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Summary: Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

Abstract Estimating growing stock is one of the main objectives of forest inventories. It refers to the stem volume of individual trees which is typically derived by models as it cannot be easily measured directly. These models are thus based on measurable tree dimensions and their parameterization depends on the available empirical data. Historically, such data were collected by measurements of tree stem sizes, which is very time- and cost-intensive. Here, we present an exceptionally large dataset with section-wise stem measurements on 40’349 felled individual trees collected on plots of the Experimental Forest Management project. It is a revised and expanded version of previously unpublished data and contains the empirically derived coarse (diameter ≥7 cm) and fine branch volume of 27’297 and 18’980, respectively, individual trees. The data were collected between 1888 and 1974 across Switzerland covering a large topographic gradient and a diverse species range and can thus support estimations and verification of volume functions also outside Switzerland including the derivation of whole tree volume in a consistent manner.

This study investigates the sagittal plane dynamics of the foot, particularly the metatarsophalangeal (MTP) joint and medial longitudinal arch (MLA) movements, in relation to obesity and foot health. The kinematics of the MTP and arch joints were measured in 17 individuals with class 2–3 obesity (BMI > 35 kg/m²) and 10 normal-weight individuals (BMI ≤ 24.9 kg/m²) using marker-based tracking. Analysis was conducted during heel lifting while seated and during walking at self-selected speeds. The results indicated that obese participants exhibited 20.92% greater MTP joint dorsiflexion at the end of the push-off phase and 19.84% greater MLA compression during the stance phase compared to normal-weight controls. However, no significant differences were found in the kinematic joint coupling ratio. While these findings reveal the different biomechanical behaviors of the MTP joint and MLA in obese compared to normal-weight individuals, it is important to interpret the implications of these differences with caution. This study identifies specific biomechanical variations that could be further explored to understand their potential impact on foot health in obese populations.

Abstract Background The Worksite Health Promotion Capacity Instrument (WHPCI) was developed to assess two key factors for effective worksite health promotion: collective willingness and the systematic implementation of health promotion activities in companies. This study evaluates the diagnostic qualities of the WHPCI based on its subscales Health Promotion Willingness and Health Promotion Management, which can be used to place companies into four different categories based on their level of health promotion capacity. Methods Psychometric evaluation was conducted using exploratory factor and reliability analyses with data taken from a random sample of managers from n = 522 German information and communication technology (ICT) companies. Receiver operating characteristic (ROC) analyses were conducted to determine further diagnostic qualities of the instrument and to establish the cut-off scores used to determine each company's level of health promotion capacity. Results The instrument's subscales, Health Promotion Willingness and Health Promotion Management, are based on one-dimensional constructs, each with very good reliability (Cronbach's alpha = 0.83/0.91). ROC analyses demonstrated satisfactory diagnostic accuracy with an area under the curve (AUC) of 0.76 (SE = 0.021; 95% CI 0.72-0.80) for the Health Promotion Willingness scale and 0.81 (SE = 0.021; 95% CI 0.77-0.86) for the Health Promotion Management scale. A cut-off score with good sensitivity (71%/76%) and specificity (69%/75%) was determined for each scale. Both scales were found to have good predictive power and exhibited good efficiency. Conclusions Our findings indicate preliminary evidence for the validity and reliability of both subscales of the WHPCI. The goodness of each cut-off score suggests that the scales are appropriate for determining companies' levels of health promotion capacity. Support in implementing (systematic) worksite health promotion can then be tailored to each company's needs based on their current capacity level.

The objective of this study was to compile the currently available evidence regarding the functional and morphologic outcomes of functional orthodontic therapy for mandibular condyle fracture. We performed searches in PubMed and Google Scholar as well as manually (IOK issues 2008–2019) using the keywords “trauma”, “TMJ”, “activator”, “condylar fracture”, “fracture”, “mandibular condylar fracture”, “occlusal splint” and “functional appliance”. Screening and analysis of study eligibility were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search strategy identified 198 studies published between 1971 and 2018, with 93 studies remaining after removing duplicate hits. Of the 93 studies, 19 were included in this study, considering the inclusion criteria. There were 12 follow-up, 4 prospective, and 3 purely retrospective studies. Some of the studies showed good functional results of mandibular condyle fracture treatment, in addition to subjective patient satisfaction. The incisal edge difference could be increased to physiological ranges of >35 mm by means of activator therapy. Partial mandibular deviations to the fractured side remained post-therapy, especially after unilateral fractures. Fractures without significant dislocation and luxation showed radiographic changes in shape, described as hypoplastic and ellipsoid, in addition to good morphologic results. One study found that collum length shortened twofold after a luxated fracture compared with fractures without significant dislocation, despite activator therapy. Straightening of the fragment occurred only in the low-dislocated fragments. Overall, children showed a higher remodeling potential than adult patients. Several studies observed an improved clinical outcome for functional therapy after mandibular condyle fracture. The outcome is essentially determined by fracture type, fracture height, and age. Further studies, especially prospective studies, are necessary to improve the evidence of functional orthodontic therapy for mandibular condyle fractures.

