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Multifocal growth is characteristic of hereditary medullary thyroid cancer (MTC), whereas origin and impact of multifocal growth is enigmatic for sporadic MTC. To address this, 460 RET-negative patients with sporadic MTC, stratified by 1 (93.3 %), 2 (5.7 %) and 3 (1.1 %) thyroid tumor foci, were compared with 219 RET-positive patients with hereditary MTC, stratified by 1 (38.4 %), 2 (45.7 %), 3 (6.4 %), 4 (6.8 %) and ≥5 (2.7 %) thyroid tumor foci. For sporadic MTC, significant associations were identified with bilateral thyroid lobe involvement, microscopic lymphatic invasion, extrathyroid extension, node and distant metastases, number of node metastases, preoperative basal calcitonin level, and decreasing biochemical cure. For hereditary MTC, significant associations were limited to bilateral thyroid lobe involvement, largest thyroid tumor diameter, and preoperative basal calcitonin level. In sporadic MTC, multifocal growth is due to lymphatic invasion with frequent node metastases, whereas in hereditary MTC, it reflects malignant progression from C-cell hyperplasia to cancer., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Intragastric botulinum neurotoxin injections (IBNI) are offered off-label in the private medical sector in a few European countries as a safe and effective weight-loss measure. In February and March 2023, an outbreak of iatrogenic botulism occurred in several European countries following IBNI treatment in Turkey. This case series describes the clinical features of severe iatrogenic botulism after IBNI., Methods: We retrospectively summarize the clinical course and emergency department and intensive care unit interventions in ten cases of severe iatrogenic botulism that occurred after receiving IBNI in this sudden outbreak in Austria and Germany., Results: Seven out of ten cases initially showed characteristic symptoms of botulism with diplopia, dysphagia, dysarthria, dysarthrophonia, and descending paralysis. All patients were hospitalized, six in an intensive care unit and partially requiring mechanical ventilation. All patients recovered and were discharged without relevant permanent deficits., Conclusion: Our study highlights ten clinical cases in this iatrogenic botulism outbreak, representing the largest reported outbreak worldwide. Clinicians should be aware of the risks associated with medical procedures involving botulinum neurotoxins and ensure measures to minimize the risk of iatrogenic botulism., (© 2024. The Author(s).)

Background: This study aimed to explore the disparities in PD-1 and PD-L1 expression among oral squamous cell carcinomas (OSCCs) in individuals categorized as never-smokers/never-drinkers versus smokers/drinkers., Methods: Immunohistochemical staining for PD-1 and PD-L1, along with PDCD1LG2/cen9 dual color probe analysis, was conducted on 130 OSCC specimens from both smoker/drinker and never-smoker/never-drinker cohorts. Associations between smoking/drinking status, clinicopathologic data, immunohistochemical antibody expression, fluorescence in situ hybridization, and survival outcomes were assessed., Results: OSCC in never-smokers/never-drinkers exhibited significantly elevated PD-1 expression (p = 0.003), increased PD-L1-TPS expression (p = 0.044), and elevated PD-L1-CPS expression (p < 0.001). High PD-L1-ICS expression was more prevalent in never-smokers (p = 0.042). Moreover, never-smokers and never-drinkers demonstrated augmented PD-L1 gene copy numbers (p = 0.081 and p = 0.054, respectively). Increased PD-L1 gene copy number, particularly amplification, correlated with PD-L1-TPS (p = 0.039 and p < 0.001). Conversely, PD-L1 gene copy loss was associated with negative PD-L1-CPS (p = 0.023). Notably, positive PD-L1-CPS was significantly linked with improved overall survival (p = 0.023)., Conclusions: OSCC arising in never-smokers/never-drinkers exhibit heightened PD-1/PD-L1 signaling, suggesting potential efficacy of immune checkpoint therapy in this subgroup of tumors., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Accumulation of immune cells and proteins in the subarachnoid space (SAS) is found during multiple sclerosis and in the animal model experimental autoimmune encephalomyelitis (EAE). Whether the flow of cerebrospinal fluid (CSF) along the SAS of the spinal cord is impacted is yet unknown. Combining intravital near-infrared (NIR) imaging with histopathological analyses, we observed a significantly impaired bulk flow of CSF tracers within the SAS of the spinal cord prior to EAE onset, which persisted until peak stage and was only partially recovered during chronic disease. The impairment of spinal CSF flow coincided with the appearance of fibrin aggregates in the SAS, however, it preceded immune cell infiltration and breakdown of the glia limitans superficialis. Conversely, cranial CSF efflux to cervical lymph nodes was not altered during the disease course. Our study highlights an early and persistent impairment of spinal CSF flow and suggests it as a sensitive imaging biomarker for pathological changes within the leptomeninges., (© 2024. The Author(s).)

