University of Lübeck

Background In amyotrophic lateral sclerosis (ALS), neurofilament light chain (NfL) was introduced as a prognostic biomarker. More recently, NfL values can be shared on the patient’s ALS app. Also, the ALS functional rating scale (ALSFRS-R) is an established patient-reported assessment of disease progression. The scale can be obtained during clinic visits or remotely. However, few systematic data are available on the patients’ perception of prognostic information about NfL and ALSFRS-R and the remote sharing of these data. Methods In a multicenter study, 149 ALS patients were assessed for their perception of shared information about NfL and ALSFRS-R using an investigator-designed survey and established questionnaires. The recommendation of NfL and ALSFRS-R to fellow patients was assessed using the Net Promoter Score (NPS). Burden by shared information was investigated in two distinct settings: (1) clinic information when receiving results on NfL and/or ALSFRS-R during clinic visits and (2) remote information about NfL values and self-rating of the ALSFRS-R via the ALS app. General anxiety was measured by the Fear of Progression Questionnaire – Short Form (FoP-Q-SF). Results Information about NfL and ALSFRS-R, respectively ( n = 149), were regarded as relevant for patients themselves (75.2% and 77.2%) and for research (98% and 96%). The NPS showed a high recommendation rate for NfL (+ 21) and ALSFRS-R (+ 26). Only a minority of patients perceived shared information about NfL as burdensome, with a lower burden in the clinic setting ( n = 1, 4.2%) than in the remote setting ( n = 8, 12%; p = 0.015). Remote digital assessment of the ALSFRS-R was well received, with a reported burden in 9.8% ( n = 9) of the participants. The FoP-Q-SF revealed fear of progression in 40% of the respondents ( n = 60). Conclusions This study underscored the relevance of information about NfL and ALSFRS-R from the patient’s perspective. Furthermore, patients proved to appreciate the relevance of this data for ALS research. Sharing information about NfL or ALSFRS-R was rarely perceived as burdensome even in a remote setting using the ALS app. These findings pave the way for further development of the patient-centered approach to sharing prognostic information in ALS.

Magnetic particle imaging (MPI) is a promising imaging modality nearing clinical introduction. MPI's tracer‐based principle allows for highly sensitive background‐free imaging. Potential clinical applications include cardiovascular imaging and endovascular interventions. In principle, medical instruments are invisible in MPI due to the missing signal generation. Therefore, permanent marking technologies have been introduced. Additionally, temporary markers are of interest for follow‐up examinations after stent implantation to prevent artifacts during postinterventional stent lumen quantification. Consequently, medical instrument markers for MPI, based on biodegradable polylactic acid (PLA) and superparamagnetic iron‐oxide nanoparticles (SPIONs), are developed in this study. To investigate the markers, signal characteristics and degradation over time are studied for 28 d in a water bath at 37 °C. The samples are analyzed using a scale, micro‐CT, microscopy, magnetic particle spectroscopy (MPS), MPI, and vibrating sample magnetometry (VSM). A continuous mass decrease is detected (≈90% after 28 d), while MPS and MPI data show no loss of signal. VSM confirms that the markers’ mass reduction can be accounted for the degradation of PLA, while the SPIONs hardly detach from the coating. The introduced marking technology, with its degradation characteristics and signal behavior, is the basis for a variety of anticipated medical application scenarios.

Onboard Decision Support Systems (DSS) for energy-efficient maritime route planning are key for global carbon reduction and sustainable transportation goals. Research indicates seafarers’ fuel reduction behaviors are hindered by goal conflicts and workload, affecting motivation and efficient use of automated systems. We studied seafarers’ (N = 22) interactions with a DSS in a high-fidelity bridge simulator, assessing Usability, User Experience, Workload, Basic Psychological Need (BPN) fulfillment, and conducted interviews. Positive system evaluations, particularly hedonic User Experience, contrasted with perceived reduced autonomy using the DSS. Seafarers often requested autonomy-enhancing features (e.g., route editing). Our findings underline the importance of BPNs, especially autonomy, in human-centered technology for maritime transportation, contributing to environmental and efficiency goals.

