatics approaches applied to image analyses that allow the recovery of specific features in specific tumor subclones

A biologically inspired neural network controller for ballistic arm movements

<p>Abstract</p> <p>Background</p> <p>In humans, the implementation of multijoint tasks of the arm implies a highly complex integration of sensory information, sensorimotor transformations and motor planning. Computational models can be profitably used to better understand the mechanisms sub-serving motor control, thus providing useful perspectives and investigating different control hypotheses. To this purpose, the use of Artificial Neural Networks has been proposed to represent and interpret the movement of upper limb. In this paper, a neural network approach to the modelling of the motor control of a human arm during planar ballistic movements is presented.</p> <p>Methods</p> <p>The developed system is composed of three main computational blocks: 1) a parallel distributed learning scheme that aims at simulating the internal inverse model in the trajectory formation process; 2) a pulse generator, which is responsible for the creation of muscular synergies; and 3) a limb model based on two joints (two degrees of freedom) and six muscle-like actuators, that can accommodate for the biomechanical parameters of the arm. The learning paradigm of the neural controller is based on a pure exploration of the working space with no feedback signal. Kinematics provided by the system have been compared with those obtained in literature from experimental data of humans.</p> <p>Results</p> <p>The model reproduces kinematics of arm movements, with bell-shaped wrist velocity profiles and approximately straight trajectories, and gives rise to the generation of synergies for the execution of movements. The model allows achieving amplitude and direction errors of respectively 0.52 cm and 0.2 radians.</p> <p>Curvature values are similar to those encountered in experimental measures with humans.</p> <p>The neural controller also manages environmental modifications such as the insertion of different force fields acting on the end-effector.</p> <p>Conclusion</p> <p>The proposed system has been shown to properly simulate the development of internal models and to control the generation and execution of ballistic planar arm movements. Since the neural controller learns to manage movements on the basis of kinematic information and arm characteristics, it could in perspective command a neuroprosthesis instead of a biomechanical model of a human upper limb, and it could thus give rise to novel rehabilitation techniques.</p

Asymptomatic and symptomatic deep venous thrombosis in hospitalized acutely ill medical patients: risk factors and therapeutic implications

Background Acutely ill medical patients experience deep venous thrombosis (DVT) during the hospitalization, however the time course of DVT is still unclear. Objectives To evaluate risk factors in acutely ill hospitalized medical patients for proximal asymptomatic DVT (ADVT) and symptomatic DVT (SDVT) at admission and discharge. Patients/Methods In this prospective observational study, consecutive acutely ill medical patients (hospitalized mainly for acute medical disease as infections, neoplasm, anemia, heart failure) underwent compression ultrasonography (CUS) of proximal lower limb veins within 48 h from admission and at discharge to diagnose ADVT and SDVT. Covid-19 patients, anticoagulant therapy, surgical procedures, acute SDVT, and acute pulmonary embolism, were exclusion criteria. Biographical characteristics at hospitalization, D-Dimer (assessed by ELISA)) and DD-improve score. Results Of 2,100 patients (1002 females, 998 males, age 71 +/- 16 years) 58 (2.7%) had proximal ADVT at admission. Logistic regression analysis showed that age, and active cancer were independently associated with ADVT at admission. The median length of hospitalization was 10 days [interquartile range: 6-15]. During the hospital stay, 6 patients (0.3%) with a negative CUS at admission experienced DVT (2 SDVT and 4 ADVT). In the subgroup of patients (n = 1118), in whom D-dimer was measured at admission, D-Dimer and IMPROVE-DD score were associated with ADVT at admission (n = 37) and with all DVT (n = 42) at discharge. ROC curve defined an IMPROVE-DD score of 2.5 as the optimal cut-off for discriminating patients with and without thrombotic events. Conclusions We provide evidence of early development of ADVT in unselected acutely ill medical patients suggesting the need of investigating patients by CUS immediately after hospital admission (within 48 h). Advanced age, active cancer, known thrombophilia and increased IMPROVE-DD score may identify patients at risk. The benefit of anticoagulation needs to be investigated in patients with these specific risk factors and negative CUS at admission

Rate and predictors of thromboprophylaxis in internal medicine wards: Results from the AURELIO study

