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The success of immune checkpoint inhibitors (ICI) in melanoma therapy has catalyzed the introduction of ICI in increasingly early stages of the disease. This exposes many patients with a lower risk of relapse to the risk of protracted adverse events, highlighting the need for biomarkers guiding the use of ICI. Already many years ago, brisk infiltration of primary melanomas by lymphocytes has been linked to improved patient outcome, but controversial findings due to a high variability in classification systems have been described CD8+ T cells have been identified as a primary mediator of antitumor immunity in patients treated with ICI. As CD8+ T cells require the presentation of antigens via MHC-I on target cells, downregulation and loss of MHC-I have been observed as resistance mechanisms to ICI. In this study, we revisit the role of MHC-I expression and CD8+ T-cell infiltration in melanoma evolution using a cohort of advanced primary and matched metastatic melanomas by using an automated immunohistochemistry and digital pathology workflow. Our results show that downregulation of MHC-I expression is a frequent event in advanced primary melanomas that is associated with decreased CD8+ T-cell infiltration and an early metastatic spread to sentinel lymph nodes. Furthermore, MHC-I downregulation and decreased infiltration with CD8+ T cells are also associated with resistance to ICI. Our results suggest that analyses of MHC-I expression and CD8+ T-cell infiltration patterns could serve as future biomarkers to guide the decision to treat patients in early stages of melanoma with ICI., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The introduction of immunotherapy (IT) has transformed clinical care of patients with metastatic melanoma. However, many patients still die as a result of progressive disease. Here we analyzed how IT improved survival in a real-world setting. Additionally, we investigated whether IT alters the dynamics and pattern of metastatic progression in different organs resulting from tissue-specific immune microenvironments., Methods: We retrospectively compared a group of 61 patients with metastatic melanoma (24 female, 37 male) treated with IT between 2015 and 2018 with a historical control group of 56 patients with metastatic melanoma (21 female, 35 male) treated with chemotherapy between 2005 and 2008 regarding treatment response rates and overall survival as well as the timing and distribution of metastatic progression., Results: Patients with metastatic melanoma treated with IT showed increased response rates and longer overall survival when compared with patients treated with chemotherapy. In addition, treatment with IT altered the dynamics but not the pattern of metastatic progression when compared with treatment with chemotherapy. Interestingly, patients receiving IT lived significantly longer after metastatic progression to lymph nodes, lungs and brain, but not after metastatic progression to the liver., Conclusion: Our results confirm the efficacy of IT in a real-world setting. The altered dynamics of metastases supports studies suggesting a unique role of immune privilege in the liver tissue microenvironment that increases resistance to immunotherapy., Competing Interests: Declarations. Conflict of Interest: Unrelated to this work, Miriam Mengoni reports travel support from Pierre Fabre Pharma GmbH and Sun Pharmaceutical Industries Ltd and honoraria for presentations and advisory tasks from Novartis Pharma GmbH, Sun Pharmaceutical Industries Ltd., Kyowa Kirin GmbH, Stemline Therapeutics B.V. and MSD Sharp & Dohme GmbH. Andreas Dominik Braun reports honoraria for advisory tasks from MSD Sharp & Dohme GmbH unrelated to this work. Thomas Tüting and Evelyn Gaffal have no conflicts of interest to declare. Ethical Approval: This retrospective study was approved by the institutional ethics committee of the Otto-von-Guericke University Magdeburg (Approval number 145/21, Ethics Committee, Otto-von-Guericke University Magdeburg, Germany). Patients still alive have provided written consent for this study. For deceased patients, as well as those unable to provide written consent, local regulations from Saxony-Anhalt, Germany waive the need for patient consent for retrospective analysis of anonymized treatment data (§17 KHG LSA)., (© 2024. The Author(s).)

This study contributes to understanding semi-automated ergonomic risk assessments in industrial manufacturing environments, proposing a practical tool for enhancing worker safety and operational efficiency. In the Industry 5.0 era, the human-centric approach in manufacturing is crucial, especially considering the aging workforce and the dynamic nature of the entire modern industrial sector, today integrating digital technology, automation, and sustainable practices to enhance productivity and environmental responsibility. This approach aims to adapt work conditions to individual capabilities, addressing the high incidence of work-related musculoskeletal disorders (MSDs). The traditional, subjective methods of ergonomic assessment are inadequate for dynamic settings, highlighting the need for affordable, automatic tools for continuous monitoring of workers' postures to evaluate ergonomic risks effectively during tasks. To enable this perspective, 2D RGB Motion Capture (MoCap) systems based on computer vision currently seem the technologies of choice, given their low intrusiveness, cost, and implementation effort. However, the reliability and applicability of these systems in the dynamic and varied manufacturing environment remain uncertain. This research benchmarks various literature proposed MoCap tools and examines the viability of MoCap systems for ergonomic risk assessments in Industry 5.0 by exploiting one of the benchmarked semi-automated, low-cost and non-intrusive 2D RGB MoCap system, capable of continuously monitoring and analysing workers' postures. By conducting experiments across varied manufacturing environments, this research evaluates the system's effectiveness in assessing ergonomic risks and its adaptability to different production lines. Results reveal that the accuracy of risk assessments varies by specific environmental conditions and workstation setups. Although these systems are not yet optimized for expert-level risk certification, they offer significant potential for enhancing workplace safety and efficiency by providing continuous posture monitoring. Future improvements could explore advanced computational techniques like machine learning to refine ergonomic assessments further., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Interferon-alpha is an important therapeutic option for the treatment of the cutaneous T-cell lymphomas (CTCL). Since the approved recombinant interferon-α-2a (IFN-α2a) has no longer been produced since January 2020, pegylated interferon-α2a (pegIFN-α2a) can be used as an alternative treatment, even though it is not approved for the treatment of CTCL. The aim of this multicentre study was to generate comprehensive data on the efficacy and tolerability of pegIFN-α2a in the treatment of CTCL., Patients and Methods: A multicenter retrospective study was conducted with 70 patients with CTCL from twelve German skin centers., Results: In total, 70 patients were included in the study, with 57.2% male and a mean age of 58.8 ± 14.9 years. Mycosis fungoides was present in 71.4% of cases and Sézary Syndrome in 28.6%. An overall response rate of 55.2% was observed with pegIFNα-2a therapy. In 50% of cases, therapy was discontinued after 63.6 ± 33.5 weeks. The most common reason for discontinuation was adverse events, which occurred in 68.6% of cases and which were classified as severe in 29.2%. Blood count changes, fatigue and liver toxicity occurred most frequently., Conclusions: Our analysis provides comprehensive data on the efficacy and tolerability of pegIFNα-2a therapy in patients with CTCL. In terms of response rates and side effect profile, pegIFNα-2a appears to be comparable to IFN-α2a therapy., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

