Increased serum NfL and GFAP levels indicate different subtypes of neurologic immune‐related adverse events during treatment with immune checkpoint inhibitors

Neurologic immune-related adverse events (nirAEs) represent rare, yet severe side effects associated with immune checkpoint inhibitor (ICI) therapy. Given the absence of established diagnostic biomarkers for nirAEs, we aimed to evaluate the diagnostic utility of serum Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP). Fifty-three patients were included at three comprehensive cancer centers, of these 20 patients with manifest nirAEs and 11 patients with irHypophysitis. Controls included patients without any irAE (n = 8) and other irAEs (n = 14). Using a single-molecule enzyme-linked immunosorbent assay (Simoa), serum levels were measured prior to, during and after the manifestation of (n)irAEs in 80 samples. Symptom severity of the (n)irAEs was graded according to the Common Criteria for Adverse Events (CTCAE) version 5.0. Serum NfL levels were significantly higher in the nirAE group (n = 20) compared to irHypophysitis (n = 11; p = .0025) and controls (n = 22; p = .0384). Subgroup analysis demonstrated a significant elevation of NfL in nirAEs of the peripheral nerves (PNirAE) in contrast to neuromuscular syndromes (NMirAE) (p = .0260). GFAP levels were highest in patients with nirAE affecting the central nervous system (CNSirAE) compared to PNirAE and NMirAE (p = .0064). Symptom severity of nirAEs was associated with increased levels of NfL and GFAP (p = .0069, .0092). Individuals with elevated NfL levels exhibited less favorable outcomes of the (n)irAEs (p = .0199). Measurement of NfL and GFAP may be helpful for the differentiation of the broad spectrum of nirAEs and may serve as an indicator of symptom severity. Further investigation is needed to evaluate their potential as diagnostic and prognostic biomarkers

Establishment of the complete life cycle of Calicophoron daubneyi under experimental conditions

The complex life cycle of the rumen fluke Calicophoron daubneyi is similar to that of the liver fluke Fasciola hepatica. Interestingly, C. daubneyi and F. hepatica share the same intermediate host, Galba truncatula. However, in contrast to its relative, experimental production of metacercariae is a major challenge for C. daubneyi, hampering a detailed analysis of its life cycle, especially in the definitive host. G. truncatula snails collected from natural habitats were bred in glass Petri dishes and fed dried organic lettuce leaves. C. daubneyi eggs were obtained from feces of naturally infected cattle and incubated until miracidia were hatching. Subsequently, these miracidia were allowed to infect snails, which were kept under specific laboratory conditions to monitor the shedding of metacercariae. In total, 177 G. truncatula snails were exposed to C. daubneyi miracidia during eleven snail infection trials. Sixty-eight of these snails survived for longer than 30 days post-infection (p.i.). From day 35 p.i., seven snails from five trials started shedding an average number of 106 metacercariae (range: 38–186) per snail. Three ewe lambs (aged 7–10 months) were inoculated orally with 150 metacercariae each. A different batch of metacercariae (obtained from three different snail trials) was used for each lamb. Another two lambs served as controls. All animals were regularly examined clinically, hematologically and coproscopically, using sedimentation techniques for the detection of trematode eggs. Low numbers of C. daubneyi eggs were detected in fecal samples of two of the three inoculated lambs on day 86 post-inoculation (yielding ≤ 2 epg), but only one lamb continued to shed eggs (up to 6 epg) until the end of the experiment (day 104 post-inoculation). None of the animals showed any abnormal clinical findings or blood parameters throughout the course of the study. Production of C. daubneyi metacercariae under laboratory conditions is reported, followed by experimental infection of the definitive host, thus completing the full life cycle of this parasite under experimental conditions. However, neither the survival rate of the snails nor the amount of metacercariae produced were comparable to previously published experiments using F. hepatica, necessitating further optimization of the laboratory protocols. Nevertheless, the results can serve as a starting point for more in-depth studies of this increasingly important trematode

The impact of endocrine disrupting chemicals on adrenal corticosteroids – A systematic review of epidemiological studies

Background The role of endocrine disrupting chemicals (EDCs) in the development of metabolic syndrome has gained increasing recognition in recent years. The underlying mechanisms are largely unresolved. Disruption of corticosteroid action and hypothalamic-pituitary-adrenal (HPA) axis are considered possible mechanisms. Objective To summarise epidemiological studies investigating an association between EDC concentration and altered levels of corticosteroids and the adrenocorticotropic hormone (ACTH). Methods Following the PRISMA guidelines, we searched PubMed and the Cochrane Library for epidemiological studies published from database inception until April 1st, 2024. Various groups of EDCs were evaluated with the prerequisite of direct measurement of the chemical, a metabolite, or biomarker. Results We identified 2094 articles. After removing duplicates and screening, 27 studies were included. Studies focused predominantly on glucocorticoids (n = 26) compared to mineralocorticoids (n = 5) and ACTH (n = 2). The most studied EDCs were pesticides (n = 9) and phthalates (n = 8). Significant associations between the concentrations of specific EDCs and hormone levels were found in all but three studies. Only one study described an association between EDCs, and hormone concentration and metabolic features. Conclusion There is clear evidence for the impact of specific EDCs on plasma corticosteroid concentrations in different age groups worldwide, however, results varied according to EDC class, study population and study methodology. Further research combining EDC and hormone concentrations, and clinical features, complemented by experimental investigations to study cell mechanisms, is needed to gain holistic knowledge of EDCs’ influence on glucocorticoid- and mineralocorticoid-related disorders

