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Deficient angiogenesis and disturbed osteogenesis are key factors for the development of nonunions. Mineral-coated microparticles (MCM) represent a sophisticated carrier system for the delivery of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2. In this study, we investigated whether a combination of VEGF- and BMP-2-loaded MCM (MCM + VB) with a ratio of 1:2 improves bone repair in non-unions. For this purpose, we applied MCM + VB or unloaded MCM in a murine non-union model and studied the process of bone healing by means of radiological, biomechanical, histomorphometric, immunohistochemical and Western blot techniques after 14 and 70 days. MCM-free non-unions served as controls. Bone defects treated with MCM + VB exhibited osseous bridging, an improved biomechanical stiffness, an increased bone volume within the callus including ongoing mineralization, increased vascularization, and a histologically larger total periosteal callus area consisting predominantly of osseous tissue when compared to defects of the other groups. Western blot analyses on day 14 revealed a higher expression of osteoprotegerin (OPG) and vice versa reduced expression of receptor activator of NF-κB ligand (RANKL) in bone defects treated with MCM + VB. On day 70, these defects exhibited an increased expression of erythropoietin (EPO), EPO-receptor and BMP-4. These findings indicate that the use of MCM for spatiotemporal controlled delivery of VEGF and BMP-2 shows great potential to improve bone healing in atrophic non-unions by promoting angiogenesis and osteogenesis as well as reducing early osteoclast activity.

Quantum error correction requires the detection of errors via reliable measurements of multiqubit correlation operators. As these operations are inherently faulty, fault-tolerant schemes for realizing quantum error correction are required. Recently, a paradigm requiring only minimal resource overhead in the form of “flag” qubits to detect and correct errors has been proposed. We experimentally demonstrate a fault-tolerant weight-4 parity-check measurement scheme, where one additional flag qubit serves to detect errors, which would otherwise proliferate into uncorrectable weight-2 errors onto the qubit register. We achieve a parity measurement fidelity of 92.3(2)%, which increases to 93.2(2)% upon conditioning to the flag readout result, which shows that the measurement scheme intercepts intrinsic errors occurring throughout the sequence. We show that the protocol is capable of reliably intercepting faults by deliberately injecting bit- and phase-flip errors. For holistic benchmarking of the parity measurement scheme, we use an entanglement witnessing scheme requiring a minimal number of measurements to verify genuine six-qubit multipartite entanglement. The demonstrated fault-tolerant parity measurement scheme constitutes the key building block in a broad class of resource-efficient flag-based quantum error correction protocols including topological color codes. Our hardware platform is based on atomic ions stored in a microchip ion trap. The qubit register is dynamically reconfigured via shuttling operations enabling effective full connectivity without operational cross talk, thereby providing key prerequisites underlying fault-tolerant circuit design. These architectural features in combination with the demonstrated approach to flag-based fault-tolerant quantum error correction open up a route toward scalable fault-tolerant quantum computing.

Huntington’s disease (HD) is a genetically caused neurodegenerative disorder characterized by heterogeneous motor, psychiatric, and cognitive symptoms. Although motor symptoms may be the most prominent presentation, cognitive symptoms such as memory deficits and executive dysfunction typically co-occur. We used functional magnetic resonance imaging (fMRI) and task fMRI-based dynamic causal modeling (DCM) to evaluate HD-related changes in the neural network underlying working memory (WM). Sixty-four pre-symptomatic HD mutation carriers (preHD), 20 patients with early manifest HD symptoms (earlyHD), and 83 healthy control subjects performed an n-back fMRI task with two levels of WM load. Effective connectivity was assessed in five predefined regions of interest, comprising bilateral inferior parietal cortex, left anterior cingulate cortex, and bilateral dorsolateral prefrontal cortex. HD mutation carriers performed less accurately and more slowly at high WM load compared with the control group. While between-group comparisons of brain activation did not reveal differential recruitment of the cortical WM network in mutation carriers, comparisons of brain connectivity as identified with DCM revealed a number of group differences across the whole WM network. Most strikingly, we observed decreasing connectivity from several regions toward right dorsolateral prefrontal cortex (rDLPFC) in preHD and even more so in earlyHD. The deterioration in rDLPFC connectivity complements results from previous studies and might mirror beginning cortical neural decline at premanifest and early manifest stages of HD. We were able to characterize effective connectivity in a WM network of HD mutation carriers yielding further insight into patterns of cognitive decline and accompanying neural deterioration.

