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Motion reconstruction provides essential inputs for analyzing human movement through musculoskeletal simulations. To reconstruct joint angles from motion capture data, several multibody kinematic optimization methods have been developed. However, a computationally efficient method yet simple to implement while ensuring consistent kinematics at all levels is lacking. Here, we propose a potential field method generated by virtual spring-dampers connecting measured-derived skin markers to segment-fixed model points to reconstruct motion in a forward dynamic manner by solving the equations of motion. The virtual spring-damper forces move the mechanical system to minimize the elastic potential and the distance between markers during the motion. Several evaluation strategies are performed which demonstrate that the potential field method is computationally fast (2.5ms per frame) with comparable accuracy to the well-established least squares method in terms of reconstructed marker trajectories and joint angles (RMSE < 0.37 mm, 1.87°) and with low marker residuals (< 18.7 ± 12.6 mm) in line with reported ranges. Furthermore, soft tissue artifacts are compensated well compared to the simulated true values (RMSE < 1.66 mm, 3.69°). Sternoclavicular, scapulothoracic and glenohumeral rotations were reconstructed well the major trends and magnitudes of experimental measurements. We anticipate our method will pave the way for complex applications that demand reliable and rapid large-scale biomechanical analysis of human movement.

The implantation of total knee replacements is an effective treatment for advanced degenerative knee joint diseases. Implant positioning relative to the bones affects the loads occurring in the artificial joint, joint stability, and postoperative functionality. Variance in implant positioning during the surgical implantation of a total knee replacement cannot be entirely ruled out. By simulating implant malpositioning in an experimental setting, particularly critical cases of malalignment can be identified, from which guidelines for orthopedic surgeons can be derived. The AMTI VIVO™ six degree of freedom joint simulator allows reproducible preclinical testing of joint endoprostheses under specific kinematic and loading conditions. It features a virtual ligament model that defines up to 100 ligament fibers between the articulating components. This paper presents a method to investigate the effect of different implant positions on the biomechanics of the knee after total knee arthroplasty. For this, the VIVO joint simulator requires no modification of the physical setup by moving virtual ligament insertion points relative to the bone. As a proof of concept, exemplary shifts and rotations of the femoral and tibial implant components are performed, and dynamic results are compared to a musculoskeletal multibody digital twin and findings from the literature. Video Abstract.

The AMTI VIVO™ six degree of freedom joint simulator allows reproducible preclinical testing of joint endoprostheses under specific kinematic and loading conditions. When testing total knee endoprosthesis, the articulating femoral and tibial components are each mounted on an actuator with two and four degrees of freedom, respectively. To approximate realistic physiological conditions with respect to soft tissues, the joint simulator features an integrated virtual ligament model that calculates the restoring forces of the ligament apparatus to be applied by the actuators. During joint motion, the locations of the ligament insertion points are calculated depending on both actuators’ coordinates. In the present study, we demonstrate that unintended elastic deformations of the actuators due to the specifically high contact forces in the artificial knee joint have a considerable impact on the calculated ligament forces. This study aims to investigate the effect of this structural compliance on experimental results. While the built-in algorithm for calculating the ligament forces cannot be altered by the user, a reduction of the ligament force deviations due to the elastic deformations could be achieved by preloading the articulating implant components in the reference configuration. As a proof of concept, a knee flexion motion with varying ligament conditions was simulated on the VIVO simulator and compared to data derived from a musculoskeletal multibody model of a total knee endoprosthesis.

Building on work in European history on culture and identity, as well as recent trends in diplomatic history, I explore questions of imperialism, nationalism, identity, and Orientalism and examine how the British press and other forms of public discourse, such as theater and sermons, constructed the image of Russia simultaneously as a barbaric, semi-Oriental, autocratic empire and as a semi-civilized Christian and European society. I argue that in depicting Russia as an Asiatic “Other,” the British defined themselves as the superior and progressive opposite of the Russians. However, just as Russia was geographically part of both Europe and Asia, the British journalists could not completely dissociate the “Western” and “Oriental” aspects of Russia. During the nineteenth century, Russia was Britain's imperial rival rather an object of commercial or colonial designs. My dissertation explores the duality of this relationship through a new paradigm, which I call “Russianism,” for interpreting British perceptions of Russia. The backdrop for this study were three wars between Russia and the Ottoman Empire in 1828–1831, 1853–1856 (Crimean War), and 1877–1878. My discussion centers on the emergence of the notion that Russia posed a sustained, strategic threat to Britain's imperial position in Asia.