The large group of negative-strand RNA viruses (NSVs) comprises many important pathogens. To identify conserved patterns in host responses, we systematically compared changes in the cellular RNA levels after infection of human hepatoma cells with nine different NSVs of different virulence degrees. RNA sequencing experiments indicated that the amount of viral RNA in host cells correlates with the number of differentially expressed host cell transcripts. Time-resolved differential gene expression analysis revealed a common set of 178 RNAs that are regulated by all NSVs analyzed. A newly developed open access web application allows downloads and visualizations of all gene expression comparisons for individual viruses over time or between several viruses. Most of the genes included in the core set of commonly differentially expressed genes (DEGs) encode proteins that serve as membrane receptors, signaling proteins and regulators of transcription. They mainly function in signal transduction and control immunity, metabolism, and cell survival. One hundred sixty-five of the DEGs encode host proteins from which 47 have already been linked to the regulation of viral infections in previous studies and 89 proteins form a complex interaction network that may function as a core hub to control NSV infections.IMPORTANCEThe infection of cells with negative-strand RNA viruses leads to the differential expression of many host cell RNAs. The differential spectrum of virus-regulated RNAs reflects a large variety of events including anti-viral responses, cell remodeling, and cell damage. Here, these virus-specific differences and similarities in the regulated RNAs were measured in a highly standardized model. A newly developed app allows interested scientists a wide range of comparisons and visualizations., Competing Interests: The authors declare no conflict of interest.

Background/objectives: Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is an antagonist of transforming growth factor (TGF)-β type 1 signaling. BAMBI functions as an anti-fibrotic protein and exerts pro- as well as anti-cancerogenic activities. Our study aimed to correlate hepatocyte BAMBI protein levels in hepatocellular carcinoma (HCC) with T stage, lymph node invasion, vessel invasion, grading, tumor size and Union for International Cancer Control (UICC) stage, as well as with liver inflammation and fibrosis stages., Methods: Hepatocyte BAMBI protein expression was assessed by immunohistochemistry in HCC tissues of 320 patients and non-tumor tissues of 51 patients., Results: In the HCC tissues of the whole cohort and sex-specific analysis, BAMBI protein was not related to T stage, vessel invasion, lymph node invasion, histologic grade, UICC stage and tumor size. Accordingly, BAMBI was not associated with overall survival, recurrence-free and metastasis-free survival. BAMBI protein levels in tumor and non-tumor tissues were not related to inflammation and fibrosis grade. BAMBI protein levels in HCC tissues and non-tumor tissues from HCC patients, which were analyzed by immunoblot in a small cohort and by immunohistochemistry in the tissues of patients described above, were similar. Notably, BAMBI protein was low-abundant in HCC tissues of hepatitis C virus (HCV) compared to hepatitis B virus (HBV)-infected patients with comparable disease severity. Immunoblot analysis revealed reduced BAMBI protein in non-tumor tissues of patients with HCV in comparison to patients with HBV and normal human liver tissues., Conclusions: In summary, this analysis showed that hepatocyte BAMBI protein levels of patients with HCC are related to HCV infection rather than the severity of the underlying liver disease and cancer staging.

