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Background: Neuromuscular diseases (NMDs) and mitochondriopathies are rare and heterogeneous disorders. Diagnosis is often difficult and delayed, partly due to the lack of reliable biomarkers. Chitotriosidase (CHIT1) as a candidate marker for lysosomal storage diseases is elevated in Niemann pick disease type C as a prototype of this group of diseases. Most recently, a relevant role of the lysosomal pathway in mitochondriopathies has been discussed, but markers of lysosomal involvement have not been investigated. Therefore, the aim of this study was to evaluate CHIT1 concentrations in a broad spectrum of NMDs and mitochondriopathies., Methods: CHIT1 serum concentration of 151 patients with NMD or primary mitochondriopathy was determined by enzyme-linked immunosorbent assay, and compared to 38 healthy controls and 8 patients with Niemann pick disease type C. Results were controlled for age, sex, CRP and CHIT1 polymorphism, and compared to several established markers (CK, FGF21, GDF15)., Results: CHIT1 levels were not altered in NMDs, but significantly increased in mitochondriopathies, within the range of Niemann-Pick patients. Compared to the established biomarkers, CHIT1 and FGF21 showed a similar diagnostic performance, while better results were found for GDF15. However, there was a tendency for higher CHIT1 concentrations in patients with central nervous system involvement (MELAS syndrome), while FGF21 and GDF15 were not relevantly altered in these patients. Consequently, a combination of biomarkers including CHIT1 provided the best overall diagnostic performance., Conclusions: Serum CHIT1 concentration is significantly elevated in mitochondriopathies compared to healthy controls and other NMD, identifying CHIT1 as potential complementary biomarker in mitochondriopathies., Competing Interests: Declarations. Conflicts of interest: AM has received speaking fees and advisory board honoraria from Hormosan and Sanofi, outside of the submitted work. All other authors report no conflicts of interest. Ethical approval: This study was approved by the institutional research committee of Martin-Luther-University of Halle-Wittenberg (vote no. 2021–101). All subjects included in this study gave their informed consent., (© 2025. The Author(s).)

Copper (Cu) is an essential trace element involved in fundamental physiological processes in the human body. Even slight disturbances in the physiological Cu homeostasis are associated with the manifestation of neurodegenerative diseases. While suggesting a crucial role of Cu in the pathogenesis, the exact mechanisms of Cu neurotoxicity involved in the onset and progression of neurological diseases are far from understood. This study focuses on the molecular and cellular mechanisms of Cu-mediated neurotoxicity in human brain cells. First, the cytotoxic potential of Cu was studied in fully differentiated, human neurons (LUHMES cells). Lysosomal integrity was considerably affected following incubation with 420 µM CuSO 4 for 48 h. Further mechanistic studies revealed mitochondria and neuronal network as most susceptible target organelles (already at 100 µM CuSO 4 , 48 h), while the generation of reactive oxygen species turned out to be a rather later consequence of Cu toxicity. Besides Cu, the homeostasis of other elements might be involved and are likely to contribute to the pathology of Cu-mediated neurological disorders. Besides Cu, also effects on the cellular levels of magnesium, calcium, iron, and manganese were observed in the neurons, presumably aggravating the consequences of Cu neurotoxicity. In conclusion, insights in the underlying mode of action will foster the development of treatment strategies against Cu-mediated neurological diseases. Particularly, the interplay of Cu with other elements might provide a powerful diagnostic tool and might be used as therapeutic approach., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: The manuscript does not contain clinical studies or patient data., (© 2024. The Author(s).)

Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: M. Sonnet gibt an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Purpose: Healthcare professionals (HCPs) play a critical role in suicide prevention and clinical guidelines recommend inquiring about suicidality as part of medical history and diagnosis. Emerging evidence indicates a lack of implementation of such policies in clinical practice. However, to date, no comprehensive mixed-methods study has examined this issue in the field of oncology., Methods: A preregistered mixed-methods study was conducted with oncological HCPs (N = 20) from various professions, using semi-structured interviews and validated questionnaires. Employing an explorative theory-generating approach, qualitative content analysis was applied to the interviews. The different data sources are integrated and contrasted. Comparisons according to sociodemographic variables (profession, age, and gender) and frequency distributions were used to examine the questionnaire data., Results: Most HCPs reported direct or indirect experiences with suicidality in cancer patients. Nineteen HCPs did not routinely explore suicidality, of whom five reported not inquiring about it at all. Those who explored suicidality were more confident, less emotionally overwhelmed and reported higher subjective knowledge. HCPs also differed regarding their endorsement of suicide myths., Conclusion: The study highlights difficulties with active suicide exploration and differences among HCPs. Integrating these findings into education and training could improve HCPs' skills and reduce disparities, supporting successful suicide prevention., Competing Interests: Declarations. Ethical approval: The study contents and procedures were approved by the ethics committee of the Rhineland-Palatinate Chamber of Physicians (No. 2023–16975). Informed consent was obtained from all individual participants included in the study. Competing interests: 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. This work is part of the dissertation of the first author., (© 2025. The Author(s).)