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (−10.2%), waist circumference (−7.7 cm) and waist-to-height ratio (−6.9%) versus placebo (−1.5%, −1.3 cm and −1.0%, respectively; P  < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and ≥40 kg m − 2 ) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide (43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo). Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4 years. ClinicalTrials.gov identifier: NCT03574597 . A prespecified analysis of the SELECT trial revealed that patients assigned to once-weekly subcutaneous semaglutide 2.4 mg lost significantly more weight than those receiving placebo and showed improvements in various anthropometric indices.

Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure–activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria.

As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics. The glycopeptide vancomycin is considered an antibiotic of last resort. Its use is challenged by bacterial strains exhibiting various types of resistance. Therefore, in this study, highly active polycationic peptide-vancomycin conjugates with varying linker characteristics or the addition of PEG moieties were synthesized to optimize pharmacokinetics while retaining or even increasing antimicrobial activity in comparison to vancomycin. The antimicrobial activity of the novel conjugates was determined by microdilution assays on susceptible and vancomycin-resistant bacterial strains. VAN1 and VAN2, the most promising linker-modified derivatives, were further characterized in vivo with molecular imaging and biodistribution studies in rodents, showing that the linker moiety influences both antimicrobial activity and pharmacokinetics. Encouragingly, VAN2 was able to undercut the resistance breakpoint in microdilution assays on vanB and vanC vancomycin-resistant enterococci. Out of all PEGylated derivatives, VAN:PEG1 and VAN:PEG3 were able to overcome vanC resistance. Biodistribution studies of the novel derivatives revealed significant changes in pharmacokinetics when compared with vancomycin. In conclusion, linker modification of vancomycin-polycationic peptide conjugates represents a promising strategy for the modulation of pharmacokinetic behavior while providing potent antimicrobial activity.

Antibiotic‐resistant enterococci represent a significant global health challenge. Unfortunately, most β‐lactam antibiotics are not applicable for enterococcal infections due to intrinsic resistance. To extend their antimicrobial spectrum, polycationic peptides are conjugated to examples from each of the four classes of β‐lactam antibiotics. Remarkably, the β‐lactam–peptide conjugates gained an up to 1000‐fold increase in antimicrobial activity against vancomycin‐susceptible and vancomycin‐resistant enterococci. Even against β‐lactam‐resistant Gram‐negative strains, the conjugates are found to be effective despite their size exceeding the exclusion volume of porins. The extraordinary gain of activity can be explained by an altered mode of killing. Of note, the conjugates showed a concentration‐dependent activity in contrast to the parent β‐lactam antibiotics that exhibited a time‐dependent mode of action. In comparison to the parent β‐lactams, the conjugates showed altered affinities to the penicillin‐binding proteins. Furthermore, it is found that peptide conjugation also resulted in a different elimination route of the compounds when administered to rodents. In mice systemically infected with vancomycin‐resistant enterococci, treatment with a β‐lactam–peptide conjugate reduced bacterial burden in the liver compared to its originator. Therefore, peptide modification of β–lactam antibiotics represents a promising platform strategy to broaden their efficacy spectrum, particularly against enterococci. Novel potent compounds are urgently required for the treatment of antibiotic‐resistant bacteria. Conjugation of polycationic peptides to β‐lactam antibiotics extends their efficacy spectrum against enterococci. The β‐lactam–peptide conjugates show significant differences in mechanism and biodistribution compared to their originators. Due to their high potency, the β‐lactam–peptide conjugates can serve as an alternative treatment option for severe enterococcal infections.