Background: Randomized controlled trials suggest that prophylactic doses of anticoagulants effectively prevent venous thromboembolism (VTE) in hospitalized medical patients with high thromboembolic risk. However, no prospective studies exist regarding the real-world prevalence of prophylactic anticoagulant use. This prospective study aimed to determine the rate and predictors of thromboprophylaxis in an unselected population of patients hospitalized in medical departments. Methods: We conducted a multicenter prospective observational study (AURELIO - rAte of venous thrombosis in acutely iLl patIents hOspitalized) to assess the rate of deep vein thrombosis (DVT) in unselected acutely ill patients hospitalized in medical wards using compression ultrasound (CUS) at admission and discharge. Additionally, we evaluated the rate of pharmacological thromboprophylaxis administration in this population and analyzed the thrombotic risk by assessing RAMs (Risk Assessment Models) such as the IMPROVE-VTE and PADUA scores following the clinician's decision to administer thromboprophylaxis. Patients with IMPROVE-VTE scores ≥3 and/or PADUA scores ≥4 were classified as high thrombotic risk; those with IMPROVE-VTE scores &lt;3 and/or PADUA scores &lt;4 were classified as low risk. Results: We recruited 2371 patients (1233 males [52&nbsp;%] and 1138 females [48&nbsp;%]; mean age 72&nbsp;±&nbsp;16&nbsp;years). The median length of hospitalization was 13&nbsp;±&nbsp;12&nbsp;days. Overall, 442/2371 (18.6&nbsp;%) patients received prophylactic parenteral anticoagulants (subcutaneous low weight molecular heparin or fondaparinux once daily) at admission. Assessing the thrombotic risk of the population recruited 1016 (42.9&nbsp;%) patients were classified as high risk and 1354 (57.1&nbsp;%) were low risk. Among high-risk patients, 339/1016 (33.4&nbsp;%) received anticoagulant prophylaxis compared to 103/1354 (7.6&nbsp;%) low-risk patients. During hospitalization, 9 patients developed DVT, comprising 7 asymptomatic and 2 symptomatic cases of proximal DVT. Of these, 3 patients were on anticoagulant prophylaxis, while 6 were not. Among the high-risk population, 7 out of 1016 patients (0.7&nbsp;%) experienced proximal DVT during hospitalization, with 2 out of these 7 (28&nbsp;%) receiving anticoagulant thromboprophylaxis. In the low-risk population, 2 out of 1354 patients (0.2&nbsp;%) developed DVT, with 1 out of these 2 (50&nbsp;%) receiving anticoagulant thromboprophylaxis. Age, heart or respiratory failure, pneumonia, active neoplasia, previous VTE, reduced mobility, and absence of kidney failure were more frequent in patients receiving prophylaxis. Multivariable logistic regression identified age (RR 1.010; CI 95&nbsp;% 1002-1019; p&nbsp;=&nbsp;0.015), heart/respiratory failure (RR 1.609; CI 95&nbsp;% 1248-2075; p&nbsp;&lt;&nbsp;0.0001), active neoplasia (RR 2.041; CI 95&nbsp;% 1222-2141; p&nbsp;&lt;&nbsp;0.0001), pneumonia (RR 1.618; CI 95&nbsp;% 1557-2676; p&nbsp;&lt;&nbsp;0.0001), previous VTE (RR 1.954; CI 95&nbsp;% 1222-3125; p&nbsp;&lt;&nbsp;0.0001), and reduced mobility (RR 4.674; CI 95&nbsp;% 3700-5905; p&nbsp;&lt;&nbsp;0.0001) as independent predictors of thromboprophylaxis. Conclusions: This study, conducted without pre-established thromboembolic risk scores, offers a comprehensive view of venous thromboembolism prophylaxis in medical patients with acute conditions hospitalized in internal medicine departments. It reveals that advanced age, heart or respiratory failure, active cancer, pneumonia, previous VTE, and reduced mobility are predictors that may influence the decision to administer thromboprophylaxis in these patients

Maximum ground reaction force in relation to tibial bone mass in children and adults

PURPOSE:: To assess maximum voluntary forefoot ground reaction force (Fm1LH) during multiple one-legged hopping (m1LH, a new jumping maneuver) and to determine the correlation between tibial volumetric bone mineral content (vBMC, a valid surrogate of bone strength) and Fm1LH. METHODS:: One hundred and eighty-five females (8-82 years old) and 138 males (8-71 years old) performed m1LH to measure Fm1LH acting on the forefoot during landing. Peripheral quantitative computed tomography (pQCT) scans were obtained to assess vBMC at 4, 14, 38 and 66% tibia length and calf muscle cross-sectional area (Ar.muscle) at the 66%-site. RESULTS:: In all 323 participants, Fm1LH corresponded to 3-3.5 times body weight, and Fm1LH predicted vBMC14% by 84.0% (P < 0.001). vBMC14% was better correlated with Fm1LH than with Ar.muscle in both males (R = 0.841 vs. R = 0.724) and females (R = 0.765 vs. R = 0.597). Fm1LH and vBMC14% both increased during growth and afterwards remained constant or decreased with age, but never increased above the values reached at the end of puberty. Fm1LH decreased by 23.6% between 21-30 and 61-82 years in females and by 14.0% between 31-40 and 51-71 years in males. vBMC14% decreased by 13.7% in females between 21-30 and 61-82 years but remained unchanged in adult males. CONCLUSIONS:: m1LH yields the highest (i.e. maximum) ground reaction force relative to other jumping maneuvers. Since bone strength is strongly governed by maximum muscle force, the concurrent assessment of pQCT-derived bone strength and Fm1LH might represent a new approach for the operational evaluation of musculoskeletal health