IntroductionDegenerative alterations in proteoglycans content and collagen structure compromise the mechanical integrity of articular cartilage and, therefore, its viscoelastic properties. Early detection of these subtle alterations is a prerequisite for enabling intervention with promising treatments under development. Although magnetic resonance imaging provides valuable compositional information, its limited spatial resolution restricts its effectiveness in evaluating thin, soft tissues such as articular cartilage. Contrast-enhanced high-resolution peripheral quantitative computed tomography (HR-pQCT) offers an optimal compromise between spatial resolution and radiation exposure, enabling high-resolution evaluation of the cartilage layer and potentially overcoming this limitation. This study investigated the feasibility of using HR-pQCT enhanced with the cationic contrast agent CA4+ to determine the proteoglycan gradient and thickness of articular cartilage from bovine stifle joints.MethodsThe accuracy of thickness measurements was assessed by comparison with micro-computed tomography (μCT) measurements. It also investigated whether the local CT number (mean HU value of the articular cartilage, either uncorrected or corrected to the HU value of CA4+ bath) correlates with tissue mechanical competence. The latter was evaluated in terms of instantaneous, stress-relaxation and equilibrium responses by indenting the cartilage layer with a spherical indenter up to 15%, a value representative of the level of tissue deformation occurring in vivo.Results and discussionA depth-wise gradient of CT number was distinguishable within the articular cartilage in contrast-enhanced HR-pQCT, allowing in post-processing the subdivision of cartilage into its three main layers. Additionally, contrast-enhanced imaging enabled the accurate quantification of articular cartilage thickness. Significant relationships of varying strength, assessed using Spearman’s rank correlation coefficient (ρ), were found between thickness and instantaneous elastic response (ρ = −0.85), stress-relaxation behaviour (ρ = −0.61), and equilibrium elastic response (ρ = −0.38) of articular cartilage. The same relationship with CT number showed comparable strength. These results, achieved through investigation of healthy bovine articular cartilage, support extending the proposed approach to human articular cartilage. The proposed approach, based on high-resolution X-ray scanner imaging enhanced with a cationic contrast agent, may have the potential to discriminate early-degenerated tissue by capturing subtle local alterations in thickness or CT number gradients. This could reveal changes in the relative thicknesses of the superficial, middle, and deep layers, across the articular surface, while also providing an indication of local alterations to the mechanical competence of the articular cartilage.

X-ray imaging of articular cartilage could be a breakthrough for the early diagnosis of tissue degeneration. This approach relies on radiopaque contrast agents to enhance the visualization of soft tissues. The potential impact of contrast agents on the mechanical response of articular cartilage should be considered in the frame of both clinical and research applications. Attention has been drawn to a solution containing molecules with six iodine atoms and four positive charges (CA4+), which has been shown to improve the X-ray visibility of articular cartilage. This study aimed to determine the effects of a CA4+ solution on tissues’ mechanical properties. An experimental pipeline based on indentation tests was applied to paired samples of articular cartilage before and after the immersion in either CA4+ or phosphate-buffered saline solution, maintained at a temperature of 22 ± 2 °C, for 22 h to determine the differences in instantaneous, viscous, and equilibrium responses between the articular cartilage of the two groups. The 22 h immersion of articular cartilage in either CA4+ or phosphate-buffered saline solution had a significant detrimental effect on the overall response, including the instantaneous, viscous, and equilibrium responses, of the articular cartilage. However, this detrimental effect was greater with exposure to the CA4+ solution. Specifically, the articular cartilage was found to be less stiff in both the instantaneous response (approximately −25%) and the equilibrium response (approximately −38%). The softening effect could be attributable to an alteration of the interaction between the proteoglycans of articular cartilage, induced by the positive charges within the CA4+ contrast agent. Further investigations are needed to elucidate whether this hypothesized mechanism is reversible.