We are developing a phase-modulating micro mirror-array spatial light modulator to be used for real holography within the EU-funded project REALHOLO, featuring millions of pixels that can be individually positioned in a piston mode at a large frame rate. We found earlier that an electrostatic comb-drive array offers the best performance for the actuators: sufficient yoke forces for fast switching even at low voltages compatible with the CMOS addressing backplane. In our first design, the well-known electrostatic cross-talk issue had already been much smaller than would have been possible for parallel-plate actuators, but it was still larger than the precision requirements for high-image-quality holography. In this paper, we report on our analysis of the crucial regions for the electrostatic cross-talk and ways to reduce it while observing manufacturing constraints as well as avoiding excessively high field strengths that might lead to electrical breakdown. Finally, we present a solution that, in FEM simulations, reduces the remaining cross-talk to well below the required specification limit. This solution can be manufactured without any additional processing steps and suffers only a very small reduction of the yoke forces.

IntroductionBarbell kinematics are an essential aspect of assessing weightlifting performance. This study aimed at analyzing the total variability of time series barbell kinematics during repeated lifts in the snatch and the clean and jerk at submaximal and maximal barbell loads.MethodsIn a test-retest design, seven male weightlifters lifted submaximal [85% planned one-repetition maximum (1RMp)] and maximal (97% 1RMp) loads in the snatch and the clean and jerk during training. Barbell trajectory, vertical velocity, and vertical acceleration were determined using video analysis. Standard error of measurement (SEM), intraclass correlation coefficient (ICC), and smallest real difference (SRD) were used to determine the total variability during the lifts. Hedge's g effect size was used to assess differences in SEM between submaximal and maximal loads.ResultsThe main findings indicated that variability—in particular for the barbell velocity—was lower at maximal compared to submaximal barbell loads (g = 0.52–2.93). SEM of time series data showed that variability increased in the snatch and the clean and jerk from the 1st pull/dip to the catch position irrespectively of the barbell load.DiscussionThis study presents values of total variability of time series barbell kinematics during the snatch, the clean, and the jerk. Further, the SRD can be used to evaluate changes in barbell kinematics in response to training. In addition, when interpreting barbell kinematics, coaches should take into account that the variability of barbell kinematics can vary depending on the exercise and the barbell load.

Machine learning models are used to identify crops in satellite data, which achieve high classification accuracy but do not necessarily have a high degree of transferability to new regions. This paper investigates the use of machine learning models for crop classification using Sentinel-2 imagery. It proposes a new testing methodology that systematically analyzes the quality of the spatial transfer of trained models. In this study, the classification results of Random Forest (RF), eXtreme Gradient Boosting (XGBoost), Stochastic Gradient Descent (SGD), Multilayer Perceptron (MLP), Support Vector Machines (SVM), and a Majority Voting of all models and their spatial transferability are assessed. The proposed testing methodology comprises 18 test scenarios to investigate phenological, temporal, spatial, and quantitative (quantitative regarding available training data) influences. Results show that the model accuracies tend to decrease with increasing time due to the differences in phenological phases in different regions, with a combined F1-score of 82% (XGBoost) when trained on a single day, 72% (XGBoost) when trained on the half-season, and 61% when trained over the entire growing season (Majority Voting).

Abstract Osaka Bay adjacent to the Kyoto–Osaka–Kobe metropolitan area was affected by severe metal pollution during the twentieth century; yet little is known about the trace metal sources and pre-industrial human activities. We have determined the elemental concentrations and zinc stable isotope ratios (δ66Zn) in bulk sediments and the trace metal concentrations in chemical fractions of a 9-m-long sediment core from Osaka Bay. Our goals were (1) to reconstruct the historical trace metal contamination, and (2) to identify anthropogenic Zn sources and the solid phases of anthropogenic trace metals. The core provided a continuous environmental record of the last 2300 years based on radiocarbon dating of molluscan shells. Copper, Zn, and Pb showed an initial enrichment from the 1670s AD, which could be caused by human activities due to an increasing population. In agreement with previous findings, the trace metal concentrations slightly increased from the 1870s, strongly increased from the beginning of the twentieth century, and peaked around 1960 before environmental pollution control laws were enacted. Increasing trace metal concentrations in the acid-labile and reducible fractions obtained by the Community Bureau of Reference (BCR) sequential extraction procedure toward the surface indicate carbonates and Mn oxyhydroxides were the primary fractions for anthropogenic trace metals. The δ66Zn values (1) were constant until the 1940s, suggesting that the average δ66Zn of industrial sources was indistinguishable from that value of the natural background, (2) showed a slight decrease from the 1950s and remained constant until the present, and (3) fell in a binary mixing process between a lithogenic (~ + 0.27‰) and an anthropogenic endmember (~ + 0.17‰), the latter likely representing a mixture of various Zn sources such as road dust, tire wear, industrial effluents, and effluents from wastewater treatment plants. We conclude the combination of Zn stable isotopes together with chemical fractions obtained by the BCR method represents a promising approach to assess the trace metal sources and their potential mobility in sediment cores from anthropogenically affected coastal areas.