Striated skeletal muscle cells from humans represent a valuable source for in vitro studies of the motoric system as well as for pathophysiological investigations in the clinical settings. Myoblasts can readily be grown from human muscle tissue. However, if muscle tissue is unavailable, myogenic cells can be generated from human induced pluripotent stem cells (hiPSCs) preferably without genetic engineering. Our study aimed to optimize the generation of hiPSCs derived myogenic cells by employing selection of CD34 positive cells and followed by distinct, stepwise culture conditions. Following the expansion of CD34 positive single cells under myogenic cell culture conditions, serum deprived myoblast-like cells finally fused and formed multinucleated striated myotubes that expressed a set of key markers for muscle differentiation. In addition, these myotubes contracted upon electrical stimulation, responded to acetylcholine (Ach) and were able to generate action potentials. Finally, we co-cultured motoneurons and myotubes generated from identical hiPSCs cell lines. We could observe the early aggregation of acetylcholine receptors in muscle cells of immature co-cultures. At later stages, we identified and characterised mature neuromuscular junctions (NMJs). In summary, we describe here the successful generation of an iPS cell derived functional cellular system consisting of two distinct communicating cells types. This in vitro co-culture system could therefore contribute to research on diseases in which the motoneurons and the NMJ are predominantly affected, such as in amyotrophic lateral sclerosis or spinal muscular atrophy.

Abstract  Twenty calves were placed on study at 3 days of age and were placed according to birth order into one of two groups: SS, which received 0.05% BW sodium zeolite A (SZA) added to their milk replacer, and CO, which received only milk replacer. Blood samples were taken on days 0, 30, and 60 for osteocalcin (OC) and deoxypyridinoline (DPD) analysis. On day 60, the calves were euthanized, and synovial fluid, articular cartilage, and both fused metacarpals were collected for bone quality analyses such as architecture and mechanical properties, mineral composition, and glycosaminoglycan concentration. There were no differences in OC concentrations because of treatment (p = 0.12), and CO calves had lower DPD concentrations than SS calves (p = 0.01), but the OC-to-DPD ratio was not different between treatments (p = 0.98). No differences in bone architecture or mechanical properties were detected. SZA supplementation increased cortical bone (p = 0.0002) and articular cartilage (p = 0.05) aluminum content. Glycosaminoglycan concentrations were not different in synovial fluid or cartilage. Supplementation of SZA appeared to alter the rate of bone turnover without altering bone strength. Aluminum concentrations in the bone and cartilage increased, which may be a concern, although the long-term consequences of such remain to be determined. [ABSTRACT FROM AUTHOR]

Abstract  The objective was to determine the effects of sodium zeolite A (SZA) on mineral metabolism and tissue mineral composition in calves. Twenty calves were placed on study at 3 days of age and were placed into one of two groups: SS, which received 0.05% BW SZA added to their milk replacer, and CO, which received only milk replacer. Blood samples were taken on days 0, 30, and 60 for mineral analysis. Urine and feces were collected on day 30 for mineral metabolism, and on day 60, the calves were euthanized, and samples were taken from numerous organs for mineral analyses. Aluminum retention was increased in the SS calves (p = 0.001). Silicon concentrations were increased in the aorta, spleen, lung, muscle, and kidney of the SS calves, and aluminum was increased in all SS tissues (p p  [ABSTRACT FROM AUTHOR]

Atrophic non-unions are a major clinical problem. Mineral coated microparticles (MCM) are electrolyte-coated hydroxyapatite particles that have been shown in vitro to bind growth factors electrostatically and enable a tuneable sustained release. Herein, we studied whether MCM can be used in vivo to apply Bone Morphogenetic Protein-2 (BMP-2) to improve bone repair of atrophic non-unions. For this purpose, atrophic non-unions were induced in femurs of CD-1 mice (n = 48). Animals either received BMP-2-coated MCM (MCM + BMP; n = 16), uncoated MCM (MCM; n = 16) or no MCM (NONE; n = 16). Bone healing was evaluated 2 and 10 weeks postoperatively by micro-computed tomographic (µCT), biomechanical, histomorphometric and immunohistochemical analyses. µCT revealed more bone volume with more highly mineralised bone in MCM + BMP femurs. Femurs of MCM + BMP animals showed a significantly higher bending stiffness compared to other groups. Histomorphometry further demonstrated that the callus of MCM + BMP femurs was larger and contained more bone and less fibrous tissue. After 10 weeks, 7 of 8 MCM + BMP femurs presented with complete osseous bridging, whereas NONE femurs exhibited a non-union rate of 100 %. Of interest, immunohistochemistry could not detect macrophages within the callus, indicating a good biocompatibility of MCM. In conclusion, the local application of BMP-2-coated MCM improved bone healing in a challenging murine non-union model and, thus, should be of clinical interest in the treatment of non-unions.