Clinically meaningful benefit and real‐world evidence in Alzheimer's disease research and care

In the realm of medical research, assessing novel therapies extends beyond statistical significance. The concept of meaningful benefits plays a pivotal role in determining the practical impact of interventions on patient outcomes. Clinical trials, which form the bedrock of evidence-based medicine, guide treatment decisions and shape health-care practices. While statistical significance remains a fundamental criterion, it falls short in fully evaluating the clinical relevance of therapeutic interventions. Clinically meaningful benefits focus on tangible improvements in patient health and well-being, transcending mere statistical thresholds. Key considerations include survival rates, symptom relief, functional status, and other patient-oriented outcomes. Determining meaningful benefits varies across diseases, patient populations, and available treatments. Balancing statistical rigor with clinical relevance is crucial. Overpowered trials may detect smaller differences than anticipated, necessitating careful interpretation. Researchers must view trial results through a patient-centric lens. Beyond survival, evaluating quality of life and side effects is equally relevant. Quantifying meaningful benefits involves metrics like numbers needed to treat and progression-free survival. Consistency across outcomes matters, as clinicians weigh gains in survival against improvements in quality of life. The pursuit of meaningful benefits elevates clinical trials from mere statistical exercises to patient-centered endeavors. Researchers, clinicians, and regulators must prioritize outcomes that genuinely matter to patients, ensuring that medical progress translates into meaningful improvements for them and their families

A Short Cognitive and Neuropsychiatric Assessment Scale for Progressive Supranuclear Palsy

Background : Patients with Progressive Supranuclear Palsy (PSP) suffer from several neuropsychological impairments. These mainly affect the frontal lobe and subcortical brain structures. However, a scale for the assessment of cognitive and neuropsychiatric disability in PSP is still missing. Objectives : To create and validate a new scale for cognitive and neuropsychiatric impairment in PSP. Methods : The Short Cognitive and Neuropsychiatric (ShoCo) scale was developed containing five items (bradyphrenia, apathy, aphasia, dysexecution and disinhibition). Each item can be categorized into 0 = no deficit, 1 = mild deficit, 2 = moderate deficit and 3 = severe deficit. The total score includes 15 points, 0 meaning no deficit and 15 severe deficits. Cross-sectional and longitudinal data from 201 baseline and 71 follow up patients were analyzed. Results : Baseline ShoCo scale results were 5.9 ± 2.9. No significant differences between patients with Richardson syndrome (PSP-RS) and variants (vPSP) could be detected in the PSP-ShoCo scale scores (PSP-RS 6.1 ± 3.0, n = 160, vPSP 5.1 ± 2.6, n = 41, P = 0.057). The scale showed good correlation with established scores (eg, Montreal cognitive assessment r = −0.535, P = 0.001). The ShoCo scale showed significant annualized change within the PSP-RS patients (baseline 6.2 ± 2.9, follow up 6.9 ± 3.1, annualized diff. 1.0 ± 3.1, n = 57, P = 0.022). Conclusions : The ShoCo scale seems a promising and valid tool to measure specific neuropsychological disabilities of PSP patients in clinical routine and research

Feasibility and potential diagnostic value of [18F]PI-2620 PET in patients with down syndrome and Alzheimer’s disease

Purpose of the report: Adults with Down Syndrome (DS) have a substantially increased risk for Alzheimer’s disease (AD) due to the triplicated amyloid-precursor-protein gene on chromosome 21, resulting in amyloid and tau accumulation. However, tau PET assessments are not sufficiently implemented in DS-AD research or clinical work-up, and second-generation tau tracers such as [18F]PI-2620 have not been thoroughly characterized in adults with DS. We aim at illustrating feasibility and potential diagnostic value of tau PET imaging with [18F]PI-2620 for the diagnosis of DS-AD. Materials and methods: Five adults with DS (40% female, aged 43–62) and cognitive decline underwent clinical assessments, neuropsychological testing, lumbar puncture and multimodal neuroimaging. All underwent [18F]PI-2620 tau PET. Visual read of tau PET scans was performed by three blinded raters, assessing increased tracer uptake in brain areas corresponding to the six Braak stage regions and basal ganglia. Results: Visual read of tau burden revealed three tau-positive individuals which corresponded to their clinical decline while two cognitively stable individuals were rated as negative. Rating showed high inter-rater reliability for all Braak stages. Conclusion: Tau PET imaging is a feasible and important biomarker assessment in the differential diagnosis of cognitive decline in adults with DS at risk of developing AD

BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis

Remyelination is a crucial regenerative process in demyelinating diseases, limiting persisting damage to the central nervous system (CNS). It restores saltatory nerve conduction and ensures trophic support of axons. In multiple sclerosis (MS) patients, remyelination has been observed in both white and grey matter and found to be more efficient in the cortex. Brain-enriched myelin-associated protein 1 (BCAS1) identifies oligodendrocyte lineage cells in the stage of active myelin formation in development and regeneration. Other than in the white matter, BCAS1+ oligodendrocytes are maintained at high densities in the cortex throughout life. Here, we investigated cortical lesions in human biopsy and autopsy tissue from patients with MS in direct comparison to demyelinating mouse models and demonstrate that following a demyelinating insult BCAS1+ oligodendrocytes in remyelinating cortical lesions shift from a quiescent to an activated, internode-forming morphology co-expressing myelin-associated glycoprotein (MAG), necessary for axonal contact formation. Noteworthy, activated BCAS1+ oligodendrocytes are found at early time points of experimental demyelination amidst ongoing inflammation. In human tissue, activated BCAS 1+ oligodendrocytes correlate with the density of myeloid cells, further supporting their involvement in an immediate regenerative response. Furthermore, studying the microscopically normal appearing non demyelinated cortex in patients with chronic MS, we find a shift from quiescent BCAS1+ oligodendrocytes to mature, myelin-maintaining oligodendrocytes, suggesting oligodendrocyte differentiation and limited replenishment of BCAS1+ oligodendrocytes in long-standing disease. We also demonstrate that part of perineuronal satellite oligodendrocytes are BCAS1+ and contribute to remyelination in human and experimental cortical demyelination. In summary, our results provide evidence from human tissue and experimental models that BCAS1+ cells in the adult cortex represent a population of pre-differentiated oligodendrocytes that rapidly react after a demyelinating insult thus enabling immediate myelin regeneration. In addition, our data suggest that limited replenishment of BCAS1+ oligodendrocytes may contribute to the remyelination failure observed in the cortex in chronic MS

Hearing impairment amongst people with Osteogenesis Imperfecta in Germany

Introduction Hearing impairment concerns a relevant percentage of individuals with Osteogenesis Imperfecta (OI). When looking at the current literature, the percentage of affected individuals with OI varies greatly from 32 to 58% of patients having mild OI and 21% to 27% of patients having moderate to severe OI. Little is known about the German population with OI. Method The goal of this study was to detect how many patients with OI, who visited the annual meeting of the German Association for Osteogenesis Imperfecta in 2023, proved to have a hearing impairment. In this prospective, cross-sectional study, each included individual obtained ear microscopy, audiometry, stapedius reflexes, tympanometry, and OAEs. Furthermore, each patient was asked a set of questions concerning the medical history. Results Of the included patients, 33% had hearing impairment. A significant difference was found for the mean air–bone gap (ABG) as well as the hearing threshold of the right ears. The difference was found between OI type III and IV (p = 0.0127) for the mean ABG and OI type I and IV (p = 0.0138) as well as III and IV (p = 0.0281) for the hearing threshold. Spearman’s rank correlation showed a high correlation between age and hearing threshold. Of the patients between 40 and 50 years old, 56% had hearing loss. Conclusion Hearing loss in individuals with OI is still a relevant problem, especially age-related in OI type I. Audiometry should be performed at least when individuals experience subjective hearing loss. The implementation of a screening starting at 40 years should be discussed and studied

Exact Computation of Any-Order Shapley Interactions for Graph Neural Networks

Albeit the ubiquitous use of Graph Neural Networks (GNNs) in machine learning (ML) prediction tasks involving graph-structured data, their interpretability remains challenging. In explainable artificial intelligence (XAI), the Shapley Value (SV) is the predominant method to quantify contributions of individual features to a ML model’s output. Addressing the limitations of SVs in complex prediction models, Shapley Interactions (SIs) extend the SV to groups of features. In this work, we explain single graph predictions of GNNs with SIs that quantify node contributions and interactions among multiple nodes. By exploiting the GNN architecture, we show that the structure of interactions in node embeddings are preserved for graph prediction. As a result, the exponential complexity of SIs depends only on the receptive fields, i.e. the message-passing ranges determined by the connectivity of the graph and the number of convolutional layers. Based on our theoretical results, we introduce GraphSHAP-IQ, an efficient approach to compute any-order SIs exactly. GraphSHAP-IQ is applicable to popular message passing techniques in conjunction with a linear global pooling and output layer. We showcase that GraphSHAP-IQ substantially reduces the exponential complexity of computing exact SIs on multiple benchmark datasets. Beyond exact computation, we evaluate GraphSHAP-IQ’s approximation of SIs on popular GNN architectures and compare with existing baselines. Lastly, we visualize SIs of real-world water distribution networks and molecule structures using a SI-Graph