Purpose: This study aims to analyze microvascular reconstruction in Oral and Maxillofacial Surgery (OMFS) in Europe., Methods: Based on previous studies, a dynamic online questionnaire was developed and subjected to internal and external evaluation. The questionnaire comprised multiple-choice, rating, and open-ended questions, addressing general and specific aspects and the impacts of the COVID-19 pandemic on microvascular reconstruction in OMFS in Europe. It was implemented into SurveyMonkey's ® online survey software and emailed to OMFS departments registered with the European Association for Cranio-Maxillofacial Surgery (EACMFS)., Results: Seventy-five participants from 23 European countries participated. Among them, 89% perform between 1 and 70 microvascular free flaps (MFF) annually. 38% of the participants reported a reduction in MFF due to the COVID-19 pandemic. The radial forearm (41% of participants) and fibula free flap (31%) are the most reported MFF. In most cases (59%), MFF procedures are exclusively performed by OMFS for OMFS patients, while 43% of participants reported cooperations with plastic surgeons to perform MFF for OMFS patients. Many participants prefer arterial end-to-end anastomoses (54%) using the facial artery (54%) and, if available, two venous anastomoses (68%). Low molecular weight heparin is the most used postoperative anticoagulant, reported by 67% of participants. For flap monitoring, clinical assessment and Doppler ultrasound are preferred by most participants (95% and 78%, respectively). Many participants (66%) indicated that tracheotomy is only performed when necessary. Differences were observed in relation to CAD/CAM (Computer-Aided Design/Computer-Aided Manufacturing) techniques, types of osteosynthesis, and dental implant treatment., Conclusion: This study highlighted variability in microvascular reconstruction in OMFS in Europe. Further studies are needed to assess these aspects in detail., Competing Interests: Declarations. Ethical approval: The survey conducted among colleagues in this study is not classified as a clinical trial. This survey aimed to gather descriptive and general information on microvascular reconstructions in Oral and Maxillofacial Surgery in Europe. No medical, surgical, or behavioral interventions were applied, neither to participants nor patients, and no experimental treatments were tested. As the survey does not involve assessing the efficacy or safety of any interventions, it does not meet the criteria for a clinical trial. Consent to participate: For this type of study, formal consent is not required. Consent to publish: For this type of study, consent to publish is not required. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Most studies on the effects of galactic cosmic rays (GCR) have relied on terrestrial irradiation using spatially homogeneous dose distributions of mono-energetic beams comprised of one ion species. Here, we exposed mice to novel beams that more closely mimic GCR, namely, comprising poly-energetic ions of multiple species. Six-month-old male and female C57BL/6J mice were exposed to 0 Gy, 0.5 Gy, or 1.5 Gy simplified simulated 5 ion GCR (GCRsim). Exposure to microgravity was simulated using hindlimb unloading (HLU). At nine months post exposure, the mice were terminated to assess for the presence of exposure-induced epigenetic alterations. DNA hypermethylation in the 5'-untranslated regions of Lx_III, MdFanc_I, and MdMus_II families of the Long Interspersed Nucleotide Element 1 (LINE-1) was observed in the lungs of male mice. These effects were accompanied by increases in the expression of DNA methyltransferases Dnmt1 and Dnmt3a, and methyl-binding protein, MecP2. Trends towards DNA hypomethylation, although insignificant, were observed in the lungs of female mice in the HLU + 1.5 Gy GCRsim group. Altogether, our findings suggest persistent and sex-specific epigenetic reprogramming in the mouse lung and suggests that the DNA methylation status of LINE-1 can serve as a robust and reliable biomarker of previous radiation exposure., Competing Interests: Declarations. Research involving animals: All animal procedures within this study were approved by the Institutional Animal Care and Use Committees at UAMS and BNL. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The presented study aimed to evaluate the effect of mandibular protrusion with a temporarily applied mandibular advancement device (MAD) on the posterior airway space and to determine a reliable metric constant based on a three-dimensional computed tomography (CT) evaluation., Materials and Methods: The study population consisted of patients with oral squamous cell carcinoma who were treated at least six months prior to the follow-up CT in supine position. Each patient received an individually adjusted MAD that was temporarily applied with three different protrusion distances (P 0  = 0 mm, P 4  = 4 mm, and P 8  = 8 mm) during follow-up CT. The open-source software Slicer was used to calculate three parameters: minimum cross-sectional area (minCSA), mean cross-sectional area (meanCSA), and volume., Results: The results showed a significant increase for all three parameters. The minCSA increased as follows: P 0  = 236.4 mm 2  ± 192.2; P 4  = 309.2 mm 2  ± 235.4; and P 8  = 430.6 mm 2  ± 265.3. The meanCSA increased significantly (p < 0.001) in all protrusion steps and all parts of the pharynx. The volume changed as follows: P 0  = 24.0 cm 3  ± 5.0; P 4  = 29.6 cm 3  ± 18.1; and P 8  = 33.6 cm 3  ± 19.0. The minCSA increased by 24.9 mm 2  ± 13.0 per millimeter mandibular protrusion. CONCLUSION AND CLINICAL RELEVANCE: The results are interesting for both conservative and surgical therapy and could find future application in dental, orthodontic, and combined oral surgical therapy. With the results of this study, surgeons and dentists may better predict the change of PAS parameter in order to better prepare for orthognathic surgery. They also could ensure the right protrusion distance for mandibular advancement devices in the case of obstructive sleep apnea., Competing Interests: Declarations. Conflict of interest: The authors have no conflict of interest. All authors have seen and approved the manuscript. Clinical trial: This manuscript does not report on a clinical trial. Off-label or investigation use: Not applicable., (© 2025. The Author(s).)