Background: In locally advanced rectal cancer, the prediction of tumor response during and after neoadjuvant treatment remains challenging. In terms of organ preservation, adaptive radiotherapy, and intensified (total) neoadjuvant therapies, biomarkers are desirable for patient stratification., Methods: In 16 patients, weekly blood samples (n = 86) to detect cell-free tumor DNA (ctDNA) during long-course neoadjuvant chemoradiotherapy were analyzed. Data were correlated with initial tumor volumes, MRI response in week 2 and 5 of radiotherapy as well as with pathologic tumor response after resection and outcome parameters., Results: Most patients showed decreasing ctDNA during the course of radiochemotherapy. However, we found heterogenous dynamics of ctDNA and could identify three groups: (1) decline (2) no clear decline and/or late shedding (3) persistence of ctDNA. In seven patients we could detect significant amounts of ctDNA in week 5 or week 6 of treatment. In our pilot cohort, we did not find significant correlations of ctDNA dynamics with pathologic response or outcome parameters. However, patients with distinct decline of ctDNA had larger tumor volumes prior to treatment, and MRI imaging in week 2 and 5 revealed bigger absolute decrease of tumor volumes. If significant levels of ctDNA were found in week 5 and / or 6, patients showed less absolute tumor volume decrease in week 2 and 5., Conclusions: Weekly measurement of ctDNA during radiochemotherapy is feasible and might represent a promising biomarker. Bigger initial primary tumors showed different ctDNA shedding profiles compared with smaller primary tumors and correlations of ctDNA dynamics with early imaging response were found., (© 2024. The Author(s).)

This paper describes the hybrid genome assembly of sucrose non-fermenting non-O1/non-O139 Vibrio cholerae isolated from human soft tissue infection. The hybrid assembled genome comprises two circular chromosomes with lengths of 3,001,999 bp and 1,264,051 bp, respectively, with a G + C content of 47.38%.

Frontal and parietal brain regions are involved in attentional control and prospective memory. It is debated, however, whether increased or decreased activity in those regions is beneficial for older adults' task performance. We therefore aimed to systematically modulate activity in those regions using high-definition transcranial direct current stimulation. We included n = 106 healthy adults (60-75 years old, 58% female) in a randomized, double-blind, and sham-controlled study. We evaluated task performance twice in the laboratory and at home and additionally assessed heart rates. Participants received cathodal, anodal, or sham stimulation of the left or right inferior frontal lobe, or the right superior parietal lobe (1 mA for 20 min). Performance improved at visit two in laboratory tasks but declined in at-home tasks. Stimulation did not modulate performance change in laboratory tasks but prevented decline in at home-tasks. Heart rates increased at visit two but only when right inferior frontal lobe activity was inhibited. Repeating a task seems more beneficial than stimulation for laboratory tasks. This might be different for at-home tasks. Inhibiting right frontal brain function increases heart rates, possibly due to a modulation of the frontal-vagal brain-heart axis., (© 2024. The Author(s).)