Spine-related neck–arm pain is heterogeneous and may present on a spectrum between nociceptive and neuropathic pain. A recently developed mechanism-based clinical framework for spine-related pain distinguishes between spinally referred pain without neurological deficits (somatic referred pain, heightened nerve mechanosensitivity, radicular pain), with neurological deficits (radiculopathy), and mixed-pain presentations. This study investigated differences in somatosensory and clinical profiles of patients with unilateral spine-related neck–arm pain grouped according to the clinical framework. Patients (n = 113) underwent a clinical examination, after which they were classified into a subgroup(s). They completed questionnaires to assess function (Neck Disability Index), psychosocial factors (Tampa Scale of Kinesiophobia, pain catastrophizing scale, Depression, anxiety, and stress scale), neuropathic pain (Douleur neuropathique 4), and central sensitization features (Central Sensitization Inventory). Standardized quantitative sensory testing (QST) was performed over the maximal pain area and contralateral side. The radiculopathy group showed a significant loss of function on the symptomatic vs asymptomatic side in cold ( P = 0.024) and warm detection ( P = 0.004), thermal sensory limen ( P = 0.001), mechanical detection ( P = 0.001), increased windup ratio ( P = 0.014), and cold hyperalgesia ( P = 0.049). No other subgroup showed significant side differences in QST parameters. Symptom descriptors, such as burning ( P < 0.031), tingling ( P < 0.018), pins and needles ( P < 0.031), numbness ( P < 0.016), spontaneous pain ( P < 0.001), and electric pain/shock ( P < 0.026) were more common in the radicular/radiculopathy groups compared with the somatic/mechanosensitivity groups. There were no differences in psychosocial parameters between the groups. The phenotypic profiles support the construct of the clinical examination and patient classification and its application in clinical practice according to a clinical framework for spine-related pain.

Background The lack of accurate and affordable monitoring of glycated hemoglobin (HbA1c) is a common issue among patients with diabetes in low- and middle-income countries. We aimed to test a tablet- and smartphone-based point-of-care (TSB POC) device against a local laboratory-based measure of HbA1c for monitoring diabetes under real-world conditions. Methods For this cross-sectional clinical method applicability study, capillary and venous blood was collected in duplicate and analyzed at local primary health care centers. For a heterogeneity test, the tests were performed by an expert, and by a team of local nurses. The study was conducted in a multicenter design in rural and urban Aceh, Indonesia in 2019, and included a total of 533 adults. We mainly used Bland-Altman plots to assess the number of readings within the 95%-limits of agreement (LoA) and Deming regressions. Results The results show a mean difference between capillary HbA1c on the test device and the reference method of −0.54 [CI0.95 = −1.6933; 0.6048] with 5.21% of measurements outside the LoA and a Pearson’s r = 0.91 in the Deming Regression. There is no significant difference in test concordance between local nurses and the expert (4.23% versus 5.13% results outside the LoA [CI0.95 = −0.0331; 0.0511]). Conclusions TSB POC for analysis of HbA1c is an acceptable alternative for accessible monitoring of diabetes patients under these conditions. This method could provide access to high-quality diagnostic decisions through regular and cost-effective HbA1c monitoring directly in healthcare facilities, thus providing better access to essential health services.

Background Digital competences are essential for lifelong learning, as highlighted by the European Commission and emphasized in the Digital Education Action Plan 2021–2027. The COVID-19 pandemic necessitated an unprecedented shift to online education, profoundly impacting fields like physiotherapy that heavily rely on practical skills. This scoping review aims to provide an overview of currently applied digitally enhanced learning methods, content, effect on knowledge gain and student perceptions in physiotherapy education. Methods Following PRISMA guidelines for scoping reviews, a comprehensive search was conducted across multiple databases, including Medline, Web of Science, and ERIC, incorporating hand searches and expert consultations. Studies were included if they reported on any digitally enhanced educational methods in physiotherapy education, involving qualitative studies, clinical trials, observational studies, or case reports published in English or German from 2010 to February 2024. Data extraction focused on the digital tools that were used, the educational contents, individually measured outcomes, and the impact of digital education. Results Out of 2988 screened studies, 67 met the inclusion criteria, encompassing 7160 participants. These sources of evidence primarily used quantitative methods (n = 51), with a minority using qualitative (n = 7) or mixed methods (n = 6). Nearly half employed hybrid educational approaches. Outcome measures included knowledge, performance, perception, satisfaction, and attitudes. Most sources of evidence reported positive impacts of digitally enhanced education, particularly in knowledge transfer and skill performance. Synchronous and asynchronous methods were used, with varying success across theoretical and practical courses. Gamification and virtual reality emerged as promising tools for enhancing engagement and learning outcomes. However, challenges included the limited direct interaction and perceived self-efficacy among students. Conclusion Digitally enhanced learning formats in physiotherapy education can enhance learning experiences and is generally welcomed by students, especially when blended with traditional methods. The integration of innovative digital strategies holds promise for the future of physiotherapy training, contingent on comprehensive support and training for educators and students alike.