We report the development of peptide-glycosaminoglycan hydrogels as injectable biomaterials for load-bearing soft tissue repair. The hydrogels are injectable as a liquid for clinical delivery, rapidly form a gel in situ , and mimic the osmotic swelling behaviour of natural tissue. We used a new in vitro model to demonstrate their application as a nucleus augmentation material for the treatment of intervertebral disc degeneration. Our study compared a complex lab gel preparation method to a simple clinical benchtop process. We showed pH differences did not significantly affect gel formation, and temperature variations had no impact on gel performance. Rheological results demonstrated consistency after benchtop mixing or needle injection. In our in vitro disc degeneration model, we established that peptide augmentation could restore the native biomechanical properties. This suggests the feasibility of minimally invasive peptide-GAG gel delivery, maintaining consistent properties across temperature and needle sizes while restoring disc height and stiffness in vitro ., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Background and Objectives: Sarcopenia is the generalized loss of muscle strength, mass, and function. The aim was to investigate whether pretherapeutic sarcopenia, as determined by the psoas muscles, affects therapy-mediated toxicity in patients with malignant melanoma undergoing immunotherapy., Patients and Methods: Measurement of psoas musculature was performed pretherapeutically using computed tomography at the level of the third lumbar vertebra in the axial plane in 75 patients between January 2011 and December 2020. Sarcopenia was defined using the psoas muscle index (PMI). Immune-related toxicity was retrospectively assessed., Results: Treatment-related toxicity was recorded in 33 of the 75 patients (44%). Of these, 16 patients (36.2%) experienced dose-limiting severe events (DLT). Pretherapeutic sarcopenia was identified in 25 patients (33.3%). Comparative analysis showed that the patients with a DLT had lower PMI values compared with the patient group without a DLT (4.65 ± 1.33 vs. 5.79 ± 1.67 cm 2 m -2 , p = 0.015) (odds ratio = 0.60, 95% confidence interval 0.40-0.92, p = 0.02)., Conclusions: Pretherapeutic sarcopenia measured based on the psoas muscle is not a significant predictor of immune-mediated toxicity in patients with malignant melanoma treated with immune checkpoint inhibitors. Patients with DLT have lower values for the psoas muscle parameters PMI compared to the group of patients without DLT., (© 2024. The Author(s).)

Haemarthrosis is an inherent clinical feature of haemophilia, a disease characterised by an absence or reduction in clotting proteins. Patients with severe haemophilia experience joint bleeding leading to blood-induced ankle arthropathy (haemarthropathy). Altered biomechanics of the ankle have been reported in people with haemophilia; however, the consequence of this on joint health is little understood. The aim of this study was to assess the changes in joint contact due to haemophilia disease-specific gait features using patient-specific modelling, to better understand the link between biomechanics and joint outcomes. Four, image-based, finite element models of haemophilic ankles were simulated through consecutive events in the stance phase of gait, using both patient-specific and healthy control group (n = 36) biomechanical inputs. One healthy control FE model was simulated through the healthy control stance phase of the gait cycle for a point of comparison. The method developed allowed cartilage contact mechanics to be assessed throughout the loading phase of the gait cycle. This showed areas of increased contact pressure in the medial and lateral regions of the talar dome, which may be linked to collapse in these regions. This method may allow the relationship between structure and function in the tibiotalar joint to be better understood., (© 2024. The Author(s).)

Significant alterations to subchondral trabecular bone microarchitecture are observed in late-stage osteoarthritis (OA). However, detailed investigation of these changes to bone in the ankle are under-reported. This study aimed to fully characterise the trabecular morphology in OA ankle bone specimens compared to non-diseased (ND) controls using both standard and individual-trabecular segmentation-based (ITS) analyses. Ten ND tibial bone specimens were extracted from three cadaveric ankles, as well as five OA bone specimens from patients undergoing total ankle arthroplasty surgery. Each specimen was scanned using microcomputed tomography from which a 4 mm cuboidal volume was extracted for analysis. Morphological parameters for the subchondral trabecular bone were measured using BoneJ (NIH ImageJ) and 3D ITS for whole volumes and at each depth level in 1 mm increments. The results show an overall increase in bone volume fraction (p<0.01) and trabecular thickness (p<0.001) with OA, with a decrease in anisotropy (p<0.05). ITS analysis showed OA bone was composed of more rod-like trabeculae and plate-like trabeculae compared to ND bone. Numerous properties were depth dependent, but the results demonstrated that towards the subchondral bone plate, both rod- and plate-like trabeculae were thicker, rods were longer and plates had increased surface area. Overall, this study has verified key microstructural alterations to ankle subchondral bone that are found in other OA lower-limb joints. Depth-based analysis has highlighted differences of interest for further evaluation into the remodelling mechanisms that occur with OA, which is critical to understanding the role of subchondral bone microarchitecture in the progression of the disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Koria et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recent pan-cancer genomic analyses have identified numerous oncogenic driver mutations that occur in a cell-type and tissue-specific distribution. For example, oncogenic mutations in Braf and Nras genes arise predominantly in melanocytic neoplasms of the epidermis, while oncogenic mutations in Gnaq/11 genes arise mostly in melanocytic lesions of the dermis or the uvea. The mechanisms promoting cell-type and tissue-specific oncogenic events currently remain poorly understood. Here, we report that Gnaq/11 hotspot mutations occur as early oncogenic drivers during the evolution of primary melanomas in Hgf-Cdk4 mice. Additional single base substitutions in the Trp53 gene and structural chromosomal aberrations favoring amplifications of the chromosomal region containing the Met receptor gene accumulate during serial tumor transplantation and in cell lines established in vitro. Mechanistically, we found that the Gnaq Q209L mutation transactivates the Met receptor. Overexpression of oncogenic Gnaq Q209L in the immortalized melanocyte cell line promoted in vivo growth that was enhanced by transgenic Hgf expression in the tumor microenvironment. This cross-signaling mechanism explains the selection of oncogenic Gnaq/11 in primary Hgf-Cdk4 melanomas and provides an example of how oncogenic driver mutations, intracellular signaling cascades, and microenvironmental cues cooperate to drive cancer development in a tissue-specific fashion., (© 2024. The Author(s).)