Background and Importance: Arteriovenous malformations (AVMs) are complex vascular anomalies that pose significant risks, including intracranial hemorrhage and neurological deficits. Surgical resection is the preferred treatment, requiring precise intraoperative imaging to ensure complete removal while preserving critical structures. This case report presents the first combined use of hyperspectral imaging (HSI) and indocyanine green video angiography (ICG VA) to visualize perfusion during brain AVM surgery, highlighting the potential benefits of these advanced imaging techniques., Case Description: A 66-year-old male presented with chronic headaches but no neurological deficits. MRI revealed a superficial AVM in the left frontal lobe within the superior frontal sulcus, measuring approximately 2.4 cm. The AVM was fed by feeders from the pericallosal artery, callosomarginal artery, and middle cerebral artery (MCA) branches, with drainage through a dilated cortical vein into the superior sagittal sinus. Preoperative embolization of two MCA feeding branches was performed, followed by microsurgical resection with ICG VA and HSI., Conclusions: This case report demonstrates the successful application of HSI and ICG VA in brain AVM surgery. The combined use of these technologies provided comprehensive intraoperative assessment, enhancing surgical precision and safety. The integration of HSI offers non-invasive, contrast-agent-free imaging, potentially improving outcomes by enabling detailed perfusion mapping. Future studies should explore the broader applications of these imaging modalities in neurovascular practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wach, Weber, Vychopen, Arlt, Pfahl, Köhler, Melzer and Güresir.)

Stress profoundly affects sleep and memory processes. Stress impairs memory consolidation, and similarly, disruptions in sleep compromise memory functions. Yet, the neural circuits underlying stress-induced sleep and memory disturbances are still not fully understood. Here, we show that activation of CRH PVN neurons, similar to acute restraint stress, decreases sleep and impairs memory in a spatial object recognition task. Conversely, inhibiting CRH PVN neurons during stress reverses stress-induced memory deficits while slightly increasing the amount of sleep. We found that both stress and stimulation of CRH PVN neurons activate neurons in the lateral hypothalamus (LH), and that their projections to the LH are critical for mediating stress-induced memory deficits and sleep disruptions. Our results suggest a pivotal role for CRH PVN neuronal pathways in regulating the adverse effects of stress on memory and sleep, an important step towards improving sleep and ameliorating the cognitive deficits that occur in stress-related disorders.

Environment-sensitive probes are frequently used in spectral and multi-channel microscopy to study alterations in cell homeostasis. However, the few open-source packages available for processing of spectral images are limited in scope. Here, we present VISION, a stand-alone software based on Python for spectral analysis with improved applicability. In addition to classical intensity-based analysis, our software can batch-process multidimensional images with an advanced single-cell segmentation capability and apply user-defined mathematical operations on spectra to calculate biophysical and metabolic parameters of single cells. VISION allows for 3D and temporal mapping of properties such as membrane fluidity and mitochondrial potential. We demonstrate the broad applicability of VISION by applying it to study the effect of various drugs on cellular biophysical properties. the correlation between membrane fluidity and mitochondrial potential, protein distribution in cell-cell contacts and properties of nanodomains in cell-derived vesicles. Together with the code, we provide a graphical user interface for easy adoption., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

While cell-free liquid biopsy (cfLB) approaches provide simple and inexpensive disease monitoring, cell-based liquid biopsy (cLB) may enable additional molecular genetic assessment of systemic disease heterogeneity and preclinical model development. We investigated 71 blood samples of 62 patients with various advanced cancer types and subjected enriched circulating tumor cells (CTCs) to organoid culture conditions. CTC-derived tumoroid models were characterized by DNA/RNA sequencing and immunohistochemistry, as well as functional drug testing. Results were linked to molecular features of primary tumors, metastases, and CTCs; CTC enumeration was linked to disease progression. Of 52 samples with positive CTC counts (≥1) from eight different cancer types, only CTCs from two salivary gland cancer (SGC) patients formed tumoroid cultures (P = 0.0005). Longitudinal CTC enumeration of one SGC patient closely reflected disease progression during treatment and revealed metastatic relapse earlier than clinical imaging. Multiomics analysis and functional in vitro drug testing identified potential resistance mechanisms and drug vulnerabilities. We conclude that cLB might add a functional dimension (to the genetic approaches) in the personalized management of rare, difficult-to-treat cancers such as SGC., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The quantum-mechanical nuclear-shell structure determines the stability and limits of the existence of the heaviest nuclides with large proton numbers Z ≳ 100 (refs. 1-3 ). Shell effects also affect the sizes and shapes of atomic nuclei, as shown by laser spectroscopy studies in lighter nuclides 4 . However, experimental information on the charge radii and the nuclear moments of the heavy actinide elements, which link the heaviest naturally abundant nuclides with artificially produced superheavy elements, is sparse 5 . Here we present laser spectroscopy measurements along the fermium (Z = 100) isotopic chain and an extension of data in the nobelium isotopic chain (Z = 102) across a key region. Multiple production schemes and different advanced techniques were applied to determine the isotope shifts in atomic transitions, from which changes in the nuclear mean-square charge radii were extracted. A range of nuclear models based on energy density functionals reproduce well the observed smooth evolution of the nuclear size. Both the remarkable consistency of model prediction and the similarity of predictions for different isotopes suggest a transition to a regime in which shell effects have a diminished effect on the size compared with lighter nuclei., (© 2024. The Author(s).)