Risankizumab is approved for treating moderate-to-severe psoriasis. This interim analysis at 25 months evaluated the effectiveness of risankizumab compared with other approved biologics (OtherBios) among patients with moderate-to-severe psoriasis in the 37-month VALUE post-marketing observational study. Patients diagnosed with psoriasis were enrolled in a 2:1 ratio to risankizumab or OtherBios, as prescribed by their physicians. A ≥ 90% improvement in Psoriasis Area Severity Index (PASI) 90 at months 4, 13, and 25 and the time to first treatment change at 25 months were evaluated. Additionally, PASI 100 and 75, static Physician Global Assessment (sPGA 0/1), Dermatology Life Quality Index (DLQI), and Treatment Satisfaction Questionnaire for Medication (TSQM) scores were evaluated. All patients treated with ≥ 1 dose of biological therapy with ≥ 1 post-baseline measurement were included in the analysis. Modified non-responder imputation was used to handle missing data, and propensity score matching accounted for imbalances between comparison groups. Overall, 1765 patients received risankizumab and 874 received OtherBios. At baseline, the mean (SD) age of the overall population was 48.5 (14.7) years and mean (standard deviation [SD]) PASI scores were 15.0 (9.0) and 13.9 (8.8) in the risankizumab and OtherBios groups, respectively. At 25 months, 70.9% of those treated with risankizumab vs. 51.5% of those treated with OtherBios achieved PASI 90. The cumulative treatment change probability was 0.16 (95%, confidence interval [CI] 0.14, 0.18) in the risankizumab group and 0.29 (95% CI 0.26, 0.32) in the OtherBios group. At 25 months, a higher proportion of patients achieved PASI 100 (56.6% vs. 40.2%), PASI 75 (84.3% vs. 67.7%), sPGA 0/1 (82.6% vs. 66.2%), and DLQI 0/1 (70.0% vs. 52.9%) in the risankizumab vs. OtherBios group, respectively, and the change in mean TSQM global score was higher in the risankizumab group (86.0 vs. 79.4). All comparisons were nominally significant (P < 0.0001). No new safety signals were identified. In this prospective study, risankizumab demonstrated higher effectiveness, longer drug survival, and better improvement of patient-reported outcomes at 25 months compared with OtherBios. ClinicalTrials.gov identifier: NCT03982394.

Background CV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death protein-1 (PD-1) therapy-naïve or anti-PD-1 therapy-refractory cutaneous melanoma (cMEL) and in patients with advanced cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma and adenoid cystic carcinoma. Methods This open-label, cohort-based, phase I dose escalation study aimed to establish the maximum tolerated dose (MTD), recommended dose (RD), safety and preliminary efficacy of CV8102 as monotherapy or in combination with a PD-1 inhibitor. The preliminary efficacy of the RD was assessed in patients with cMEL in the expansion cohorts. Results Between September 2017 and October 2022, 98 patients were enrolled in monotherapy and combination therapy dose escalation and dose expansion cohorts. Two patients in the CV8102 monotherapy dose escalation cohort experienced relevant toxicities at the 900 µg dose level. One patient had Grade 3 aspartate transaminase/alanine aminotransferase elevation which met dose-limiting toxicity (DLT) criteria. Another patient experienced Grade 3 immune-mediated pneumonitis. No DLTs occurred in the combination therapy dose escalation cohort. The MTD was not formally reached and the RD for expansion was 600 µg. Common treatment-emergent adverse events were fever (57%), chills (37%) and fatigue (25%). In the dose escalation part, objective responses occurred in 3/33 patients treated with CV8102 as monotherapy and in 2/25 patients treated with CV8102 plus a PD-1 inhibitor. In the expansion cohorts in patients with anti-PD-1 therapy-refractory melanoma, 0/10 patients treated with CV8102 as monotherapy and 5/30 patients (17%) treated in combination with a PD-1 inhibitor experienced objective responses. Conclusions IT CV8102 was generally well tolerated with preliminary signs of efficacy as monotherapy and in combination with a PD-1 inhibitor. Trial registration number NCT03291002 .