The rational design of engineered nanomaterials (NMs) with improved functionality and their increasing industrial application requires reliable, validated, and ultimately standardized characterization methods for their application-relevant, physicochemical key properties such as size, size distribution, shape, or surface chemistry. This calls for nanoscale (certified) reference materials (CRMs; RMs) and well-characterized reference test materials (RTMs) termed also quality control (QC) samples, assessed, e.g., in interlaboratory comparisons, for the validation and standardization of commonly used characterization methods. Thereby, increasing concerns regarding potential risks of NMs are also addressed and the road for safe and sustainable-by-design concepts for the development of new functional NMs and their use as nanomedicines is paved. With this respect, we will provide an overview of relevant international standardization and regulatory activities, definitions, and recommendations on characterization methods and review currently available organic or inorganic nanoscale CRMs, RMs, and RTMs, including their characterization or certification. In addition, we will highlight typical applications to streamline the regulatory approval process and improve manufacturability including the special challenges imposed by the colloidal nature and sometimes limited stability of NMs. Subsequently, we will critically assess the limitations of currently available nanoscale RMs and RTMs and address the gaps to be filled in the future such as the availability of NMs that come with reference data on properties other than commonly addressed particle size, such as surface chemistry or particle number concentration, or more closely resemble commercially available formulations or address application-relevant matrices., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

The tumorigenic dose 50 (TD 50 ) is a widely used measure of carcinogenic potency which has historically been used to determine acceptable intake limits for carcinogenic compounds. Although broadly used, the TD 50 model was not designed to account for important biological factors such as DNA repair and cell compensatory mechanisms, changes in absorption, etc., leading to the development of benchmark dose (BMD) approaches, which use more flexible dose-response models that are better able to account for these processes. Using a nitrosamine dataset as a case study, we compare the impact of moving to a BMD-based limit as opposed to a TD 50 -based limit. Although there are differences in individual potency estimates between the two approaches for some compounds, we show that the key metrics such as the 5 th percentile of the respective potency distributions, used when calculating class-specific default acceptable intakes, are not greatly affected. Furthermore, potency estimates for nitrosamine compounds relevant to read-across do not vary by more than a factor of 3, which is little in the context of the inherent variability in a biological response, in an overall landscape wherein potencies can vary by four orders of magnitude. This suggests a move to BMD-based limits is achievable without significant disruption to existing limits while utilising a more robust methodology., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest, financial or otherwise. GJ is a consultant who evaluates the risks posed by pharmaceutical impurities. His clients did not influence the content of this manuscript. Ethical approval: The manuscript does not contain clinical studies or patient data., (© 2025. The Author(s).)

Objectives: The study aimed to assess the percent correct shade identification of four intraoral scanners (IOS) and a spectrophotometer, focusing on how reliably each device selects the correct tooth shade compared to a visual observer's selection. The research question addresses how much clinicians can trust the device-selected shade without visual verification., Materials and Methods: Sixteen participants with natural, unrestored teeth were included. The teeth evaluated were tooth 21 (left maxillary central incisor), tooth 23 (left maxillary canine), and tooth 26 (first left maxillary molar). Tooth color was measured using four IOS devices and the Vita Easyshade V in three regions: incisal, middle, and cervical. The nearest 3D Master shade selected by each device was compared to the visual observer's selection. The percent exact match, acceptable match (> 1.2, ≤ 2.7 ∆E ab ), and mismatch type A (< 2.7, ≤ 5.4 ∆E ab ) were calculated. Statistical analysis was performed using a chi-square test with a 95% confidence level., Results: The overall clinical pass rate was highest for Carestream (78.2%), followed by Easyshade (63.5%), Primescan (51.2%), Trios (39.5%), and Medit (31.3%). Carestream also recorded the highest rate of mismatch type A (47.7%). Significant differences between devices were observed for all categories (p < 0.05)., Conclusions: Carestream demonstrated the highest overall clinical pass rate, while Medit exhibited the lowest. The study highlights the variability between devices in shade matching performance., Clinical Relevance: This study highlights the importance of considering device performance when relying on IOS or spectrophotometers for shade selection without visual assessment, as the reliability can vary significantly across devices., Competing Interests: Declarations. Ethical Approval: This study was conducted according to the Declaration of Helsinki and was approved by the Ethics Committee of the Medical Faculty of Albert-Ludwigs University Freiburg (Approval number: EK-Freiburg 21-1169; approval date: 17.08.2021). Informed consent: All participants provided written informed consent prior to their participation in the study. Details that might disclose their identity were excluded. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

One group of elements attracting more and more attention are so-called technology-critical elements (TCEs). In comparison with legacy pollutants, the anthropogenic impact of TCEs on the environment might still be minor, but various applications introduce them to the most remote places in the world including the marine environment. One area prone to pollution is the Baltic Sea, partly due to the lack of water exchange with the North Sea. In this study, a sediment core from the German Baltic Sea was used to analyze a total of 42 elemental mass fractions. Based on radiometric dating of 210 Pb and 137 Cs, results were classified in a recent (2020-2000) and a past period (< 1920), calculating background concentrations based on the Median + 2 Median Absolute Deviation (M2MAD) and the Tukey Inner Fence (TIF). Six legacy pollutants (Ni, Cu, Zn, As, Cd, Pb) and six TCEs (Ga, Ge, Nb, La, Gd, Ta) are discussed in detail. Anthropogenic impacts of both groups were assessed, and local enrichment factors were calculated showing an increase for the legacy pollutants (past period (≤ 0.8); recent period (≥ 1.2)), but also a minor increase for Ga, Ge and Nb (past period (0.9); recent period (1.1)). Values ≥ 1.5, indicating anthropogenic impact, were found for Cu, Zn, Cd and Pb, but also for Ge. Proposed background values may be considered as baseline for future studies., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests to declare., (© 2025. The Author(s).)