ObjectivePathomorphological alterations of the central nervous system in dogs, such as syringomyelia and Chiari-like malformation, can cause cranial and cervical hyperesthesia and neuropathic pain. The long-term activity of the pain network can induce functional alteration and eventually even morphological changes in the pain network. This may happen especially in the prefrontal and cingulate cortex, where atrophy of the gray matter (GM) was observed in humans with chronic pain, irrespective of the nature of the pain syndrome. We tested the hypothesis that Cavalier King Charles Spaniels (CKCS) with Chiari-like malformation and associated syringomyelia (SM) and pain show cerebral morphological differences compared to animals without signs of syringomyelia and pain.MethodsVolumetric datasets of 28 different brain structures were analyzed in a retrospective manner, including voxel-based morphometry, using magnetic resonance imaging data obtained from 41 dogs.ResultsVolumetric analyses revealed a decrease in GM volumes in the cingulate gyrus (CG) in CKCS with SM and chronic pain when normalized to brain volume. This finding was supported by voxel-based morphometry, which showed a cluster of significance within the CG.ConclusionGM atrophy in the CG is associated with chronic pain and thus may serve as an objective readout parameter for the diagnosis or treatment of canine pain syndromes.

Background/Objectives: New drugs are required for the treatment of liver cancers and protozoal parasite infections. Analogs of the known anticancer active and antileishmanial 2′,4′,6′-trimethoxychalcone SU086 were prepared and investigated. Methods: The chalcones were prepared according to the Claisen–Schmidt condensation protocol and analyzed. They were tested for activity against two liver cancer cell lines (HepG2 and HuH-7) and protozoal parasites (Toxoplasma gondii and Leishmania major). Unspecific toxicity and expression of Hsp90 and Hsp70 upon treatment were analyzed in liver cancer cells. Results: A new chalcone, 2′,4′,6′-trimethoxy-3-pentafluorosulfanylchalcone (246TMP-3SF5), with a pentafluorosulfanyl (SF5) substituent showed pronounced activities against liver cancer cells and T. gondii parasites which were superior to the activities of the parent chalcone SU086 in these models. In contrast, SU086 and its anthracene analog 2′,4′,6′-trimethoxy-9-anthracenylchalcone (246TMP-Anth) were most active against L. major promastigotes. The new SF5-substituted chalcone behaved like the known Hsp90 inhibitor 17-AAG and upregulated Hsp70 expression in liver cancer cells. Conclusions: The SF5-substituted SU086 analog has potential to become a new drug for the therapy of hepatoma and toxoplasmosis. [ABSTRACT FROM AUTHOR]

Orthodontic tooth movement (OTM) is thought to be impeded by bisphosphonate (BP) therapy, mainly due to increased osteoclast apoptosis and changes in the periodontal ligament (PdL), a connecting tissue between the alveolar bone and teeth. PdL cells, mainly fibroblasts (PdLFs), are crucial regulators in OTM by modulating force-induced local inflammatory processes. Recently, we identified the TGF-β/BMP superfamily member GDF15 as an important modulator in OTM, promoting the pro-inflammatory mechanoresponses of PdLFs. The precise impact of the highly potent BP zoledronate (ZOL) on the mechanofunctionality of PdLFs is still under-investigated. Therefore, the aim of this study was to further characterize the ZOL-induced changes in the initial inflammatory mechanoresponse of human PdLFs (hPdLFs) and to further clarify a potential interrelationship with GDF15 signaling. Thus, two-day in vitro treatment with 0.5 µM, 5 µM and 50 µM of ZOL altered the cellular properties of hPdLFs partially in a concentration-dependent manner. In particular, exposure to ZOL decreased their metabolic activity, the proliferation rate, detected using Ki-67 immunofluorescent staining, and survival, analyzed using trypan blue. An increasing occurrence of DNA strand breaks was observed using TUNEL and an activated DNA damage response was demonstrated using H2A.X (phosphoS139) staining. While the osteogenic differentiation of hPdLFs was unaffected by ZOL, increased cellular senescence was observed using enhanced p21Waf1/Cip1/Sdi1 and β-galactosidase staining. In addition, cytokine-encoding genes such as IL6, IL8, COX2 and GDF15, which are associated with a senescence-associated secretory phenotype, were up-regulated by ZOL. Subsequently, this change in the hPdLF phenotype promoted a hyperinflammatory response to applied compressive forces with an increased expression of the pro-inflammatory markers IL1β, IL6 and GDF15, as well as the activation of monocytic THP1 cells. GDF15 appeared to be particularly relevant to these changes, as siRNA-mediated down-regulation balanced these hyperinflammatory responses by reducing IL-1β and IL-6 expression (IL1B p-value < 0.0001; IL6 p-value < 0.001) and secretion (IL-1β p-value < 0.05; IL-6 p-value < 0.001), as well as immune cell activation (p-value < 0.0001). In addition, ZOL-related reduced RANKL/OPG values and inhibited osteoclast activation were enhanced in GDF15-deficient hPdLFs (both p-values < 0.0001; all statistical tests: one-way ANOVA, Tukey’s post hoc test). Thus, GDF15 may become a promising new target in the personalized orthodontic treatment of bisphosphonatepatients.