The auditory mismatch negativity (MMN) has been widely used to investigate deficits in early auditory information processing, particularly in psychosis. Predictive coding theories suggest that impairments in sensory learning may arise from disturbances in hierarchical message passing, likely due to aberrant precision-weighting of prediction errors (PEs). This study employed a modified auditory oddball paradigm with varying phases of stability and volatility to disentangle the impact of hierarchical PEs on auditory MMN generation in 43 healthy controls (HCs). Single-trial EEG data were modeled with a hierarchical Bayesian model of learning to identify neural correlates of low-level PEs about tones and high-level PEs about environmental volatility. Our analysis revealed a reduced expression of the auditory MMN in volatile compared to stable phases of the paradigm. Additionally, lower Global Functioning (GF): Social scores were associated with a reduced difference waveform at 332 ms after stimulus presentation across the entire MMN paradigm. Further analysis revealed that this association was present during the volatile phase but not the stable phase of the paradigm. Source reconstruction suggested that the association between the stable difference waveform and psychosocial functioning originated in the left superior temporal gyrus. Finally, we found significant EEG signatures of both low- and high-level PEs and precision ratios. Our findings highlight the value of computational models in understanding the neural mechanisms involved in early auditory information processing and their connection to psychosocial functioning.

Objective People with a difference of sex development (DSD) have to deal with complex medical and psychosocial challenges making it difficult to provide treatment adapted to their needs and in line with guidelines. Within the project DSDCare in Germany quality of care of people with DSD is evaluated regularly focusing on patient satisfaction as an indicator of good quality. Design Nationwide, longitudinal multicentre observational study in Germany including people with DSD. Methods Ten specialised DSD centres recruit since May 2021 people with DSD and collect patient-related medical data in a registry. Participants and in case of minors the legal guardians receive a questionnaire including questions about satisfaction with care using the Y/CHC-SUN questionnaire. Medical and self-reported data were merged and analysed descriptively. Results Of the 141 adults and 232 parents completing a questionnaire between May 2021 and December 2023, 81.9% of adults and 86.4% of parents stated to be “very” or “extremely satisfied” with their health care. Scores in the dimensions “doctor’s behaviour” and “patient-centred care” were very high for both adults and parents while the dimensions “clinical environment,” “diagnosis/information,” and “coordination” were rated slightly lower. Some participants missed DSD training, psychological counselling, contact to self-advocacy groups and, in the case of adults, nutritional counselling. Conclusion People with DSD treated at specialised DSD centres in Germany are very satisfied with their care. The next step is to ensure that all people with DSD have access to a specialised centre to receive care that meets their needs.

Murayama and Jach point out that we do not sufficiently understand the constructs and mental computations underlying higher-order motivated behaviors. Although this may be generally true, we would like to add and contribute to the discussion by outlining how interdisciplinary research on novelty-evoked exploration has advanced the study of learning and curiosity.

Background Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement therapy fails to alleviate progressive neurodegeneration as infused NPC2 cannot cross the blood–brain barrier (BBB). Genetic modification of brain endothelial cells (BECs) is thought to enable secretion of recombinant proteins thereby overcoming the restrictions of the BBB. We hypothesized that an adeno-associated virus (AAV-BR1) encoding the Npc2 gene could cure neurological symptoms in Npc2−/− mice through transduction of BECs, and possibly neurons via viral passage across the BBB. Methods Six weeks old Npc2−/− mice were intravenously injected with the AAV-BR1-NPC2 vector. Composite phenotype scores and behavioral tests were assessed for the following 6 weeks and visually documented. Post-mortem analyses included gene expression analyses, verification of neurodegeneration in Purkinje cells, determination of NPC2 transduction in the CNS, assessment of gliosis, quantification of gangliosides, and co-detection of cholesterol with NPC2 in degenerating neurons. Results Treatment with the AAV-BR1-NPC2 vector improved motor functions, reduced neocortical inflammation, and preserved Purkinje cells in most of the mice, referred to as high responders. The vector exerted tropism for BECs and neurons resulting in a widespread NPC2 distribution in the brain with a concomitant reduction of cholesterol in adjacent neurons, presumably not transduced by the vector. Mass spectrometry imaging revealed distinct lipid alterations in the brains of Npc2−/− mice, with increased GM2 and GM3 ganglioside accumulation in the cerebellum and hippocampus. AAV-BR1-NPC2 treatment partially normalized these ganglioside distributions in high responders, including restoration of lipid profiles towards those of Npc2+/+ controls. Conclusion The data suggests cross-correcting gene therapy to the brain via delivery of NPC2 from BECs and neurons.