Drug toxicity is an important cause of chronic liver damage, which in the long term can lead to impaired bone homeostasis through an imbalance in the liver-bone axis. For instance, non-steroidal anti-inflammatory drugs (e.g., diclofenac), which are commonly used to control pain during orthopaedic interventions, are known to reduce bone quality and are the most prevalent causes of drug-induced liver damage. Therefore, we used human cell lines to produce a stable, reproducible, and reliable in vitro liver-bone co-culture model, which mimics the impaired bone homeostasis seen after diclofenac intake in vivo. To provide the best cell culture conditions for the two systems, we tested the effects of supplements contained in liver and bone cell culture medium on liver and bone cell lines, respectively. Additionally, different ratios of culture medium combinations on bone cell scaffolds and liver spheroids' viability and function were also analysed. Then, liver spheroids and bone scaffolds were daily exposed to 3-6 µM diclofenac alone or in co-culture to compare and evaluate its effect on the liver and bone system. Our results demonstrated that a 50:50 liver:bone medium combination maintains the function of liver spheroids and bone scaffolds for up to 21 days. Osteoclast-like cell activity was significantly upregulated after chronic exposure to diclofenac only in bone scaffolds co-cultured with liver spheroids. Consequently, the mineral content and stiffness of bone scaffolds treated with diclofenac in co-culture with liver spheroids were significantly reduced. Interestingly, our results show that the increase in osteoclastic activity in the system is not related to the main product of diclofenac metabolism. However, osteoclast activation correlated with the increase in oxidative stress and inflammation associated with chronic diclofenac exposure. In summary, we established a long-term stable liver-bone system that represents the interaction between the two organs, meanwhile, it is also an outstanding model for studying the toxicity of drugs on bone homeostasis., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: This study does not contain any studies with human or animal subjects performed by any of the authors., (© 2024. The Author(s).)

Lipids are major constituents of food but are also highly relevant substructures of drugs and are increasingly applied for the development of lipid-based drug delivery systems. Lipids are prone to oxidative degradation, thus affecting the quality of food or medicines. Therefore, analytical methods or tools that enable the degree of lipid oxidation to be assessed are of utmost importance to guarantee food and drug safety. Herein, we report the design, synthesis and application of the first-in-class fluorogenic triacylglycerols that enable dynamic monitoring of lipid oxidation via straightforward fluorescence readout. Our fluorogenic triacylglycerols can be used in both aqueous and lipid-based environments. Furthermore, we showed that the sensitivity of our fluorescent tracers towards oxidation could be tuned by incorporating either saturated or unsaturated acyl chains in their triacylglycerol core structure. With this, we provide a first proof of principle for the applicability of fluorescently labelled triacylglycerols as tracers to monitor the dynamics of lipid oxidation, thus paving the way for novel discoveries in the area of lipid analytics., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

The analysis of serum for biomarkers is a standard method in clinical diagnosis and health assessment. The application of Raman spectroscopy to probe biomarkers in serum is increasingly investigated due to its time- and cost-efficiency. However, time-consuming sample preparation is often required to analyze the serum samples. Additionally, hemolyzed samples are commonly discarded due to interference in the measurements. This study focuses on the application of the online coupling of size exclusion chromatography (SEC) to diode array detector (DAD) and capillary-enhanced Raman spectroscopy (CERS) for direct analysis of hemolyzed serum samples. We demonstrate that different protein classes such as serum albumin and immunoglobulin G (IgG) can be identified in hemolyzed serum according to a calculated hit quality index (HQI). Additionally, different oxidation and binding states of the heme prosthetic group are investigated at 532-nm excitation. The online coupling of SEC-DAD-CERS enables the detailed characterization of blood serum proteins, including the differentiation of IgG, serum albumin, and hemoglobin., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Alternaria mycotoxins may pose significant challenges to food safety and public health due to the wide spectrum of reported adverse effects. Despite this, critical information on the immunomodulatory and antiestrogenic properties of most of these contaminants is still lacking. The present study aimed to identify the mycotoxins responsible for the immunosuppressive and antiestrogenic effects of a complex extract of Alternaria mycotoxins (CE) obtained by growing an Alternaria alternata strain on rice. Through a toxicity-guided fractionation procedure involving the production of CE-fractions by supercritical fluid chromatography and mycotoxin quantification by LC-MS/MS, the mycotoxins alternariol (AOH), tenuazonic acid (TeA), altertoxin I (ATX-I), and alterperylenol (ALTP) were identified as potential toxicologically relevant constituents contributing to the in vitro effects exerted by the extract. The assessment of the immunomodulatory effects, performed by applying the NF-κB reporter gene assay in THP1-Lucia™ monocytes, revealed the scarce contribution of AOH to the effects exerted by the CE. TeA showed no effect on the NF-κB pathway up to 250 µM, whereas ATX-I and ALTP suppressed the LPS-mediated pathway activation at concentrations ≥ 1 µM. The evaluation of antiestrogenic effects, performed in Ishikawa cells by applying the alkaline phosphatase assay, revealed the ability of ALTP (≥ 0.4 µM) and ATX-I (≥ 2 µM) to suppress the estrogen-dependent expression of enzyme activity. Given the risk of detrimental impacts stemming from alterations in endocrine and systemic immune responses by the investigated mycotoxins, further studies are needed to elucidate their underlying mechanisms of action and comprehensively evaluate the health risks posed by these toxins., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s).)