Background: The introduction of tyrosine kinase inhibitors (TKI) has greatly improved the management of metastatic melanoma. Recent studies have uncovered a relationship between the body mass index (BMI) and outcome of patients with metastatic melanoma. However, conflicting results have challenged the relevance of this finding. In the current work, we aim to dissect body composition features of melanoma patients treated with TKI to evaluate their value as biomarkers., Patients and Methods: We analyze body composition features via CT scans in a retrospective cohort of 57 patients with non-resectable stage III/IV melanoma receiving first-line treatment with TKI in our department, focusing on the impact of body composition on treatment efficacy and occurrence of adverse events., Results: In uni- and multivariate analyses, we identify an association between the visceral adipose tissue gauge index (VATGI) and survival. We furthermore profile additional body composition features including sarcopenia, which was also associated with a shorter overall survival. Finally, we detected an enrichment of cases with fatigue in patients with low VATGI., Conclusions: Our study represents the first exploratory study evaluating the suitability of body composition measurements as biomarkers for melanoma patients treated with TKI. Our data suggest a putative use of VATGI as a biomarker predicting patient outcome., (© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Finite element studies of the tibiofemoral joint have increased use in research, with attention often placed on the material models. Few studies assess the effect of meniscus modelling assumptions in image-based models on contact mechanics outcomes. This work aimed to assess the effect of modelling assumptions of the meniscus on knee contact mechanics and meniscus kinematics. A sensitivity analysis was performed using three specimen-specific tibiofemoral models and one generic knee model. The assumptions in representing the meniscus attachment on the tibia (shape of the roots and position of the attachment), the material properties of the meniscus, the shape of the meniscus and the alignment of the joint were evaluated, creating 40 model instances. The values of material parameters for the meniscus and the position of the root attachment had a small influence on the total contact area but not on the meniscus displacement or the force balance between condyles. Using 3D shapes to represent the roots instead of springs had a large influence in meniscus displacement but not in knee contact area. Changes in meniscus shape and in knee alignment had a significantly larger influence on all outcomes of interest, with differences two to six times larger than those due to material properties. The sensitivity study demonstrated the importance of meniscus shape and knee alignment on meniscus kinematics and knee contact mechanics, both being more important than the material properties or the position of the roots. It also showed that differences between knees were large, suggesting that clinical interpretations of modelling studies using single geometries should be avoided., (© 2024. The Author(s).)

Purpose: Adjuvant immunotherapy with immune checkpoint blockade(ICB) has greatly reduced the risk of recurrence and metastatic spread in early and advanced melanoma. However, not all patients benefit from adjuvant treatment: many patients show disease recurrence despite therapy, while those without recurrence harbor the risk for potentially irreversible adverse events. Biomarkers to select patients benefitting most from adjuvant therapy are currently lacking. As body composition assessment using CT images has shown promising results as a prognostic biomarker in stage IV melanoma, we aim to study the applicability of body composition parameters also in adjuvant melanoma treatment., Methods: We analyze body composition features via CT scans in a retrospective cohort of 109 patients with resected stage IIB-IV melanoma receiving an adjuvant first-line treatment with ICB in our department. In this analysis, we focus on the impact of body composition, especially the presence of low skeletal muscle mass (LSMM), on patients' survival and occurrence of adverse events (AEs)., Results: In uni- and multivariate analyses, we identify an association between CT-measured LSMM and melanoma-specific survival in patients treated with adjuvant ICB. Furthermore, LSMM is associated with a lower risk for therapy-related AEs, especially hypothyroidism, fatigue, and xerostomia. Conventional serological biomarkers e.g. S100 and LDH and measures of adipose tissue compartments did not show a correlation with survival or the occurrence of AEs., Conclusions: LSMM constitutes a novel biomarker for melanoma-specific survival in patients treated with adjuvant ICB., (© 2024. The Author(s).)

Osteochondral grafting has demonstrated positive outcomes for treating articular cartilage defects by replacing the damaged region with a cylindrical graft consisting of bone with a layer of cartilage. However, factors that cause graft subsidence are not well understood. The aim of this study was to develop finite element (FE) models of osteochondral grafts within a tibiofemoral joint, suitable for an investigation of parameters affecting graft stability. Cadaveric femurs were used to experimentally calibrate the bone properties and graft-bone frictional forces for use in corresponding image-based FE models, generated from µCT scan data. Effects of cartilage defects and osteochondral graft repair were measured by examining contact pressure changes using further in vitro tests. Here, six defects were created in the femoral condyles, which were subsequently treated with osteochondral autografts or metal pins. Matching image-based FE models were created, and the contact patches were compared. The bone material properties and graft-bone frictional forces were successfully calibrated from the initial tests with good resulting levels of agreement (CCC = 0.87). The tibiofemoral joint experiment provided a range of cases that were accurately described in the resultant pressure maps and were well represented in the FE models. Cartilage defects and repair quality were experimentally measurable with good agreement in the FE model pressure maps. Model confidence was built through extensive validation and sensitivity testing. It was found that specimen-specific properties were required to accurately represent graft behaviour. The final models produced are suitable for a range of parametric testing to investigate immediate graft stability., (© 2024. The Author(s).)

The perception of sound greatly impacts users' emotional states, expectations, affective relationships with products, and purchase decisions. Consequently, assessing the perceived quality of sounds through jury testing is crucial in product design. However, the subjective nature of jurors' responses may limit the accuracy and reliability of jury test outcomes. This research explores the utility of facial expression analysis in jury testing to enhance response reliability and mitigate subjectivity. Some quantitative indicators allow the research hypothesis to be validated, such as the correlation between jurors' emotional responses and valence values, the accuracy of jury tests, and the disparities between jurors' questionnaire responses and the emotions measured by FER (facial expression recognition). Specifically, analysis of attention levels during different statuses reveals a discernible decrease in attention levels, with 70 percent of jurors exhibiting reduced attention levels in the 'distracted' state and 62 percent in the 'heavy-eyed' state. On the other hand, regression analysis shows that the correlation between jurors' valence and their choices in the jury test increases when considering the data where the jurors are attentive. The correlation highlights the potential of facial expression analysis as a reliable tool for assessing juror engagement. The findings suggest that integrating facial expression recognition can enhance the accuracy of jury testing in product design by providing a more dependable assessment of user responses and deeper insights into participants' reactions to auditory stimuli.