PurposeTo investigate whether the risk of peripheral nerve stimulation increases in the presence of bulky metallic prostheses implanted in a patient's body.MethodsA computational tool was used to calculate the electric field (E-field) induced in a realistic human model due to the action of gradient fields. The calculations were performed both on the original version of the anatomical model and on a version modified through "virtual surgery" to incorporate knee, hip, and shoulder prostheses. Five exam positions within a body gradient coil and one position using a head gradient coil were simulated, subjecting the human model to the readout gradient from an EPI sequence. The induced E-field in models with and without prostheses was compared, focusing on the nerves and all other tissues (both including and excluding the bones from the analysis).ResultsIn the nerves, the most pronounced increase in the E-field (+24%) was observed around the knee implant during an abdominal MRI (Y axis readout). When extending the analysis to encompass all tissues (excluding bones), the greatest amplification (+360%) occurred around the knee implant during pelvic MRI (Z axis readout). Notable increases in E-field peaks were also identified around the shoulder and hip implants in multiple scenarios.ConclusionBased on the presented results, further investigations aimed at quantifying the threshold of nerve stimulation in the presence of bulky implants are desirable.

The biological aspects of infancy within late Upper Palaeolithic populations and the role of southern refugia at the end of the Last Glacial Maximum are not yet fully understood. This study presents a multidisciplinary, high temporal resolution investigation of an Upper Palaeolithic infant from Grotta delle Mura (Apulia, southern Italy) combining palaeogenomics, dental palaeohistology, spatially-resolved geochemical analyses, direct radiocarbon dating, and traditional anthropological studies. The skeletal remains of the infant - Le Mura 1 - were directly dated to 17,320-16,910 cal BP. The results portray a biological history of the infant's development, early life, health and death (estimated at similar to 72 weeks). They identify, several phenotypic traits and a potential congenital disease in the infant, the mother's low mobility during gestation, and a high level of endogamy. Furthermore, the genomic data indicates an early spread of the Villabruna-like components along the Italian peninsula, confirming a population turnover around the time of the Last Glacial Maximum, and highlighting a general reduction in genetic variability from northern to southern Italy. Overall, Le Mura 1 contributes to our better understanding of the early stages of life and the genetic puzzle in the Italian peninsula at the end of the Last Glacial Maximum.

PURPOSE:To quantify the extent of gradient-induced vibrations, and the magnitude of motion-induced displacement forces ("Lenz effect"), in conductive nonmagnetic orthopedic prostheses. METHODS:The investigation is carried out through numerical simulations, for a 3 T scanner. For gradient-induced torques and vibrations, a knee and a shoulder implant are considered, at dB/dt equal to 42 T/s (rms). For motion-induced forces associated with the Lenz effect, a knee and a hip implant are studied, considering a patient who translates on the examination couch, or walks next to it. RESULTS:Gradient-induced torques may be within the same order of magnitude as the worst case gravitational torque defined in the ASTM standards. However, for all investigated cases, they result to be lower. In vacuum, the extent of the corresponding vibration reduces with frequency. At the lowest investigated frequency (270 Hz), it keeps below 25 μm. For an implant partially embedded in bone, the extent of the vibration increases with frequency. Nevertheless, the displacement is far lower than the worst case observed in vacuum (negligible in contact with the bone; ˜1 μm or less where the implant emerges from the bone). The Lenz effect induced by the motion of the patient through the stationary magnetic field produces forces on the order of a few millinewtons (i.e., at least two orders of magnitude lower than the implant weight). CONCLUSION:Comparing the results with mechanical loads caused by ordinary activities of daily living, and with the levels of tolerable micromotions, a good safety margin is confirmed.

Micro-computed tomography ( CT) is the gold standard for nondestructive 3D imaging of biomedical samples in the centimeter scale, but it has limited effectiveness in revealing intricate soft tissue details due to the limited attenuation contrast. Radiopaque contrast agents that accumulate in the structures of interest are employed to enhance their visibility. However, the increased attenuation provided by the contrast agents does not guarantee discrimination among tissues. This issue can be solved by spectral CT (S CT) systems employing small-pixel chromatic photon-counting detectors. These detectors, combined with material decomposition algorithms, allow the generation of high-resolution material-specific 3D maps. This work aims to demonstrate the potential of photon-counting X-ray S CT on osteochondral samples loaded with a cationic iodinated contrast agent (CA4+) at a spatial resolution below 50 m, and to compare the results against a conventional CT system. An osteochondral sample extracted from a bovine stifle joint was loaded with CA4+ and imaged with a novel multimodal X-ray imaging system, featuring a 62 m pixel CdTe spectral detector (Pixirad1-PixieIII). After material decomposition, quantitative 3D density maps of iodine and hydroxyapatite were reconstructed. The same sample was also scanned with a commercial CT scanner with matched spectrum and exposure time. SCT images at a (measured) spatial resolution comparable with the commercial scanner ( ∼ 45 m) were obtained. Spectral images allowed for a fully automatic segmentation of cartilage and subchondral bone. The unambiguous discrimination between iodine and hydroxyapatite revealed a more realistic representation of proteoglycan distribution compared to conventional imaging.