Falls in senior home residents are common. Individual preventive training can lower the fall risk. To detect the need for training, a systematic assessment of the individual fall risk is needed. The aim of this study was thus to assess whether a fall risk score based on free field insole measurements can distinguish between an at-risk group of senior home residents and a healthy young control group. A published fall risk score was used in senior home residents over the age of 75 and a young (< 40 years) control group to determine the individual fall risk. In addition, the fall events over 12 months were assessed. Statistical analysis including ROC analysis was performed to determine the ability of the score to detect participants at heightened fall risk. In total, 18 nursing home residents and 9 young control participants were included. Of the nursing home residents, 15 had at least one fall, with a total of 37 falls recorded over 12 months. In the control group, no falls were recorded. The fall risk score was significantly different between nursing home residents and the control group (9.2 + 3.2 vs. 5.7 ± 2.2). Furthermore, the score significantly differentiated fallers from non-fallers (10.3 ± 1.8 vs. 5.2 ± 2.5), with a cut-off > 7.5 (AUC: 0.95) and a sensitivity of 86.7% (specificity 83.3%). The fall risk score is able to detect the difference between senior nursing home residents and young, healthy controls, as well as between fallers and non-fallers. Its main proof of concept is demonstrated, as based on movement data outside special gait labs, and it can simplify the risk of fall determination in geriatric nursing home residents and can now be used in further, prospective studies., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The ultimate goal of value-based laboratory medicine is maximizing the effectiveness of laboratory tests in improving patient outcomes, optimizing resources and minimizing unnecessary costs. This approach abandons the oversimplified notion of test volume and cost, in favor of emphasizing the clinical utility and quality of diagnostic tests in the clinical decision-making. Several key elements characterize value-based laboratory medicine, which can be summarized in some basic concepts, such as organization of in vitro diagnostics (including appropriateness, integrated diagnostics, networking, remote patient monitoring, disruptive innovations), translation of laboratory data into clinical information and measurable outcomes, sustainability, reimbursement, ethics (e.g., patient empowerment and safety, data protection, analysis of big data, scientific publishing). Education and training are also crucial, along with considerations for the future of the profession, which will be largely influenced by advances in automation, information technology, artificial intelligence, and regulations concerning in vitro diagnostics. This collective opinion paper, composed of summaries from presentations given at the two-day European Federation of Laboratory Medicine (EFLM) Strategic Conference "A vision to the future: value-based laboratory medicine" (Padova, Italy; September 23-24, 2024), aims to provide a comprehensive overview of value-based laboratory medicine, projecting the profession into a more clinically effective and sustainable future., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Direct-to-consumer testing (DTCT) refers to commercial laboratory tests initiated by laypersons without the involvement of healthcare professionals. As this market grows in size and variety of products, a clear definition of DTCT to ground the conceptualization of their harms and benefits is needed. We describe how three different modalities of DTCT (home self-testing, self-sampled tests, and direct access tests) present caveats to the traditional testing process ('brain-to-brain loop'), and how this might differ between medical vs. non-medical laboratories. We make recommendations for ways to improve quality and reduce errors with respect to DTCT. The potential benefits and harms of DTCT will invariably depend on the context and situation of individual consumers and the types of tests involved. Importantly, implications for both consumers and the healthcare system should be considered, such as the effects on improving health outcomes and reducing unnecessary testing and use of clinical resources. 'Consumer initiation' must be a central defining characteristic of DTCT, to clearly demarcate the key drawbacks as well as opportunities of this type of testing from a laboratory specialists' perspective. The concept of 'consumer initiated testing' should also help define DTCT regulation, and provide a locus of efforts to support consumers as the main decision-makers in the purchasing and conducting of these tests in the absence of clinician gatekeeping., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: To compare linear distance of glenoid fossa to frontomaxillary nasal suture in skeletal Class-I and II malocclusions., Methods: This cross-sectional study was conducted at the Department of Orthodontics, Altamash Institute of Dental Medicine, Karachi Pakistan. The duration of study was one year from January, 2019 to January, 2020. After taking informed consent from patient and hospital ethical committee a total of 60 patients were included in the study using WHO sample size calculator. Two groups comprising 30 patients each i.e., Skeletal Class-I malocclusion and Skeletal Class-II malocclusion with mandibular retrusion both having normal vertical relationship were included in the study. The cephalometric measurements SNA, SNB, SNMP, FHMP, GF-FMN, CO-GO, CO GN on lateral cephalograms were measured and compared between the two groups. Independent t test was applied and p value ≤ 0.05 was considered as significant., Results: In skeletal Class-I malocclusion the mean linear distance of GF-FMN was 70.2 ± 4.02 mm and in skeletal Class-II malocclusion it was 73.4 ± 4.04 mm (p value .004). Glenoid fossa was 3.2 mm distally placed in patients with Class-II malocclusion., Conclusion: Glenoid fossa position is a diagnostic feature of Class-II malocclusion associated with mandibular retrusion. One of the effective cephalometric measurements to check glenoid fossa position is the distance from the glenoid fossa(GF) to the frontomaxillary nasal suture FMN (GF-FMN)., Competing Interests: Conflict of interest: None., (Copyright: © Pakistan Journal of Medical Sciences.)

To investigate the effects of adverse and protective childhood experiences on symptom improvement in outpatient psychotherapy., We evaluated n  = 648 completed outpatient psychodynamic psychotherapies. First, we estimated the rate of symptom improvement for each patient using a two-stage hierarchical linear model. We then calculated the direct and indirect influences of childhood experiences on the improvement rate using a structural equation model. Personality functioning, according to the Operationalized Psychodynamic Diagnosis system, was examined as being a possible mediating factor., The presence of adverse childhood experiences was directly associated with a slower improvement rate in psychotherapy. Moreover, a higher number of adverse childhood experiences was associated with greater impairments in the ability to communicate as one dimension of personality functioning, which in turn was associated with a slower improvement of symptoms. Protective childhood experiences were associated with fewer impairments in specific dimensions of personality functioning, but had no direct effect on the improvement rate., Adverse childhood experiences can directly influence the course of psychotherapy. In addition, the communication dimension of personality functioning appears to be a central mediator on which adverse and protective childhood experiences act antagonistically and can thus indirectly affect the improvement rate in psychotherapy.