Rationale and Objectives: Despite the impressive efficacy of immune checkpoint inhibitors (ICIs) in the treatment of metastatic melanoma, not all patients respond to therapy. In addition, ICI harbors the risk for serious adverse events (AEs), highlighting the need for novel biomarkers predicting treatment response and occurrence of AEs. Recently, the identification of enhanced response to ICI in obese patients has indicated that body composition might influence treatment efficacy. The aim of the current study is to assess radiologic measurements of body composition as biomarkers for treatment response and AEs to ICI in melanoma., Materials and Methods: In the current work, we analyze adipose tissue abundance and density, as well as muscle mass via computed tomography scans in a retrospective cohort of 100 patients with non-resectable stage III/IV melanoma receiving first-line treatment with ICI in our department. From these, we investigate the impact of the subcutaneous adipose tissue gauge index (SATGI) and other parameters of body composition on treatment efficacy and occurrence of AEs., Results: Low SATGI was associated with prolonged progression-free survival (PFS) in univariate and multivariate analyses (hazard ratio 2.56 [95% CI 1.18-5.55], P = .02), as well as an enhanced objective response rate (50.0% vs 27.1%; P = .02). Further analysis with a random forest survival model highlighted a nonlinear relationship between SATGI and PFS with a clear separation into high- and low-risk cohorts separated by the median. Finally, a significant enrichment of cases with vitiligo, but no other AEs, was observed in the SATGI-low cohort (11.5% vs 0%; P = .03)., Conclusion: We identify SATGI as a biomarker predicting treatment response to ICI without increased risk for severe AEs in melanoma., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MM reports travel support from Pierre Fabre Pharma GmbH unrelated to this work. In addition, MM also reports honoraria for presentations and advisory tasks unrelated to this work from Novartis Pharma GmbH, Sun Pharmaceutical Industries Ltd., and MSD Sharp & Dohme GmbH unrelated to this work., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Most clinically applied cancer immunotherapies rely on the ability of CD8 + cytolytic T cells to directly recognize and kill tumour cells 1-3 . These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment 4-6 . The ability of CD4 + effector cells to contribute to antitumour immunity independently of CD8 + T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified 7-10 . Here, we describe a mechanism whereby a small number of CD4 + T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8 + T cell targeting. The CD4 + effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II + CD11c + antigen-presenting cells. We show that T helper type 1 cell-directed CD4 + T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4 + T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4 + T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8 + T cells and natural killer cells and advance cancer immunotherapies., (© 2023. The Author(s).)

Barlow disease represents the extreme form of the degenerative mitral valve spectrum described by Carpentier. The myxoid degeneration of the mitral valve may result in a billowing leaflet or in a prolapse and myxomatous degeneration of the mitral leaflets. There are increasing evidences of the association between Barlow disease and sudden cardiac death. It is common in young women. Symptoms include anxiety, chest pain and palpitation. In this case report, the markers of risk for sudden death such as typical ECG changes, complex ventricular ectopy, a spiked configuration of the lateral annular velocities, mitral annular disjunction and evidence of myocardial fibrosis were assessed.

Background: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland., Methods: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence., Results: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials., Conclusions: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

This paper aims to explore the potential offered by emotion recognition systems to provide a feasible response to the growing need for audience understanding and development in the field of arts organizations. Through an empirical study, it was investigated whether the emotional valence measured on the audience through an emotion recognition system based on facial expression analysis can be used with an experience audit to: (1) support the understanding of the emotional responses of customers toward any clue that characterizes a staged performance; and (2) systematically investigate the customer's overall experience in terms of their overall satisfaction. The study was carried out in the context of opera live shows in the open-air neoclassical theater Arena Sferisterio in Macerata, during 11 opera performances. A total of 132 spectators were involved. Both the emotional valence provided by the considered emotion recognition system and the quantitative data related to customers' satisfaction, collected through a survey, were considered. Results suggest how collected data can be useful for the artistic director to estimate the audience's overall level of satisfaction and make choices about the specific characteristics of the performance, and that emotional valence measured on the audience during the show can be useful to predict overall customer satisfaction, as measured using traditional self-report methods.

Neurocognitive impairments of memory, speech, and attention can occur in cancer patients as a direct result of the cancer but also in the context of therapy. With the development of modern immunotherapies and their use in combination with surgery and radiation therapy, the number of long-term survivors has significantly increased. As a result, detrimental effects on brain function and structure in cancer patients not only during treatment but also after completion of therapy have become a key issue in clinical oncology. Early diagnosis and treatment of neurocognitive disorders is of great importance for quality of life, therapy adherence, and overall survival of the affected patients. In this review, we discuss the underlying mechanisms with a special focus on metastatic melanoma. Furthermore, practice-relevant diagnostics, prophylaxis, and intervention options are discussed., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Treatment options for metastatic colorectal cancer (CRC) are mostly ineffective. We present new evidence that tumor tissue collagen type X alpha 1 (COL10A1) is a relevant candidate biomarker to improve this dilemma., Methods: Several public databases had been screened to observe COL10A1 expression in transcriptome levels with cell lines and tissues. Protein interactions and alignment to changes in clinical parameters and immune cell invasion were performed, too. We also used algorithms to build a novel COL10A1-related immunomodulator signature. Various wet-lab experiments were conducted to quantify COL10A1 protein and transcript expression levels in disease and control cell models., Results: COL10A1 mRNA levels in tumor material is clinical and molecular prognostic, featuring upregulation compared to non-cancer tissue, increase with histomorphological malignancy grading of the tumor, elevation in tumors that invade perineural areas, or lymph node invasion. Transcriptomic alignment noted a strong positive correlation of COL10A1 with transcriptomic signature of cancer-associated fibroblasts (CAFs) and populations of the immune compartment, namely, B cells and macrophages. We verified those findings in functional assays showing that COL10A1 are decreased in CRC cells compared to fibroblasts, with strongest signal in the cell supernatant of the cells., Conclusion: COL10A1 abundance in CRC tissue predicts metastatic and immunogenic properties of the disease. COL10A1 transcription may mediate tumor cell interaction with its stromal microenvironment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kahlert, Shi, Strecker, Scherpinski, Wartmann, Dölling, Perrakis, Relja, Mengoni, Braun and Croner.)