Metal components of hip prostheses cause severe artifacts in CT images, influencing diagnostic accuracy. Metal artifact reduction (MAR) software and virtual monoenergetic reconstructions on dual-energy CT (DECT) systems are possible solutions that should be considered. In this study, we created a customized adjustable phantom to quantify the severity of artifacts on periprosthetic tissues (cortical and spongious bone, soft tissues) for hip prostheses. The severity of artifacts was classified by different thresholds of deviation from the CT numbers for reference objects not affected by artifacts. The in vitro setup was applied on four unilateral and three bilateral configurations of hip prostheses (made of titanium, cobalt, and stainless steel alloys) with a DECT system, changing the energy of virtual monoenergetic reconstructions, with and without MAR. The impact of these tools on the severity of artifacts was scored, looking for the best scan conditions for the different configurations. For titanium prostheses, the reconstruction at 110 keV, without MAR, always minimized the artifacts. For cobalt and stainless-steel prostheses, MAR should always be applied, while monoenergetic reconstruction alone did not show clear advantages. The available tools for reducing metal artifacts must therefore be applied depending on the examined prosthetic configuration.

Objectives The study of the development of human bipedalism can provide a unique perspective on the evolution of morphology and behavior across species. To generate new knowledge of these mechanisms, we analyze changes in both internal and external morphology of the growing human talus in a sample of modern human juveniles using an innovative approach. Materials and Methods The sample consists of high-resolution microCT scans of 70 modern juvenile tali, aged between 8 postnatal weeks and 10 years old, from a broad chronological range from Middle/Late Neolithic, that is, between 4800 and 4500 BCE, to the 20th century. We applied geometric morphometric and whole-bone trabecular analysis (bone volume fraction, degree of anisotropy, trabecular number, thickness, and spacing) to all specimens to identify changes in the external and internal morphology during growth. Morphometric maps were also generated. Results During the first year of life, the talus has an immature and globular shape, with a dense, compact, and rather isotropic trabecular architecture, with numerous trabeculae packed closely together. This pattern changes while children acquire a more mature gait, and the talus tends to have a lower bone volume fraction, a higher anisotropy, and a more mature shape. Discussion The changes in talar internal and external morphologies reflect the different loading patterns experienced during growth, gradually shifting from an "unspecialized" morphology to a more complex one, following the development of bipedal gait. Our research shows that talar plasticity, even though genetically driven, may show mechanical influences and contribute to tracking the main locomotor milestones.

The manual segmentation of muscles on magnetic resonance images is the gold standard procedure to reconstruct muscle volumes from medical imaging data and extract critical information for clinical and research purposes. (Semi)automatic methods have been proposed to expedite the otherwise lengthy process. These, however, rely on manual segmentations. Nonetheless, the repeatability of manual muscle volume segmentations performed on clinical MRI data has not been thoroughly assessed. When conducted, volumetric assessments often disregard the hip muscles. Therefore, one trained operator performed repeated manual segmentations (n = 3) of the iliopsoas (n = 34) and gluteus medius (n = 40) muscles on coronal T1-weighted MRI scans, acquired on 1.5 T scanners on a clinical population of patients elected for hip replacement surgery. Reconstructed muscle volumes were divided in sub-volumes and compared in terms of volume variance (normalized variance of volumes - nVV), shape (Jaccard Index-JI) and surface similarity (maximal Hausdorff distance-HD), to quantify intra-operator repeatability. One-way repeated measures ANOVA (or equivalent) tests with Bonferroni corrections for multiple comparisons were conducted to assess statistical significance. For both muscles, repeated manual segmentations were highly similar to one another (nVV: 2-6%, JI > 0.78, HD < 15 mm). However, shape and surface similarity were significantly lower when muscle extremities were included in the segmentations (e.g., iliopsoas: HD -12.06 to 14.42 mm, P < 0.05). Our findings show that the manual segmentation of hip muscle volumes on clinical MRI scans provides repeatable results over time. Nonetheless, extreme care should be taken in the segmentation of muscle extremities.