The analysis of polar analytes with the help of hydrophilic interaction liquid chromatography (HILIC) using classic methods of high-performance liquid chromatography is not without its downsides. In these applications, acetonitrile is prevalent as main eluent and sample diluent. This results not only in slow diffusion processes during the separation, but also in often unstable sample solutions where polar analytes are concerned. Furthermore, there are ecological concerns. With the use of supercritical fluid chromatography (SFC) which uses supercritical carbon dioxide as eluent, and other green solvents as alternative for the sample preparation, the separation of polar analytes could be vastly improved with this technique. Fast diffusion within carbon dioxide led to shorter analysis times and higher plate numbers. Regarding sample diluents, small alcohols such as ethanol and 2-propanol, as well as acetone, yielded promising results while analytes showed higher solubility and stability within these solvents compared to acetonitrile. Other green solvents such as dihydrolevoglucosenone (Cyrene) and dimethyl carbonate were found to be unsuitable sample diluents for applications in SFC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Purpose: To report on the failure rates of an expandable interbody spacer, used for spinal instrumented transforaminal lumbar interbody fusion (TLIF) or posterior thoracolumbar interbody fusion (PLIF)., Methods: In this retrospective, single-center observational cohort study we reviewed consecutive PLIF/TLIF patients using the Catalyft™ PL and PL40 expandable titanium interbody implant (Medtronic, Minneapolis (USA)) between 07/2022 and 11/2023. We recorded patient demographics, surgical parameters, adverse events, radiological parameters and clinical outcomes according to the MacNab criteria., Results: We identified 53 patients (mean age 68.6 ± 11.5 years; 49.1% female; mean BMI 25.7 ± 4.4 kg/m 2 ), in which 92 Catalyft™ spacers were implanted, mostly at L4/5 (n = 35; 38.0%) and L5/S1 (n = 31; 33.7%) for degenerative (n = 44; 83.0%), deformity (n = 7; 13.2%) or other indications (n = 2; 3.8%). We noticed secondary collapse of 20 (21.7%) spacers in 11 patients (20.7%) occurring after a mean time of 4.0 ± 4.1 months postoperatively. Age < 70 years was identified as risk factor for secondary collapse (OR 3.71, 95% CI 1.31-10.5, p = 0.014), but no association was found regarding other patient-specific or surgery-related variables. Pseudarthrosis was evident in seven patients (13.2%), of which four (7.6%) required revision surgery. Clinical outcome at last follow-up (mean 6.4 ± 4.2 months) was excellent/good in 29 (54.7%), fair in 14 (26.4%) and poor in six patients (11.3%)., Conclusion: We provide a critical analysis of our series of patients with use of a specific type of expandable interbody spacer. We noticed failure and secondary collapse in an unacceptably high number of implants, some of which required revision surgery., Competing Interests: Declarations. Conflict of interest: The authors report no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Determining the primary origin of non-organ-confined neuroendocrine tumors (NETs) for accurate diagnosis and management. Neuroendocrine tumors are rare neoplasms with diverse clinical behaviors. Determining their primary origin remains challenging in cases of non-organ-confined NETs. This study explores the histogenesis of a retroperitoneal, non-functional NET localized between the duodenum and pancreatic head, utilizing advanced molecular diagnostics to elucidate its probable primary source., Methods: Initial diagnostic methods, including imaging and histopathology, failed to resolve the tumor's origin. The tumor was subjected to single-cell RNA sequencing (scRNA-seq) and whole exome sequencing (WES). Publicly available transcriptomic datasets from pancreatic and small intestine NETs were used to develop and validate a molecular gene signature for tissue-of-origin identification., Results: The gene signature distinguished pancreatic and small intestine NETs with high accuracy. The tumor cells presented a molecular profile consistent with a pancreatic origin, likely derived from ectopic pancreatic tissue., Conclusions: This case demonstrates the value of integrating scRNA-seq and WES for the molecular characterization of complex NETs. Identifying the tumor's pancreatic origin informed a targeted management approach, avoiding unnecessary systemic treatment and underscoring the potential of single-cell approaches in personalized oncology., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Adolescent and young adult cancer survivors (AYA-CS) face a long working life after treatment, yet factors related to a successful return to work remain largely unexplored. We therefore aimed to investigate the use of occupational adjustments and their impact on work ability upon return to work., Methods: As part of the AYA-LE study, we surveyed AYA-CS (aged 18-39 at diagnosis) who returned to work and assessed work ability (Work Ability Index) as well as use and benefit of occupational adjustments. We analyzed predictors of use and benefit of occupational adjustments on average 4 years post-diagnosis using multivariate linear and logistic regression., Results: Out of 438 AYA-CS, 389 (88.8%) returned to work after cancer diagnosis and were included in analyses. Mean work ability was M = 36.2 (SD = 6.9), 11.4% reported poor, 34.7% moderate, 41.4% good and 12.5% excellent work ability. Following treatment, 82.3% used occupational adjustments, most frequently: flexible working hours, gradual reintegration and reduced working hours. The probability of a reduction in working hours was found to be higher among older AYA-CS (≥ 30), female gender and with a fatigue index ≥ 11 (R2 = 0.073). A fatigue index < 11, elevated levels of pain and the presence of metastases/recurrence were associated with a lower benefit of reduced working hours (R2 = 0.183). Younger age (< 30) and stem cell transplant were associated with a lower benefit of support from colleagues (R2 = 0.077)., Conclusion: Our results highlight the need for targeted occupational counselling throughout the treatment and even beyond the return-to-work process, considering individual and social factors., Competing Interests: Declarations. Ethics approval: The study received the approval of the ethics committee of the medical faculty of the University of Leipzig, Germany (Ref. No. 436-17-13112017). Consent to participate: Informed consent was obtained from all individual participants included in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Spasmodic dysphonia (SD) is now generally considered to be a task-specific focal dystonia. For the first time, we wanted to explore the relationship between SD and dystonia from a combined neurological and phoniatric perspective. For this, we studied 115 patients with non-psychogenic SD by a combined neurological and phoniatric evaluation. Onset of SD was 49.7 ± 19.0 (6-68) years. The female/male ratio was 2. 63% had additional dystonia manifestations (cervical dystonia 35%, arm dystonia 15%, blepharospasm 11%, oromandibular dystonia 11%, writer's cramp 11%, pharyngeal dystonia 10%, generalised dystonia 4%, axial dystonia 2%, spasmodic dyspnoea 2% and segmental dystonia 1%). 71% occurred before, 25% after and 4% together with SD. 17% had a family history of dystonia and 6% a history of exposure to dopamine receptor blocking agents. 41% had mixed SD (SD-M), 31% abductor SD (SD-AB) and 28% adductor SD (SD-AD). SD-M was significantly correlated with additional dystonia manifestations and tremulous SD. No patient showed essential tremor or Parkinsonian syndromes. Two third of SD patients have additional dystonia manifestations and one fifth have a family history of dystonia, considerably more than previously described. In half of all patients, SD starts with non-SD dystonia. Our combined approach revealed a high prevalence of SD-M associated with frequent additional dystonia manifestations including dystonic tremor and a family history of dystonia. Patients presenting with SD should be evaluated for additional dystonia manifestations and dystonia patients should be evaluated for SD. Relevant coexistence of essential tremor and Parkinsonian syndromes cannot be confirmed., Competing Interests: Declarations. Conflict of interest: DD received honoraria for services provided to Allergan, Ipsen, Merz, Lanzhou Institute of Biological Products, Medy-Tox, Revance, Desitin, Syntaxin, AbbVie, Medtronic, St Jude, Boston Scientific, Almirall, Bayer, Sun, Teva, UCB, WizMedi, IAB-Interdisciplinary Working Group for Movement Disorders. He is shareholder of Allergan and holds patents on botulinum toxin and botulinum toxin therapy. FAS is founder and owner of IAB—Interdisciplinary Working Group for Movement Disorders. She received reimbursement from Abbot, AbbVie, Almirall, Allergan, Bayer, Desitin, Dynamed, Hempel GesundheitsPartner, Ipsen, Johnson & Johnson, Licher, Meda, Medtronic, Merz, Orion, PTZ Nawrath, Sensomotorik & Rehabilitation Hellmuth & Thiel, Sintetica, Sporlastic, Sun, Teva, Tricumed, TRS Med, UCB. LP and BK have nothing to disclose., (© 2024. The Author(s).)