We present a modified limited memory BFGS (L-BFGS) method that converges globally and linearly for nonconvex objective functions. Its distinguishing feature is that it turns into L-BFGS if the iterates cluster at a point near which the objective is strongly convex with Lipschitz gradients, thereby inheriting the outstanding effectiveness of the classical method. These strong convergence guarantees are enabled by a novel form of cautious updating, where, among others, it is decided anew in each iteration which of the stored pairs are used for updating and which ones are skipped. In particular, this yields the first modification of cautious updating for which all cluster points are stationary while the spectrum of the L-BFGS operator is not permanently restricted, and this holds without Lipschitz continuity of the gradient. In fact, for Wolfe–Powell line searches we show that continuity of the gradient is sufficient for global convergence, which extends to other descent methods. Since we allow the memory size to be zero in the globalized L-BFGS method, we also obtain a new globalization of the Barzilai–Borwein spectral gradient (BB) method. The convergence analysis is developed in Hilbert space under comparably weak assumptions and covers Armijo and Wolfe–Powell line searches. We illustrate the theoretical findings with numerical experiments. The experiments indicate that if one of the parameters of the cautious updating is chosen sufficiently small, then the modified method agrees entirely with L-BFGS/BB. We also discuss this in the theoretical part. An implementation of the new method is available on arXiv.

Introduction PD1/PD-L1 inhibition (ICi) has recently become a new standard of care for patients with advanced MMR-deficient (MMRd) endometrial cancers. Nevertheless, response to immunotherapy is more complex than the presence of a single biomarker and therefore it remains challenging to predict patients response to ICi beyond MMRd tumors. Elevated PD-L1 expression (CPS ≥ 1) is often used as a prognostic marker as well as a predictive biomarker of response to ICi in different tumor types. In a retrospective, patient derived study, we analyzed PD1- and PD-L1 staining and correlated the results of different scores to clinical data to evaluate the prognostic impact of these scores. Materials and methods Immunohistochemical analysis of the receptor PD1 and the receptor ligand PD-L1 were performed on TMAs of primary paraffin‑embedded tumor samples. All patients were treated for primary endometrial cancer in the Department of Gynecology and Obstetrics, University Medical Center Schleswig–Holstein, Campus-Lübeck, Germany between the years 2006–2018. The evaluation and determination of the tumor proportion scoring (TPS), the combined positive score (CPS) and the immune cell scoring (IC) was automatically assessed semi-quantitatively, and results were correlated with clinicopathological characteristics and survival. Results 130 samples were evaluable and 64% showed a positivity (IC > 0) for the receptor PD1 and 56% for the receptor ligand PD-L1. Patients with a PD1 IC Score ≥ 1 showed a significant longer disease-free survival of 140 months (95% confidence interval (CI): 124–158) compared to patients with a lower IC < 1 for PD1 of 89 months (95% confidence interval (CI): 69–110); p = 0.017). Furthermore, the disease-free survival for patients with a CPS ≥ 5 for PD1 was longer (153.7 months (95% confidence interval (CI): 134–173.6) vs. 98.6 months (95% confidence interval (CI): 83–114); p = 0.036). Additionally, a PD1 CPS ≥ 5 showed a better overall survival but the result was not statistically significant. No difference in survival was found between patients with PD-L1 higher or lower than CPS 5. Conclusion In this study we pointed out that there are significant clinical differences among several immunohistochemical scoring systems. In our trial, a PD1-positivity with CPS ≥ 5 and IC ≥ 1 were significantly associated to a better disease-free survival while there was no association with TPS. The PD1-IC scoring was associated with MMRd while the TPS scoring was not. Therefore, PD1-IC could be more appropriate for endometrial carcinomas compared to TPS and could also add prognostic information beside the more established PD-L1-staining. Further prospective studies are needed for a validation of these scores in combination with other biomarkers.