Background: Subchondral bone cysts are a common presentation in ankle haemarthropathy. The relationship with ankle joint health has however not previously been investigated. The aim of this study was to assess the influence of subchondral bone cysts of differing shapes, volumes and depths on joint health., Methods: Chronologically sequential Magnetic Resonance imaging scans of four hemophilic ankles with subchondral bone cysts present (N = 18) were used to build patient specific finite element models under two cystic conditions to assess their influence on cartilage contact pressures. Variables such as location, volume and depth were considered individually, to investigate whether certain cystic conditions may be more detrimental to cartilage health., Findings: Significant quantifiable contact redistribution was seen in the presence of subchondral bone cysts and this redistribution reflected the shape and size of the cysts, however, with the presence of cysts in both bones in 10 of the 18 cases a direct relationship to volume could not be correlated., Interpretation: This work demonstrated a redistribution of contact pressures in the presence of subchondral bone cysts. This alteration to loading history could be linked to cartilage degeneration due to the biological response to abnormal loading., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Osteoarthritis (OA) is the most prevalent chronic rheumatic disease worldwide with knee OA having an estimated lifetime risk of approximately 14%. Autologous osteochondral grafting has demonstrated positive outcomes in some patients, however, understanding of the biomechanical function and how treatments can be optimised remains limited. Increased short-term stability of the grafts allows cartilage surfaces to remain congruent prior to graft integration. In this study methods for generating specimen specific finite element (FE) models of osteochondral grafts were developed, using parallel experimental data for calibration and validation. Experimental testing of the force required to displace osteochondral grafts by 2 mm was conducted on three porcine knees, each with four grafts. Specimen specific FE models of the hosts and grafts were created from registered μCT scans captured from each knee (pre- and post-test). Material properties were based on the μCT background with a conversion between μCT voxel brightness and Young's modulus. This conversion was based on the results of the separate testing of eight porcine condyles and optimization of specimen specific FE models. The comparison between the experimental and computational push-in forces gave a strong agreement with a concordance correlation coefficient (CCC) = 0.75, validating the modelling approach. The modelling process showed that homogenous material properties based on whole bone BV/TV calculations are insufficient for accurate modelling and that an intricate description of the density distribution is required. The robust methodology can provide a method of testing different treatment options and can be used to investigate graft stability in full tibiofemoral joints., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Flattening of the trochlear tali is clinically observed as structural and functional changes advance in patients with hemarthropathy of the ankle. However, the degree of this flattening has not yet been quantified, and distribution of the morphological changes across the talus not yet defined. Chronologically sequential MR images of both a hemophilic patient group (N = 5) and a single scan from a nondiseased, sex-matched, control group (N = 11) were used to take four measurements of the trochlear talus morphology at three locations (medial, central and lateral) along the sagittal plane. Three ratios of interest were defined from these to assess whether the talar dome flattens with disease. The control group MRI measurements were validated against literature data obtained from CT scans or planar X-Rays. The influence of disease on talar morphology was assessed by direct comparison of the hemophilic cases with the control group. The values for all three ratios, in all locations, differed between the control and the hemophilic group. Flattening was indicated in the hemophilic group in the medial and lateral talus, but differences in the central talus were not statistically significant. This work demonstrates that morphological assessment of the talus from MR images is similar to that from CT scans or planar X-Rays. Talar flattening does occur with hemarthropathy, especially at the medial and lateral edges of the joint surface. General flattening of the trochlear talus was confirmed in this small patient sample, however the degree and rate of change is unique to each ankle., (© 2021 The Authors. Clinical Anatomy published by Wiley Periodicals LLC on behalf of American Association of Clinical Anatomists.)

Finite element modelling of the spinal unit is a promising preclinical tool to assess the biomechanical outcome of emerging interventions. Currently, most models are calibrated and validated against range of motion and rarely directly against soft-tissue deformation. The aim of this contribution was to develop an in vitro methodology to measure disc bulge and assess the ability of different specimen-specific modelling approaches to predict disc bulge. Bovine bone-disc-bone sections ( N = 6) were prepared with 40 glass markers on the intervertebral disc surface. These were initially magnetic resonance (MR)-imaged and then sequentially imaged using peripheral-qCT under axial compression of 1 mm increments. Specimen-specific finite-element models were developed from the CT data, using three different methods to represent the nucleus pulposus geometry with and without complementary use of the MR images. Both calibrated specimen-specific and averaged compressive material properties for the disc tissues were investigated. A successful methodology was developed to quantify the disc bulge in vitro , enabling observation of surface displacement on qCT. From the finite element model results, no clear advantage was found in using geometrical information from the MR images in terms of the models' ability to predict stiffness or disc bulge for bovine intervertebral disc., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mengoni, Zapata-Cornelio, Wijayathunga and Wilcox.)

There is an increased interest in studying the biomechanics of the facet joints. For in silico studies, it is therefore important to understand the level of reliability of models for outputs of interest related to the facet joints. In this work, a systematic review of finite element models of multi-level spinal section with facet joints output of interest was performed. The review focused on the methodology used to model the facet joints and its associated validation. From the 110 papers analysed, 18 presented some validation of the facet joints outputs. Validation was done by comparing outputs to literature data, either computational or experimental values; with the major drawback that, when comparing to computational values, the baseline data was rarely validated. Analysis of the modelling methodology showed that there seems to be a compromise made between accuracy of the geometry and nonlinearity of the cartilage behaviour in compression. Most models either used a soft contact representation of the cartilage layer at the joint or included a cartilage layer which was linear elastic. Most concerning, soft contact models usually did not contain much information on the pressure-overclosure law. This review shows that to increase the reliability of in silico model of the spine for facet joints outputs, more needs to be done regarding the description of the methods used to model the facet joints, and the validation for specific outputs of interest needs to be more thorough, with recommendation to systematically share input and output data of validation studies.

In computational modelling of musculoskeletal applications, one of the critical aspects is ensuring that a model can capture intrinsic population variability and not only representative of a "mean" individual. Developing and calibrating models with this aspect in mind is key for the credibility of a modelling methodology. This often requires calibration of complex models with respect to 3D experiments and measurements on a range of specimens or patients. Most Finite Element (FE) software's do not have such a capacity embedded in their core tools. This paper presents a versatile interface between Finite Element (FE) software and optimisation tools, enabling calibration of a group of FE models on a range of experimental data. It is provided as a Python toolbox which has been fully tested and verified on Windows platforms. The toolbox is tested in three case studies involving in vitro testing of spinal tissues., (Copyright © 2020. Published by Elsevier Inc.)