Botulinum toxin (BT) therapy is the therapy of choice for most forms of dystonia. We want to describe its costs, if all dystonia patients in Germany would have access to optimal BT therapy. For this, we combined the latest data on epidemiology of dystonia and dosing of BT therapy for dystonia. Missing data were generated for this study. Based on official German pharmacy sales prices, optimal treatment for all dystonia patients in Germany with a population of 84.1 million would generate annual drug costs of €155.5 million (cervical dystonia 89.3, tardive dystonia 22.1, generalised dystonia 17.9, blepharospasm 9.3, segmental dystonia 5.9, writer's cramp 5.3, arm dystonia 3.2, oromandibular dystonia 2.3, musician's dystonia 0.3, spasmodic dysphonia 0.1) This is €1.85 annually per capita or 0.3% of the total 2021 drug budget and 42% of the 2021 Parkinson drug budget of German public insurance companies. Actual costs for the health care system are considerably lower, as there are various discounts to consider. Further reductions would be possible. BT therapy's individual costs are high. Its costs for the health care system, however, are marginal. Comparing projected and actual costs, would allow estimating availability and quality of BT therapy of dystonia in Germany., (© 2024. The Author(s).)

Objective: Splenectomy is regularly performed in total and distal pancreatectomy due to technical reasons, lymph node dissection and radicality of the operation. However, the spleen serves as an important organ for competent immune function, and its removal is associated with an increased incidence of cancer and a worse outcome in some cancer entities (Haematologica 99:392-398, 2014; Dis Colon Rectum 51:213-217, 2008; Dis Esophagus 21:334-339, 2008). The impact of splenectomy in pancreatic cancer is not fully resolved (J Am Coll Surg 188:516-521, 1999; J Surg Oncol 119:784-793, 2019)., Methods: We therefore compared the outcome of 193 pancreatic cancer patients who underwent total or distal pancreatectomy with (Sp) or without splenectomy (NoSp) between 2015 and 2021 using the StuDoQ|Pancreas registry of the German Society for General and Visceral Surgery. In addition, we integrated our data into the existing literature in a meta-analysis of studies on splenectomy in pancreatic cancer patients., Results: There was no difference between the Sp and NoSp groups regarding histopathological parameters, number of examined or affected lymph nodes, residual tumor status, or postoperative morbidity and mortality. We observed a significantly prolonged survival in pancreatic cancer patients who underwent total pancreatectomy, when a spleen-preserving operation was performed (median survival: 9.6 vs. 17.3 months, p = 0.03). In this group, splenectomy was identified as an independent risk factor for shorter overall survival [HR (95%CI): 2.38 (1.03 - 6.8)]. In a meta-analysis of the existing literature in combination with our data, we confirmed splenectomy as a risk factor for a shorter overall survival in pancreatic cancer patients undergoing total pancreatectomy, distal pancreatectomy, or pancreatic head resection [HR (95%CI): 1.53 (1.11 - 1.95)]., Conclusion: Here, we report on a strong correlations between removal of the spleen and the survival of pancreatic cancer patients undergoing total pancreatectomy. This should encourage pancreatic surgeons to critically assess the role of splenectomy in total pancreatectomy and give rise to further investigations., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Poly(butylene succinate-co-adipate) (PBSA), a biodegradable plastic, is significantly colonized and degraded by soil microbes under natural field conditions, especially by fungal plant pathogens, raising concerns about potential economic losses. This study hypothesizes that the degradation of biodegradable plastics may increase the presence and abundance of plant pathogens by serving as an additional carbon source, ultimately posing a risk to forest ecosystems. We investigated (i) fungal plant pathogens during the exposure of PBSA in European broadleaved and coniferous forests (two forest types), with a specific focus on potential risk to tree health, and (ii) the response of such fungi to environmental factors, including tree species, soil pH, nutrient availability, moisture content, and the physicochemical properties of leaf litter layer. Next-generation sequencing (NGS) revealed that PBSA harbored a total of 318 fungal plant pathogenic amplicon sequence variants (ASVs) belonging to 108 genera. Among the identified genera (Alternaria, Nectria, Phoma, Lophodermium, and Phacidium), some species have been reported as causative agents of tree diseases. Plenodomus was present in high relative abundances on PBSA, which have not previously been associated with disease in broadleaved and coniferous forests. Furthermore, the highest number of fungal plant pathogens were detected at 200 days of PBSA exposure (112 and 99 fungal plant pathogenic ASV on PBSA degraded under Q. robur and F. sylvatic-dominated forest, respectively), which was double compared mature leaves and needles from the same forest sites. These findings suggest that PBSA attracts fungal plant