Huntington's disease (HD), due to expansion of a CAG repeat in HTT , is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5'-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.

Huntington's disease (HD) predominantly affects the brain, causing a mixed movement disorder, cognitive decline and behavioural abnormalities. It also causes a peripheral phenotype involving skeletal muscle. Mitochondrial dysfunction has been reported in tissues of HD models, including skeletal muscle, and lymphoblast and fibroblast cultures from patients with HD. Mutant huntingtin protein (mutHTT) expression can impair mitochondrial quality control and accelerate mitochondrial ageing. Here, we obtained fresh human skeletal muscle, a post-mitotic tissue expressing the mutated HTT allele at physiological levels since birth, and primary cell lines from HTT CAG repeat expansion mutation carriers and matched healthy volunteers to examine whether such a mitochondrial phenotype exists in human HD. Using ultra-deep mitochondrial DNA (mtDNA) sequencing, we showed an accumulation of mtDNA mutations affecting oxidative phosphorylation. Tissue proteomics indicated impairments in mtDNA maintenance with increased mitochondrial biogenesis of less efficient oxidative phosphorylation (lower complex I and IV activity). In full-length mutHTT expressing primary human cell lines, fission-inducing mitochondrial stress resulted in normal mitophagy. In contrast, expression of high levels of N-terminal mutHTT fragments promoted mitochondrial fission and resulted in slower, less dynamic mitophagy. Expression of high levels of mutHTT fragments due to somatic nuclear HTT CAG instability can thus affect mitochondrial network dynamics and mitophagy, leading to pathogenic mtDNA mutations. We show that life-long expression of mutant HTT causes a mitochondrial phenotype indicative of mtDNA instability in fresh post-mitotic human skeletal muscle. Thus, genomic instability may not be limited to nuclear DNA, where it results in somatic expansion of the HTT CAG repeat length in particularly vulnerable cells such as striatal neurons. In addition to efforts targeting the causative mutation, promoting mitochondrial health may be a complementary strategy in treating diseases with DNA instability such as HD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Adverse childhood experiences were previously identified as relevant risk factors for the development of anxiety disorders. Furthermore, anxiety disorders were shown to be associated with impairments of personality functioning. The objective of this study was to investigate adverse and protective childhood experiences as well as personality functioning, as defined by the Operationalized Psychodynamic Diagnosis system, as potential predictors for the speed of recovery during psychotherapy for patients with anxiety disorders., Methods: The sample consisted of n = 312 completed psychotherapies. The speed of recovery, defined as symptom abatement over time, was calculated using a two-stage hierarchical linear model. The effects of adverse and protective childhood experiences as well as personality functioning on the speed of recovery during psychotherapy were then examined using a structural equation model., Results: The presence of adverse childhood experiences predicted a lower speed of recovery during psychotherapy. In addition, a higher number of adverse childhood experiences was associated with greater impairments in the abilities of perception and regulation as dimensions of personality functioning. A higher number of protective childhood experiences was associated with fewer impairments in the communication and attachment dimensions. Impairments in personality functioning in patients with anxiety disorders did not predict the speed of recovery during psychotherapy., Conclusions: Among patients with anxiety disorders, adverse childhood experiences lead to a lower speed of recovery during psychotherapy. Therefore, childhood adversity should be routinely assessed before and thoroughly addressed during psychotherapy in patients with anxiety disorders., 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 © 2024 Nowak, Nikendei, Rollmann, Orth, Friederich and Kindermann.)