The aryl hydrocarbon receptor (AHR) is a ligand binding-transcription factor of the basic helix-loop-helix family regulating multiple cellular functions such as differentiation, cell cycle, apoptosis, and inflammatory reactions. In neoplastic diseases, the AHR has been described to modulate proliferation and differentiation in dichotomous ways, either inhibiting or augmenting the growth of tumors. The precise role of AHR in melanoma is mostly unknown. Here, we report a functional effect of AHR activation on inflammation-induced melanoma cell dedifferentiation and the development of lung metastases in a mouse model. Via in silico analyses of "The Cancer Genome Atlas" human melanoma cohort, we detected a correlation between AHR expression levels and a dedifferentiated melanoma cell phenotype with an invasive gene signature, which we were able to functionally recapitulate in a panel of human melanoma cell lines. Both human and mouse melanoma cell lines upregulated AHR expression after inflammatory stimulation with tumor necrosis factor-α (TNF-α). Activation of AHR in human and mouse melanoma cell lines with the endogenous ligand formylindolo(3,2-b)carbazole (FICZ) promoted inflammation-induced dedifferentiation in vitro. Importantly, mouse melanoma cells with CRISPR/Cas9-mediated disruption of the AHR gene showed impaired in vivo tumor growth after transplantation in the skin as well as decreased numbers of spontaneous lung metastases. Taken together, our results demonstrate a functional role for AHR expression in melanoma development and metastatic progression. This provides a scientific basis for future experiments that further dissect the underlying molecular mechanisms and assess the potential for AHR inhibition as part of multimodal melanoma treatment strategies., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Tissue-level properties of bone play an important role when characterising apparent-level bone biomechanical behaviour and yet little is known about its effect at this hierarchical level. In combination with trabecular morphological data these properties can be used to predict bone strength, which becomes an invaluable tool for clinicians in patient treatment planning. This study developed specimen-specific micro-finite element (μFE) models using validated continuum-level models, containing grayscale-derived material properties, to indirectly establish tissue-level properties of porcine talar subchondral bone. Specimen-specific continuum finite element (hFE) models of subchondral trabecular bone were setup using μCT data of ten cylindrical specimens extracted from juvenile porcine tali. The models were validated using quasi-static uniaxial compression testing. Validated hFE models were used to calibrate the tissue modulus of corresponding μFE models by minimising the difference between the μFE and hFE stiffness values. Key trabecular morphological indices (BV/TV, DA, Conn.D, Tb.Th, EF) were evaluated. Good agreement was observed between hFE models and experiment (CCC = 0.66). Calibrated E tiss was 504 ± 37.65 MPa. Average BV/TV and DA for μFE specimens were 0.37 ± 0.05 and 0.68 ± 0.11, respectively. BV/TV (r 2  = 0.667) correlated highly with μFE stiffness. The small intra-specimen variation to tissue-level properties suggests that variations to apparent-level stiffness originate from variations to microarchitecture rather than tissue mechanical properties., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oncogenic mutations in the BRAF kinase gene represent the most frequent genomic driver in acquired melanocytic nevi and in cutaneous melanomas. It is currently thought that oncogene-induced senescence and cell cycle arrest limit the ability of oncogenic BRAF to promote melanocyte proliferation in benign nevi. The molecular and cellular mechanisms that allow an oncogenic BRAF mutation to fully transform melanocytes into invasively growing melanoma cells that are able to metastasize systemically are only partially understood. In this study, we show in a genetic mouse model that constitutively enhanced Hgf-Met signaling cooperates with oncogenic BRAF to drive tumor development and metastatic spread. Activation of oncogenic BRAF in mice with transgenic Hgf overexpression and an oncogenic CDK4 germline mutation accelerated and increased the development of primary cutaneous melanomas. Primary melanomas showed considerable phenotypic heterogeneity with frequent signs of dedifferentiation. BRAF activation in Hgf-CDK4 mice also increased the number of lung metastases. Melanoma cells showed a pronounced angiotropic growth pattern both at the invasive front in primary tumors and in metastatic lesions of the lung. Taken together, our work supports the notion that activated Hgf-Met signaling and oncogenic BRAF can cooperate in melanoma pathogenesis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Skin lesions associated with internal malignancy may present as cutaneous metastases or as typical lesions occurring in the context of certain cancer-associated genetic syndromes. Paraneoplastic syndromes, on the other hand, are only indirectly associated with an underlying malignancy and are not malignant per se. Historically, a distinction has been made between "obligate" and "facultative" paraneoplastic disorders, depending on the likelihood with which they are potentially associated with malignancy. In addition, there are nonspecific cutaneous manifestations that are only rarely associated with an underlying malignancy. Another possible classification is based on the pathophysiological mechanisms underlying the cutaneous lesions. In everyday practice, it is essential that dermatologists recognize potentially cancer-associated dermatoses, as this will frequently contribute to the initial diagnosis of an underlying neoplasm., (© 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

The guided gliding of cytoskeletal filaments, driven by biomolecular motors on nano/microstructured chips, enables novel applications in biosensing and biocomputation. However, expensive and time-consuming chip production hampers the developments. It is therefore important to establish protocols to regenerate the chips, preferably without the need to dismantle the assembled microfluidic devices which contain the structured chips. We here describe a novel method toward this end. Specifically, we use the small, nonselective proteolytic enzyme, proteinase K to cleave all surface-adsorbed proteins, including myosin and kinesin motors. Subsequently, we apply a detergent (5% SDS or 0.05% Triton X100) to remove the protein remnants. After this procedure, fresh motor proteins and filaments can be added for new experiments. Both, silanized glass surfaces for actin-myosin motility and pure glass surfaces for microtubule-kinesin motility were repeatedly regenerated using this approach. Moreover, we demonstrate the applicability of the method for the regeneration of nano/microstructured silicon-based chips with selectively functionalized areas for supporting or suppressing gliding motility for both motor systems. The results substantiate the versatility and a promising broad use of the method for regenerating a wide range of protein-based nano/microdevices.