The ecosystem of brain tumors is considered immunosuppressed, but our current knowledge may be incomplete. Here we analyzed clinical cell and tissue specimens derived from patients presenting with glioblastoma or nonmalignant intracranial disease to report that the cranial bone (CB) marrow, in juxtaposition to treatment-naive glioblastoma tumors, harbors active lymphoid populations at the time of initial diagnosis. Clinical and anatomical imaging, single-cell molecular and immune cell profiling and quantification of tumor reactivity identified CD8 + T cell clonotypes in the CB that were also found in the tumor. These were characterized by acute and durable antitumor response rooted in the entire T cell developmental spectrum. In contrast to distal bone marrow, the CB niche proximal to the tumor showed increased frequencies of tumor-reactive CD8 + effector types expressing the lymphoid egress marker S1PR1. In line with this, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker indicating focal association with improved progression-free survival. The data of this study advocate preservation and further exploitation of these cranioencephalic units for the clinical care of glioblastoma., (© 2024. The Author(s).)

Background and Importance: Agitation of elderly patients in the emergency department (ED) often complicates workup and therapy., Objective: In this study, we investigated if agitation in the ED can be reduced by showing calming video sequences in elderly agitated patients., Designs: Prospective randomized intervention study., Settings and Participants: ED patients aged ≥65 years were screened for the risk of agitation/delirium using the 4-A's test (4-AT) test. In case of ≥4 4-AT points, patients were scored using the Richmond Agitation-Sedation Scale (RASS) and the Nursing Delirium Screening Scale (Nu-DESC). They were included in the study if RASS was ≥+2 and Nu-DESC ≥ 4 after informed consent of the legal representative. Patients were then randomized to the intervention or control group. A total of n = 57 patients were included in the study., Intervention: Patients in the intervention group were exposed to projections of calming video sequences for 60 min. Patients in the control group received standard care., Outcome Measures and Analysis: Changes in RASS and Nu-DESC were assessed 30 and 60 min after the intervention was started., Main Results: A total of 57 patients were included in the study, with 30 patients in the intervention group and 27 patients in the control group. Before the intervention, the median (interquartile range) RASS scores were comparable between the intervention group [3 (2-3)] and the control group [3 (2-3)]. After 30 min of exposure to calming video sequences, patients in the intervention group showed significantly lower RASS and Nu-DESC scores compared to the control group [RASS: 1 (0-1) vs. 2 (1.5-3), P < 0.001; Nu-DESC: 3 (2-4) vs. 5 (4-6), P < 0.001]. This difference persisted at 60 min [RASS: 0 (0-1) vs. 2 (1-2.5), P < 0.001; Nu-DESC: 2 (2-3) vs. 5 (4-6), P < 0.001]. Additionally, fewer patients in the intervention group required additional sedating or antipsychotic medication (1/30) compared to the control group (9/27), with this difference being statistically significant (P = 0.004)., Conclusion: In this randomized controlled trial, the use of calming video sequences in elderly patients with agitation in the ED resulted in significant reductions in agitation and the need for additional sedative or antipsychotic medication., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen. Its RNA genome consists of two negative-sense segments (L and M) with one gene each, and one ambisense segment (S) with two opposing genes separated by the noncoding "intergenic region" (IGR). These vRNAs and the complementary cRNAs are encapsidated by nucleoprotein (N). Using iCLIP2 (individual-nucleotide resolution UV crosslinking and immunoprecipitation) to map all N-vRNA and N-cRNA interactions, we detect N coverage along the L and M segments. However, the S segment vRNA and cRNA each contain approximately 100 non-encapsidated nucleotides stretching from the IGR into the 5'-adjacent reading frame. These exposed regions are RNase-sensitive and predicted to form stem-loop structures with the mRNA transcription termination motif positioned near the top. Moreover, optimal S segment transcription and replication requires the entire exposed region rather than only the IGR. Thus, the RVFV S segment contains a central, non-encapsidated RNA region with a functional role., (© 2024. The Author(s).)