Objective. To quantify the effects of different levels of realism in the description of the anatomy around hip, knee or shoulder implants when simulating, numerically, radiofrequency and gradient-induced heating in magnetic resonance imaging. This quantification is needed to define how precise the digital human model modified with the implant should be to get realistic dosimetric assessments. Approach. The analysis is based on a large number of numerical simulations where four 'levels of realism' have been adopted in modelling human bodies carrying orthopaedic implants. Main results. Results show that the quantification of the heating due to switched gradient fields does not strictly require a detailed local anatomical description when preparing the digital human model carrying an implant. In this case, a simple overlapping of the implant CAD with the body anatomy is sufficient to provide a quite good and conservative estimation of the heating. On the contrary, the evaluation of the electromagnetic field distribution and heating caused by the radiofrequency field requires an accurate description of the tissues around the prosthesis. Significance. The results of this paper provide hints for selecting the 'level of realism' in the definition of the anatomical models with embedded passive implants when performing simulations that should reproduce, as closely as possible, the in vivo scenarios of patients carrying orthopaedic implants.

Osteoporosis-related hip fragility fractures are a catastrophic event for patient lives but are not frequently observed in prospective studies, and therefore phase III clinical trials using fractures as primary clinical endpoint require thousands of patients enrolled for several years to reach statistical significance. A novel answer to the large number of subjects needed to reach the desired evidence level is offered by In Silico Trials, that is, the simulation of a clinical trial on a large cohort of virtual patients, monitoring the biomarkers of interest. In this work we investigated if statistical aliasing from a custom anatomy atlas could be used to expand the patient cohort while retaining the original biomechanical characteristics. We used a pair-matched cohort of 94 post-menopausal women (at the time of the CT scan, 47 fractured and 47 not fractured) to create a statistical anatomy atlas through principal component analysis, and up-sampled the atlas in order to obtain over 1000 synthetic patient models. We applied the biomechanical computed tomography pipeline to the resulting virtual cohort and compared its fracture risk distribution with that of the original physical cohort. While the distribution of femoral strength values in the non-fractured sub-group was nearly identical to that of the original physical cohort, that of the fractured sub-group was lower than in the physical cohort. Nonetheless, by using the classification threshold used for the original population, the synthetic population was still divided into two parts of approximatively equal number.

The aim of this study was the preliminary assessment of a new cationic contrast agent, the CA4+, via the analysis of spatial distribution in cartilage of ex vivo bovine samples, at micrometer and millimeter scale. Osteochondral plugs (n = 18) extracted from bovine stifle joints (n = 2) were immersed in CA4+ solution up to 26 h. Planar images were acquired at different time points, using a microCT apparatus. The CA4+ distribution in cartilage and saturation time were evaluated. Tibial plates from bovine stifle joints (n = 3) were imaged with CT, before and after 24 h-CA4+ bath immersion, at different concentrations. Afterward, potential CA4+ washout from cartilage was investigated. From microCT acquisitions, the CA4+ distribution differentiated into three distinct layers inside the cartilage, reflecting the spatial distribution of proteoglycans. After 24 h of diffusion, the iodine concentration reached in cartilage was approximately seven times that of the CA4+ bath. The resulting saturation time was 1.9 ± 0.9 h and 2.6 ± 2.9 h for femoral and tibial samples, respectively. Analysis of clinical CT acquisitions confirmed overall contrast enhancement of cartilage after 24 h immersion, observed for each CA4+ concentration. Distinct contrast enhancement was reached in different cartilage regions, depending on tissue's local features. Incomplete but remarkable washout of cartilage was observed. CA4+ significantly improved cartilage visualization and its qualitative analysis.

Due to the large variety of possible clinical scenarios, a reliable heating-risk assessment is not straightforward when patients with arthroplasty undergo MRI scans. This paper proposes a simple procedure to estimate the thermal effects induced in patients with hip, knee, or shoulder arthroplasty during MRI exams. The most representative clinical scenarios were identified by a preliminary frequency analysis, based on clinical service databases, collecting MRI exams of 11,658 implant carrier patients. The thermal effects produced by radiofrequency and switching gradient fields were investigated through 588 numerical simulations performed on an ASTM-like phantom, considering four prostheses, two static field values, seven MR sequences, and seven regions of imaging. The risk assessment was inspired by standards for radiofrequency fields and by scientific studies for gradient fields. Three risk tiers were defined for the radiofrequency, in terms of whole-body and local SAR averages, and for GC fields, in terms of temperature elevation. Only 50 out of 588 scenarios require some caution to be managed. Results showed that the whole-body SAR is not a self-reliant safety parameter for patients with metallic implants. The proposed numerical procedure can be easily extended to any other scenario, including the use of detailed anatomical models.