pathogens in forests as an additional carbon source, potentially leading to increased disease outbreaks and disrupting the stability of forest ecosystems. The fungal plant pathogenic community compositions were mainly shaped by forest type, PBSA exposure time, site locations, leaf litter layer water content, and N:P ratio from leaf litter layer in both forest types. This study provides valuable insights into the potential risks posed by biodegradable plastic degradation in forests after 200 and 400 days of exposure, respectively. Further comprehensive evaluations of their effects on tree health and ecosystems, ideally on a long-term basis, are needed. These evaluations should include integrating microbial investigation, soil health monitoring, and ecosystem interaction assessments. Nevertheless, it should be noted that our interpretation of plant pathogens is solely based on high-throughput sequencing, bioinformatics, and annotation tools., Competing Interests: Declarations. Ethics Approval: Ethical review and approval were waived for this study as ethical considerations of humans or animals were not addressed. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Follow-up results of modern zirconia implants inserted in fibula free and deep circumflex iliac artery (DCIA) flaps with fixed dentures are scarce. This study aimed to evaluate crestal bone changes and the survival rate of zirconia implants for up to 1.5 years of prospective follow-up., Materials and Methods: Ten patients with six fibula and four DCIA flaps underwent reconstruction in the lower and upper jaws using vascularized composite flaps and were treated with zirconia implants. Peri-implant bone resorption was measured using radiographic images that were taken immediately after implant surgery (T1) and after three (T2), 12 (T3), and 18 months (T4)., Results: Between the day of operation and T3, a significant increase in distance was recorded for the fibula flaps. After occlusal loading (T2) of 41 zirconia implants for up to 1.5 years, no significant bone loss in each flap was observed overall. An overall survival rate of 96.56% was reported., Conclusions: When comparing both composite flaps, no significant difference in periimplant bone levels was measured between the same timepoints., Clinical Relevance: For fixed dentures, modern zirconia implants can be used in the DCIA and fibula flaps, however further long-term data is necessary., Competing Interests: Declarations. Ethical approval: The study protocol received ethical approval from the appropriate local authorities. Informed consent: Informed consent was obtained from all individual participants included in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To evaluate a useful, non-contact method for the follow-up of pericardium patch graft changes in patients undergoing PAUL ® Glaucoma Implant (PGI) surgery using high-resolution anterior segment optical coherence tomography (OCT) to predict tube erosions., Methods: Prospective analysis over six months of tube pericardium patch graft thickness of PGI surgical cases at the University Eye Hospital Bonn, Germany, from November 2021 to August 2022. In all eyes, Tutopatch ® (RTI Surgical, United States) pericardium was used to cover the implant intra-operatively. Anterior segment OCT (AS-OCT, Heidelberg ANTERION ® Swept-Source-OCT) examinations were performed following a standardized protocol to measure quantitative and qualitative aspects of the patch grafts before surgery, and at three and six months after surgery., Results: Twenty-six eyes of 26 patients were included. Thickness of the patch material was 1188 µm (IQR 415 µm) directly after implantation and decreased over time to 1068 µm (IQR 478 µm) at 3 months and 846 µm (IQR 677 µm) at 6 months. No significant differences between groups were shown concerning gender (p = 0.128), ethnicity (p = 1.000), age (p = 0.741), glaucoma type (p = 0.173), other concurrent diseases (p = 0.302), former glaucoma surgeries (p = 1.000) and the quadrant of implantation (p = 0.555). Five eyes developed implant exposure. When comparing eyes with and without tube exposure, no significant differences were shown in average patch thickness above the tube directly after implantation (p = 0.476). However, significant differences in average thickness were observed at 3 months (p = 0.013) and 6 months (p = 0.005)., Conclusions: Pericardial patch grafts tend to thin over time which can be assessed by AS-OCT, the latter proving to be a useful method to follow-up patients who undergo patch graft implantation during PGI surgery. This investigation could potentially help identify patients at risk of tube exposure which in turn could lead to modification of patient management. It could also possibly be used in future studies to find more suitable patch materials., Competing Interests: Declarations. All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the University Hospital Bonn. Informed consent: Informed consent was obtained from all individual participants included in the study and the authors affirm that human research participants provided informed consent for publication of the images used in Figs. 1 and 3., (© 2024. The Author(s).)