Background: Monitoring of gait patterns by insoles is popular to study behavior and activity in the daily life of people and throughout the rehabilitation process of patients. Live data analyses may improve personalized prevention and treatment regimens, as well as rehabilitation. The M-shaped plantar pressure curve during the stance phase is mainly defined by the loading and unloading slope, 2 maxima, 1 minimum, as well as the force during defined periods. When monitoring gait continuously, walking uphill or downhill could affect this curve in characteristic ways., Objective: For walking on a slope, typical changes in the stance phase curve measured by insoles were hypothesized., Methods: In total, 40 healthy participants of both sexes were fitted with individually calibrated insoles with 16 pressure sensors each and a recording frequency of 100 Hz. Participants walked on a treadmill at 4 km/h for 1 minute in each of the following slopes: -20%, -15%, -10%, -5%, 0%, 5%, 10%, 15%, and 20%. Raw data were exported for analyses. A custom-developed data platform was used for data processing and parameter calculation, including step detection, data transformation, and normalization for time by natural cubic spline interpolation and force (proportion of body weight). To identify the time-axis positions of the desired maxima and minimum among the available extremum candidates in each step, a Gaussian filter was applied (σ=3, kernel size 7). Inconclusive extremum candidates were further processed by screening for time plausibility, maximum or minimum pool filtering, and monotony. Several parameters that describe the curve trajectory were computed for each step. The normal distribution of data was tested by the Kolmogorov-Smirnov and Shapiro-Wilk tests., Results: Data were normally distributed. An analysis of variance with the gait parameters as dependent and slope as independent variables revealed significant changes related to the slope for the following parameters of the stance phase curve: the mean force during loading and unloading, the 2 maxima and the minimum, as well as the loading and unloading slope (all P<.001). A simultaneous increase in the loading slope, the first maximum and the mean loading force combined with a decrease in the mean unloading force, the second maximum, and the unloading slope is characteristic for downhill walking. The opposite represents uphill walking. The minimum had its peak at horizontal walking and values dropped when walking uphill and downhill alike. It is therefore not a suitable parameter to distinguish between uphill and downhill walking., Conclusions: While patient-related factors, such as anthropometrics, injury, or disease shape the stance phase curve on a longer-term scale, walking on slopes leads to temporary and characteristic short-term changes in the curve trajectory., (©Christian Wolff, Patrick Steinheimer, Elke Warmerdam, Tim Dahmen, Philipp Slusallek, Christian Schlinkmann, Fei Chen, Marcel Orth, Tim Pohlemann, Bergita Ganse. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.05.2024.)

Many Mendelian disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic causes, additional genetic factors may influence the rate of those monogenic disorders. Notably, genome-wide association studies discovered somewhat expected modifiers, particularly mismatch repair genes involved in the CAG repeat instability, impacting age at onset of HD. Strikingly, FAN1 , previously unrelated to repeat instability, produced the strongest HD modification signals. Diverse FAN1 haplotypes independently modify HD, with rare genetic variants diminishing DNA binding or nuclease activity of the FAN1 protein, hastening HD onset. However, the mechanism behind the frequent and the most significant onset-delaying FAN1 haplotype lacking missense variations has remained elusive. Here, we illustrated that a microRNA acting on 3'-UTR (untranslated region) SNP rs3512, rather than transcriptional regulation, is responsible for the significant FAN1 expression quantitative trait loci signal and allelic imbalance in FAN1 messenger ribonucleic acid (mRNA), accounting for the most significant and frequent onset-delaying modifier haplotype in HD. Specifically, miR-124-3p selectively targets the reference allele at rs3512, diminishing the stability of FAN1 mRNA harboring that allele and consequently reducing its levels. Subsequent validation analyses, including the use of antagomir and 3'-UTR reporter vectors with swapped alleles, confirmed the specificity of miR-124-3p at rs3512. Together, these findings indicate that the alternative allele at rs3512 renders the FAN1 mRNA less susceptible to miR-124-3p-mediated posttranscriptional regulation, resulting in increased FAN1 levels and a subsequent delay in HD onset by mitigating CAG repeat instability., Competing Interests: Competing interests statement:J.-M.L. consults for Life Edit Therapeutics and serves on the scientific advisory board of GenEdit Inc. J.F.G. was a Founder and Scientific Advisory Board member with a financial interest in Triplet Therapeutics Inc. His NIH-funded project is using genetic and genomic approaches to uncover other genes that significantly influence when diagnosable symptoms emerge and how rapidly they worsen in HD. The company was developing new therapeutic approaches to address triplet repeat disorders such as HD, myotonic dystrophy, and SCAs. J.F.G.’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.F.G. also consults for Transine Therapeutics Ltd and has been a consultant for Wave Life Sciences USA Inc., Biogen Inc., and Pfizer Inc. V.C.W. was a Scientific Advisory Board member of Triplet Therapeutics, Inc., a company developing new therapeutic approaches to address triplet repeat disorders such HD and myotonic dystrophy. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. She is a scientific advisory board member of LoQus23 Therapeutics and has provided paid consulting services to Alnylam, Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc. and Passage Bio. S.L. is currently employee of Illumina, Inc., a public company that develops and markets systems for genetic analysis. Within the last 5 y D.G.M. has been a scientific consultant and/or received an honoraria/grants from AMO Pharma, Dyne, F. Hoffman-La Roche, LoQus23, MOMA Therapeutics, Novartis, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Rgenta Therpeutics, Sanofi, Sarepta Therapeutics Inc, Script Biosciences, Triplet Therapeutics, and Vertex Pharmaceuticals. D.G.M. also had research contracts with AMO Pharma and Vertex Pharmaceuticals. T.H.M. is an associate member of the scientific advisory board of LoQus23 Therapeutics Ltd.