OBJECTIVE:The development of bipedalism is a very complex activity that contributes to shaping the anatomy of the foot. The talus, which starts ossifying in utero, may account for the developing stages from the late gestational phase onwards. Here, we explore the early development of the talus in both its internal and external morphology to broaden the knowledge of the anatomical changes that occur during early development.MATERIALS AND METHODS:The sample consists of high-resolution microCT scans of 28 modern juvenile tali (from 36 prenatal weeks to 2 years), from a broad chronological range from the Late Roman period to the 20th century. We applied geometric morphometric and whole-bone trabecular analysis to investigate the early talar morphological changes.RESULTS:In the youngest group (<6 postnatal months), the immature external shell is accompanied by an isotropic internal structure, with thin and densely packed trabeculae. After the initial attempts of locomotion, bone volume fraction decreases, while anisotropy and trabecular thickness increase. These internal changes correspond to the maturation of the external shell, which is now more defined and shows the development of the articular surfaces.DISCUSSION:The internal and external morphology of the human talus reflects the diverse load on the foot during the initial phases of the bipedal locomotion, with the youngest group potentially reflecting the lack of readiness of the human talus to bear forces and perform bipedal walking. These results highlight the link between mechanical loading and bone development in the human talus during the acquisition of bipedalism, providing new insight into the early phases of talar development.

Hutchinson-Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin-6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin-6 activity by tocilizumab, a neutralizing antibody raised against interleukin-6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G/G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging-related disorders.

Modelling approaches to handle large-scale computing needs are here presented, with reference to the dosimetric analysis of patients carrying implants undergoing medical treatments that involve electromagnetic-based technologies. The main features of this type of analysis are put in evidence, showing three examples of applications related to magnetic resonance imaging and magnetic hyperthermia treatment.

Nuclear Magnetic Resonance (NMR) is a well-suited methodology to study bone composition and structural properties. This is because the NMR parameters, such as the T2 relaxation time, are sensitive to the chemical and physical environment of the 1H nuclei. Although magnetic resonance imaging (MRI) allows bone structure assessment in vivo, its cost limits the suitability of conventional MRI for routine bone screening. With difficulty accessing clinically suitable exams, the diagnosis of bone diseases, such as osteoporosis, and the associated fracture risk estimation is based on the assessment of bone mineral density (BMD), obtained by the dual-energy X-ray absorptiometry (DXA). However, integrating the information about the structure of the bone with the bone mineral density has been shown to improve fracture risk estimation related to osteoporosis. Portable NMR, based on low-field single-sided NMR devices, is a promising and appealing approach to assess NMR properties of biological tissues with the aim of medical applications. Since these scanners detect the signal from a sensitive volume external to the magnet, they can be used to perform NMR measurement without the need to fit a sample inside a bore of a magnet, allowing, in principle, in vivo application. Techniques based on NMR single-sided devices have the potential to provide a high impact on the clinical routine because of low purchasing and running costs and low maintenance of such scanners. In this review, the development of new methodologies to investigate structural properties of trabecular bone exploiting single-sided NMR devices is reviewed, and current limitations and future perspectives are discussed.

The evolution and development of human mortuary behaviors is of enormous cultural significance. Here we report a richly-decorated young infant burial (AVH-1) from Arma Veirana (Liguria, northwestern Italy) that is directly dated to 10,211–9910 cal BP (95.4% probability), placing it within the early Holocene and therefore attributable to the early Mesolithic, a cultural period from which well-documented burials are exceedingly rare. Virtual dental histology, proteomics, and aDNA indicate that the infant was a 40–50 days old female. Associated artifacts indicate significant material and emotional investment in the child’s interment. The detailed biological profile of AVH-1 establishes the child as the earliest European near-neonate documented to be female. The Arma Veirana burial thus provides insight into sex/gender-based social status, funerary treatment, and the attribution of personhood to the youngest individuals among prehistoric hunter-gatherer groups and adds substantially to the scant data on mortuary practices from an important period in prehistory shortly following the end of the last Ice Age.