Background: Impingement resulting in soft tissue damage has been observed in hips with abnormal morphologies. Geometric parameterisation can be used to automatically generate a range of bone geometries for use in computational models, including femurs with cam deformity on the femoral neck., Methods: This study verified patient-specific parametric finite element models of 20 patients with cam deformity (10 female, 10 male) through comparison to their patient-specific segmentation-based equivalents. The parameterisation system was then used to generate further models with parametrically defined geometry to investigate morphological changes in both the femur and acetabulum and their effects on impingement., Findings: Similar findings were observed between segmentation-based and parametric models when assessing soft tissue strains under impingement conditions, resulting from high flexion and internal rotations. Parametric models with cam morphology demonstrated that clinically used alpha angles should not be relied on for estimating impingement severity since planar views do not capture the full three-dimensional geometry of the joint. Furthermore, the parametric approach allowed study of labral shape changes, indicating higher strains can result from bony overcoverage., Interpretation: The position of cams, as well as their size, can affect the level of soft tissue strain occurring in the hip. This highlights the importance of reporting the full details of three-dimensional geometry used when developing computational models of the hip joint and suggests that it could be beneficial to stratify the patient population when considering treatment options, since certain morphologies may be at greater risk of elevated soft tissue strain., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Previous findings suggest that apathy symptoms independently of depressive symptoms measured using the Geriatric Depression Scale (GDS) are associated with cardiovascular disease (CVD) in older individuals., Aims: To study whether apathy and depressive symptoms in older people are associated with future CVD, stroke, and mortality using individual patient-data meta-analysis., Methods: Medline, Embase, and PsycInfo databases up to September 3, 2013, were systematically searched without language restrictions. We sought prospective studies with older (mean age ≥65 years) community-dwelling populations in which the GDS was employed and subsequent stroke and/or CVD were recorded to provide individual participant data. Apathy symptoms were defined as the three apathy-related subitems of the GDS, with depressive symptoms the remaining items. We used myocardial infarction (MI), stroke, and all-cause mortality as main outcomes. Analyses were adjusted for age, sex, and MI/stroke history. An adaptation of the Newcastle-Ottawa scale was used to evaluate bias. Hazard ratios were calculated using one-stage random-effect Cox regression models., Results: Of the 52 eligible studies, 21 (40.4%) were included, comprising 47,625 older people (mean age [standard deviation] 74 [7.4] years), over a median follow-up of 8.8 years. Participants with apathy symptoms had a 21% higher risk of MI (95% confidence interval [CI] 1.08-1.36), a 37% higher risk of stroke (95% CI 1.18-1.59), and a 47% higher risk of all-cause mortality (95% CI 1.38-1.56). Participants with depressive symptoms had a comparably higher risk of stroke (HR 1.36, 95% CI 1.18-1.56) and all-cause mortality (HR 1.44, 95% CI 1.35-1.53), but not of MI (HR 1.08, 95% CI 0.91-1.29). Associations for isolated apathy and isolated depressive symptoms were comparable. Sensitivity analyses according to risk of bias yielded similar results., Conclusion: Our findings stress the clinical importance of recognizing apathy independently of depressive symptoms, and could help physicians identify persons at increased risk of vascular disease., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Intervertebral disc degeneration is one of the leading causes of back pain, but treatment options remain limited. Recently, there have been advances in the development of biomaterials for nucleus augmentation; however, the testing of such materials preclinically has proved challenging. The aim of this study was to develop methods for fabricating and testing bone-disc-bone specimens in vitro for examining the performance of nucleus augmentation procedures. Control, nucleotomy and treated intervertebral disc specimens were fabricated and tested under static load. The nucleus was removed from nucleotomy specimens using a trans-endplate approach with a bone plug used to restore bony integrity. Specimen-specific finite element models were developed to elucidate the reasons for the variations observed between control specimens. Although the computational models predicted a statistically significant difference between the healthy and nucleotomy groups, the differences found experimentally were not significantly different. This is likely due to variations in the material properties, hydration and level of annular collapse. The deformation of the bone was also found to be non-negligible. The study provides a framework for the development of testing protocols for nucleus augmentation materials and highlights the need to control disc hydration and the length of bone retained to reduce inter-specimen variability.

Abnormal bony morphology is a factor implicated in hip joint soft tissue damage and an increased lifetime risk of osteoarthritis. Standard 2-dimensional radiographic measurements for diagnosis of hip deformities, such as cam deformities on the femoral neck, do not capture the full joint geometry and are not indicative of symptomatic damage. In this study, a 3-dimensional geometric parameterisation system was developed to capture key variations in the femur and acetabulum of subjects with clinically diagnosed cam deformity. The parameterisation was performed for computed tomography scans of 20 patients (10 female and 10 male). Novel quantitative measures of cam deformity were taken and used to assess differences in morphological deformities between males and females. The parametric surfaces matched the more detailed, segmented hip bone geometry with low fitting error. The quantitative severity measures captured both the size and the position of cams and distinguished between cam and control femurs. The precision of the measures was sufficient to identify differences between subjects that could not be seen with the sole use of 2-dimensional imaging. In particular, cams were found to be more superiorly located in males than in females. As well as providing a means to distinguish between subjects more clearly, the new geometric hip parameterisation facilitates the flexible and rapid generation of a range of realistic hip geometries including cams. When combined with material property models, these stratified cam shapes can be used for further assessment of the effect of the geometric variation under impingement conditions., (© 2017 The Authors International Journal for Numerical Methods in Biomedical Engineering Published by John Wiley & Sons Ltd.)

Image-based continuum-level finite element models have been used for bones to evaluate fracture risk and the biomechanical effects of diseases and therapies, capturing both the geometry and tissue mechanical properties. Although models of vertebrae of various species have been developed, an inter-species comparison has not yet been investigated. The purpose of this study was to derive species-specific modelling methods and compare the accuracy of image-based finite element models of vertebrae across species. Vertebral specimens were harvested from porcine (N = 12), ovine (N = 13) and bovine (N = 14) spines. The specimens were experimentally loaded to failure and apparent stiffness values were derived. Image-based finite element models were generated reproducing the experimental protocol. A linear relationship between the element grayscale and elastic modulus was calibrated for each species matching in vitro and in silico stiffness values, and validated on independent sets of models. The accuracy of these relationships were compared across species. Experimental stiffness values were significantly different across species and specimen-specific models required species-specific linear relationship between image grayscale and elastic modulus. A good agreement between in vitro and in silico values was achieved for all species, reinforcing the generality of the developed methodology.

The development of current surgical treatments for intervertebral disc damage could benefit from virtual environment accounting for population variations. For such models to be reliable, a relevant description of the mechanical properties of the different tissues and their role in the functional mechanics of the disc is of major importance. The aims of this work were first to assess the physiological hoop strain in the annulus fibrosus in fresh conditions ( n  = 5) in order to extract a functional behaviour of the extrafibrillar matrix; then to reverse-engineer the annulus fibrosus fibrillar behaviour ( n  = 6). This was achieved by performing both direct and global controlled calibration of material parameters, accounting for the whole process of experimental design and in silico model methodology. Direct-controlled models are specimen-specific models representing controlled experimental conditions that can be replicated and directly comparing measurements. Validation was performed on another six specimens and a sensitivity study was performed. Hoop strains were measured as 17 ± 3% after 10 min relaxation and 21 ± 4% after 20-25 min relaxation, with no significant difference between the two measurements. The extrafibrillar matrix functional moduli were measured as 1.5 ± 0.7 MPa. Fibre-related material parameters showed large variability, with a variance above 0.28. Direct-controlled calibration and validation provides confidence that the model development methodology can capture the measurable variation within the population of tested specimens., Competing Interests: The authors have no competing interests.