A first principle soft-sensor for biomass and substrate estimation in upstream bioprocessing based on the fusion of elemental balancing and nonlinear kinetics is presented. It aims to extend the validity range of well-established elemental balancing soft sensors to substrate saturated and overfeeding conditions that often occur in induced production phases. An experimental study with recombinant E. coli cultivations was conducted to illustrate the soft-sensor principle and to analyze the accuracy as well as generalizability of the approach. Under substrate limited growth the extended soft-sensor showed similar performance as classical elemental balancing. In induced production phases however, a decline in maximum substrate uptake capacity ( q Smax ) of up to 80% was observed, where the extended soft-sensor showed up to 41 % better estimates for the biomass and up to 75 % better estimates for the substrate in terms of NRMSE. The paper discusses the possible benefits as well as the requirements for the implementation of the extended elemental balancing soft-sensor., Competing Interests: Declarations. Conflict of 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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: It is well known that myelin disruption and neuroinflammation are early and distinct pathological hallmarks in multiple system atrophy (MSA) as well as in idiopathic Parkinson's disease and in other atypical Parkinsonian syndromes. The objective of this study was to assess the value of non-neuronal biomarker candidates that reflect myelin disruption and neuroinflammation., Methods: Myelin basic protein (MBP) and the soluble form of TREM2 were quantified in a comprehensive movement disorder cohort from two different neurological centers, comprising a total of 171 CSF samples. Commercially available ELISA systems were employed for quantification., Results: The results of the MBP analysis revealed a significant increase in cerebrospinal fluid (CSF) MBP levels in all atypical Parkinsonian conditions compared to PD. This differentiation was more pronounced in the MSA-c subtype compared to MSA-p. Receiver operating characteristic (ROC) analysis revealed a significant discrimination between PD and MSA (p = 0.032, AUC = 0.70), PD and DLB (p = 0.006, AUC = 0.79) and PD and tauopathies (p = 0.006, AUC = 0.74). The results of the TREM2 analysis demonstrated no significant differences between the PD and atypical Parkinsonian groups if not adjusted for confounders. After adjusting for age, sex, and disease duration, the PD group exhibited significantly higher TREM2 levels compared to the DLB group (p = 0.002)., Conclusions: In conclusion, MBP, but not TREM2, is elevated in the CSF of not only MSA but in all atypical Parkinsonian conditions compared to idiopathic Parkinson's disease. This highlights the value of the evaluation of myelin/oligodendrocyte-associated markers in neurodegenerative movement disorders., (© 2024. The Author(s).)

Introduction: While ≥ 40 CAG repeat expansions in HTT present a well-established cause of Huntington's disease (HD), an enrichment of HTT repeat expansions was recently reported also in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including FTD/ALS patients with additional HD neuropathology. This raises the question whether the phenotypic spectrum of HTT expansions can be extended to ALS and FTD, and whether HTT should be considered as a new causative gene of FTD/ALS. If HTT repeat expansions were indeed systematically related to FTD/ALS, one would expect an increased frequency of HTT carriers in FTD/ALS, who can clinically/neuropathologically not be explained better than by the presence of the HTT repeat expansions., Methods: Screening of HTT repeat expansions in 249 consecutive patients with ALS or FTD by short-read genome sequencing took place. The post-mortem neuropathological examination was performed in the identified HTT repeat expansion carrier., Results: One HTT repeat expansion [40/22 repeats (± 1)] was identified in an ALS patient, giving a frequency of 0.4% (1/249) (frequency in the general population: 0.03-0.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed-in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions-HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration., Conclusions: Our study does not support the notion of an increased frequency of HTT repeat expansions in FTD/ALS. Moreover, the phenotype of the HTT carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which-given the low repeat number-is likely to become manifest only later in life. These findings corroborate the concept that HTT repeat expansions are likely co-existent/coincidental, but not causative in FTD/ALS., Competing Interests: Declarations. Conflict of interest: Dr. Milan Zimmermann reports no disclosures. Dr. David Mengel reports no disclosures. Dr. Katrin Klein reports no disclosures. Dr. Tobias Haack reports no disclosures. Dr. Manuela Neumann reports no disclosures. Dr. Matthis Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Servier, Solaxa, Biogen, Reata, GenOrph, AviadoBio, Biohaven, Zevra,and Lilly, all unrelated to the present manuscript., (© 2024. The Author(s).)