Introduction: The management of fractured bones is a key domain within orthopedic trauma surgery, with the prevention of delayed healing and non-unions forming a core challenge. This study evaluates the efficacy of the AO Fracture Monitor in conjunction with biomechanical simulations to better understand the local mechanics of fracture gaps, which is crucial for comprehending mechanotransduction, a key factor in bone healing. Through a series of experiments and corresponding simulations, the study tests four hypotheses to determine the relationship between physical measurements and the predictive power of biomechanical models. Methods: Employing the AO Fracture Monitor and Digital Image Correlation techniques, the study demonstrates a significant correlation between the surface strain of implants and interfragmentary movements. This provides a foundation for utilizing one-dimensional AO Fracture Monitor measurements to predict three-dimensional fracture behavior, thereby linking mechanical loading with fracture gap dynamics. Moreover, the research establishes that finite element simulations of bone-implant systems can be effectively validated using experimental data, underpinning the accuracy of simulations in replicating physical behaviors. Results and Discussion: The findings endorse the combined use of monitoring technologies and simulations to infer the local mechanical conditions at the fracture site, offering a potential leap in personalized therapy for bone healing. Clinically, this approach can enhance treatment outcomes by refining the assessment precision in trauma trials, fostering the early detection of healing disturbances, and guiding improvements in future implant design. Ultimately, this study paves the way for more sophisticated patient monitoring and tailored interventions, promising to elevate the standard of care in orthopedic trauma surgery., Competing Interests: TP is president and board member of the AO Foundation, Switzerland, and extended board member of the German Society of Orthopedic Trauma Surgery (DGU), the German Society of Orthopedic Surgery and Traumatology (DGOU), and the German Society of Surgery (DGCH). TP is also the speaker of the medical advisory board of the German Ministry of Defense. The remaining 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 © 2024 Wickert, Roland, Andres, Diebels, Ganse, Kerner, Frenzel, Tschernig, Ernst, Windolf, Müller, Pohlemann and Orth.)

Introduction: Monitoring changes in gait during rehabilitation allows early detection of complications. Laboratory-based gait analyses proved valuable for longitudinal monitoring of lower leg fracture healing. However, continuous gait data recorded in the daily life may be superior due to a higher temporal resolution and differences in behavior. In this study, ground reaction force-based gait data of instrumented insoles from longitudinal intermittent laboratory assessments were compared to monitoring in daily life. Methods: Straight walking data of patients were collected during clinical visits and in between those visits the instrumented insoles recorded all stepping activities of the patients during daily life. Results: Out of 16 patients, due to technical and compliance issues, only six delivered sufficient datasets of about 12 weeks. Stance duration was longer ( p = 0.004) and gait was more asymmetric during daily life (asymmetry of maximal force p < 0.001, loading slope p = 0.001, unloading slope p < 0.001, stance duration p < 0.001). Discussion: The differences between the laboratory assessments and the daily-life monitoring could be caused by a different and more diverse behavior during daily life. The daily life gait parameters significantly improved over time with union. One of the patients developed an infected non-union and showed worsening of force-related gait parameters, which was earlier detectable in the continuous daily life gait data compared to the lab data. Therefore, continuous gait monitoring in the daily life has potential to detect healing problems early on. Continuous monitoring with instrumented insoles has advantages once technical and compliance problems are solved., Competing Interests: TP is president and board member of the AO Foundation, Switzerland, and extended board member of the German Society of Orthopedic Trauma Surgery (DGU), the German Society of Orthopedic Surgery and Traumatology (DGOU), and the German Society of Surgery (DGCH). TP is also the speaker of the medical advisory board of the German Ministry of Defence. The remaining 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 © 2024 Warmerdam, Wolff, Orth, Pohlemann and Ganse.)

Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington's disease and several of spinocerebellar ataxias. In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of Huntington's disease corrected for individual HTT CAG repeat length (i.e. residual age-at-onset), is modified by repeat instability-related DNA maintenance/repair genes as demonstrated by recent genome-wide association studies. Modification of one polyglutamine disease (e.g. Huntington's disease) by the repeat length of another (e.g. ATXN3, CAG expansions in which cause spinocerebellar ataxia 3) has also been hypothesized. Consequently, we determined whether age-at-onset in Huntington's disease is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes that were polymorphic in Huntington's disease participants but did not influence Huntington's disease age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set ( n = 1388) confirmed the lack of association between Huntington's disease residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our Huntington's disease onset modifier genome-wide association studies single nucleotide polymorphism data nor imputed short tandem repeat data supported the involvement of other polyglutamine disease genes in modifying Huntington's disease. By contrast, our genome-wide association studies based on imputed short tandem repeats revealed significant modification signals for other genomic regions. Together, our short tandem repeat genome-wide association studies show that modification of Huntington's disease is associated with short tandem repeats that do not involve other polyglutamine disease-causing genes, refining the landscape of Huntington's disease modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers., Competing Interests: J.F.G. was a Scientific Advisory Board member and had a financial interest in Triplet Therapeutics, Inc. His NIH-funded project is using genetic and genomic approaches to uncover other genes that significantly influence when diagnosable symptoms emerge and how rapidly they worsen in Huntington disease. The company is developing new therapeutic approaches to address triplet repeat disorders such Huntington's disease, myotonic dystrophy and SCAs. His interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.F.G. has also been a consultant for Wave Life Sciences USA, Inc., Biogen, Inc. and Pfizer, Inc. Within the last five years D.G.M. has been a scientific consultant and/or received an honoraria/stock options from AMO Pharma, Dyne, F. Hoffman-La Roche, LoQus23, Novartis, Ono Pharmaceuticals, Rgenta Therapeutics, Sanofi, Sarepta Therapeutics Inc, Script Biosciences, Triplet Therapeutics, and Vertex Pharmaceuticals and held research contracts with AMO Pharma and Vertex Pharmaceuticals. J.D.L. is a paid Advisory Board member for F. Hoffmann-La Roche Ltd and uniQure biopharma B.V., and he is a paid consultant for Vaccinex Inc, Wave Life Sciences USA Inc, Genentech Inc, Triplet Inc, and PTC Therapeutics Inc. T.H.M. is an associate member of the scientific advisory board of LoQus23 Therapeutics. L.J. was a member of the scientific advisory boards of LoQus23 Therapeutics and Triplet Therapeutics. V.C.W. was a Scientific Advisory Board member of Triplet Therapeutics, Inc., a company developing new therapeutic approaches to address triplet repeat disorders such Huntington's disease and myotonic dystrophy. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. She is a scientific advisory board member of LoQus23 Therapeutics and has provided paid consulting services to Alnylam, Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc. and Passage Bio. J.M.L consults for Life Edit Therapeutics and serves in the scientific advisory board of GenEdit, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The translocator protein (TSPO) has been proven to have great potential as a target for the positron emission tomography (PET) imaging of glioblastoma. However, there is an ongoing debate about the potential various sources of the TSPO PET signal. This work investigates the impact of the inoculation-driven immune response on the PET signal in experimental orthotopic glioblastoma., Methods: Serial [ 18 F]GE-180 and O -(2-[ 18 F]fluoroethyl)-L-tyrosine ([ 18 F]FET) PET scans were performed at day 7/8 and day 14/15 after the inoculation of GL261 mouse glioblastoma cells (n = 24) or saline (sham, n = 6) into the right striatum of immunocompetent C57BL/6 mice. An additional n = 25 sham mice underwent [ 18 F]GE-180 PET and/or autoradiography (ARG) at days 7, 14, 21, 28, 35, 50 and 90 in order to monitor potential reactive processes that were solely related to the inoculation procedure. In vivo imaging results were directly compared to tissue-based analyses including ARG and immunohistochemistry., Results: We found that the inoculation process represents an immunogenic event, which significantly contributes to TSPO radioligand uptake. [ 18 F]GE-180 uptake in GL261-bearing mice surpassed [ 18 F]FET uptake both in the extent and the intensity, e.g., mean target-to-background ratio (TBR mean ) in PET at day 7/8: 1.22 for [ 18 F]GE-180 vs. 1.04 for [ 18 F]FET, p < 0.001. Sham mice showed increased [ 18 F]GE-180 uptake at the inoculation channel, which, however, continuously decreased over time (e.g., TBR mean in PET: 1.20 at day 7 vs. 1.09 at day 35, p = 0.04). At the inoculation channel, the percentage of TSPO/IBA1 co-staining decreased, whereas TSPO/GFAP (glial fibrillary acidic protein) co-staining increased over time ( p < 0.001)., Conclusion: We identify the inoculation-driven immune response to be a relevant contributor to the PET signal and add a new aspect to consider for planning PET imaging studies in orthotopic glioblastoma models.