The aims of this study were to assess the damage and failure strengths of lamellar fibrous tissues, such as the anterior annulus fibrosus (AF), and to develop a mathematical model of damage propagation of the lamellae and inter-lamellar connections. This level of modelling is needed to accurately predict the effect of damage and failure induced by trauma or clinical interventions. 26 ovine anterior AF cuboid specimens from 11 lumbar intervertebral discs were tested in radial tension and mechanical parameters defining damage and failure were extracted from the in-vitro data. Equivalent 1D analytical models were developed to represent the specimen strength and the damage propagation, accounting for the specimen dimensions and number of lamellae. Model parameters were calibrated on the in-vitro data. Similar to stiffness values reported for other orientations, the outer annulus was found stronger than the inner annulus in the radial direction, with failure at higher stress values. The inner annulus failed more progressively, showing macroscopic failure at a higher strain value. The 1D analytical model of damage showed that lamellar damage is predominant in the failure mechanism of the AF. The analytical model of the connections between lamellae allowed us to represent separately damage processes in the lamellae and the inter-lamellar connections, which cannot be experimentally tested individually., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Subject-specific finite element models could improve decision making in canine long-bone fracture repair. However, it preliminary requires that finite element models predicting the mechanical response of canine long bone are proposed and validated. We present here a combined experimental-numerical approach to test the ability of subject-specific finite element models to predict the bending response of seven pairs of canine humeri directly from medical images. Our results show that bending stiffness and yield load are predicted with a mean absolute error of 10.1% (±5.2%) for the 14 samples. This study constitutes a basis for the forthcoming optimization of canine long-bone fracture repair., (© IMechE 2016.)

The complex motion and geometry of the spine in the cervical region makes it difficult to determine how loads are distributed through adjacent vertebrae or between the zygapophysial (facet) joints and the intervertebral disc. Validated finite element modes can give insight on this distribution. The aim of this contribution was to produce direct validation of subject-specific finite element models of Functional Spinal Units (FSU׳s) of the cervical spine and to evaluate the importance of including fibre directionality in the mechanical description of the annulus fibrosus. Eight specimens of cervical FSU׳s were prepared from five ovine spines and mechanically tested in axial compression monitoring overall load and displacements as well as local facet joints pressure and displacement. Subject-specific finite element models were produced from microCT image data reproducing the experimental setup and measuring global axial force and displacement as well as local facet joints displacement and contact forces. Material models and parameters were taken from the literature, testing isotropic and anisotropic materials for the annulus fibrosus. The validated models showed that adding the direction of the fibres to their non-linear behaviour in the description of the annulus fibrosus improves the predictions at large strain values but not at low strain values. The load transferred through the facet joints was always accurate, irrespective of the annulus material model, while the predicted facet displacement was larger than the measured one but not significantly. This is, to the authors׳ knowledge, the first subject-specific direct validation study on a group of specimens, accounting for inter-subject variability., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Present study provides a novel MATLAB-based parameter estimation procedure for individual assessment of hepatic insulin degradation (HID) process from standard frequently-sampled intravenous glucose tolerance test (FSIGTT) data. Direct access to the source code, offered by MATLAB, enabled us to design an optimization procedure based on the alternating use of Gauss-Newton's and Levenberg-Marquardt's algorithms, which assures the full convergence of the process and the containment of computational time. Reliability was tested by direct comparison with the application, in eighteen non-diabetic subjects, of well-known kinetic analysis software package SAAM II, and by application on different data. Agreement between MATLAB and SAAM II was warranted by intraclass correlation coefficients ≥0.73; no significant differences between corresponding mean parameter estimates and prediction of HID rate; and consistent residual analysis. Moreover, MATLAB optimization procedure resulted in a significant 51% reduction of CV% for the worst-estimated parameter by SAAM II and in maintaining all model-parameter CV% <20%. In conclusion, our MATLAB-based procedure was suggested as a suitable tool for the individual assessment of HID process., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

MeCP2 is the founder member of a family of methyl-CpG-binding proteins able to repress transcription from methylated DNA. To date, MeCP2 action seems to involve the delivery on modified DNA of histone deacetylase activity, followed by histone methylating activity. It has been recently demonstrated that MECP2 mutations cause Rett syndrome, a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that a novel Xenopus laevis protein of 20 kDa, p20, is able to interact in vivo and in vitro with MeCP2. The p20 sequence revealed that it belongs to the family of the WAP (whey acidic protein) proteins, often functioning as a protease inhibitor. Therefore, we asked whether the p20 can influence the MeCP2 half-life. We demonstrate that, indeed, the xp20 not only can significantly increase the stability of an exogenously expressed MeCP2 in Xenopus oocytes but also can stabilize the human endogenous MeCP2. The capability of the mammalian methyl-CpG-binding protein to interact with p20 is confirmed by co-immunoprecipitation experiments performed overexpressing the WAP protein. Glutathione S-transferase pull-down assays reveal that the MeCP2 residues localized between the methyl-binding domain and the transcriptional repression domain is the primary interaction surface. Our data suggest that regulation of MeCP2 metabolism might be of relevant importance; in accordance with this, previous results have shown that some Rett syndrome mutations are characterized by a decrease in MeCP2 stability.

The structural response of the ribosomes of the extremely thermophilic archaeon Sulfolobus solfataricus was analysed and compared to that of the mesophilic (E. coli) ribosomes by assaying ethidium bromide (EB) binding to the native 70S particles as a function of magnesium concentration. We found that the thermophilic ribosomes bound more EB than their mesophilic counterparts; on the other hand, inhibition of EB binding by Mg2+ ions was more effective in the E. coli 70S particle. In Sulfolobus, the separated 30S and 50S subunits and the 70S particle bound the drug in a similar fashion, whereas the E. coli 70S had a reduced number of binding sites with respect to the subunits. Light scattering measurements as a function of Mg2+ concentration were carried out at various temperatures to study the interaction between the ribosomal subunits from the thermophilic and the mesophilic bacteria. As expected, the association of ribosomal subunits in E. coli was magnesium dependent and could be observed also at low temperature. By contrast, the interaction between Sulfolobus ribosomal subunits was obligatorily dependent upon both magnesium ions and a temperature of at least 80 degrees C, close to the physiological optimum for cell growth (87 degrees C).

Thirty patients admitted to our Intensive Care Unit for respiratory insufficiency attributable to a variety of disease conditions were treated with a combination of cefuroxime plus acetylcysteine. Clinical and laboratory variables were evaluated, and bacteriological tests were performed on tracheal aspirate. At the end of treatment, 12 patients were judged to be recovered, 14 improved and 4 unchanged. No side effects were observed.