Infection of grapevines with the grey mold pathogen Botrytis cinerea results in severe problems for winemakers worldwide. Browning of wine is caused by the laccase-mediated oxidation of polyphenols. In the last decades, Botrytis management has become increasingly difficult due to the rising number of resistances and the genetic variety of Botrytis strains. During the search for sustainable fungicides, polyphenols showed great potential to inhibit fungal growth. The present study revealed two important aspects regarding the effects of grape-specific polyphenols and their polymerized oxidation products on Botrytis wild strains. On the one hand, laccase-mediated oxidized polyphenols, which resemble the products found in infected grapes, showed the same potential for inhibition of growth and laccase activity, but differed from their native forms. On the other hand, the impact of phenolic compounds on mycelial growth is not correlated to the effect on laccase activity. Instead, mycelial growth and relative specific laccase activity appear to be modulated independently. All phenolic compounds showed not only inhibitory but also inductive effects on fungal growth and/or laccase activity, an observation which is reported for the first time. The simultaneous inhibition of growth and laccase activity demonstrated may serve as a basis for the development of a natural botryticide. Yet, the results showed considerable differences between genetically distinguishable strains, impeding the use of a specific phenolic compound against the genetic variety of wild strains. The present findings might have important implications for future understanding of Botrytis cinerea infections and sustainable Botrytis management including the role of polyphenols., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kim Marie Umberath reports financial support was provided by German Ministry of Economics and Technology. Louis Backmann reports financial support was provided by German Ministry of Economics and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: No genomic data have been put forth that prove beyond a shadow of doubt that sporadic medullary thyroid cancer (MTC) occurs in infancy, childhood, and/or adolescence., Methods: This was a retrospective comparative study of consecutive patients with MTC who had neck surgery at a tertiary center over a 30-year period., Results: Included were 1252 patients with MTC (337 hereditary and 915 sporadic), of whom 107 (8.5%) were operated before the age of 18 yrs. Only 4 (3.7%) of the 107 pediatric patients, aged 14, 16, 17 and 17 years, had sporadic MTC. These 4 patients, 3 of whom had been referred for completion surgery, revealed much larger thyroid tumors (medians of 20 mm vs. 1.5-5 mm) than the 103 pediatric patients with hereditary MTC. As for extrathyroid extension and nodal metastases, the 4 patients with sporadic MTC were more comparable to the 37 carriers of highest-risk mutations, 31 (84%) of whom were index patients with de novo disease, than to the 66 carriers of high-risk, intermediate-risk, or low-risk RET mutations (25-38% vs. 0-8%, and medians of 9-9.5 vs. 0 node metastases after dissection of more (medians of 72-91.5 vs. 4.5-9) nodes)., Conclusion: Sporadic MTC, arising rarely, if ever, below the age of 14 years, is exceptional in infancy and childhood, and infrequent in adolescence. At diagnosis, it is almost as widely metastatic as hereditary MTC of the highest-risk category which almost always, like sporadic MTC, presents as de novo disease., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: During sleep periods, most mammals alternate multiple times between rapid-eye-movement (REM) sleep and non-REM (NREM) sleep. A common theory proposes that these transitions are governed by an "hourglass-like" homeostatic need to enter REM sleep that accumulates during the inter-REM interval and partially discharges during REM sleep. However, markers or mechanisms for REM homeostatic pressure remain undetermined. Recently, an analysis of sleep in mice demonstrated that the cumulative distribution function (CDF) of the amount of NREM sleep between REM bouts correlates with REM bout duration, suggesting that time in NREM sleep influences REM sleep need. Here, we build on those results and construct a predictive measure for the propensity to enter REM sleep as a function of time in NREM sleep since the previous REM episode., Methods: The REM propensity measure is precisely defined as the probability to enter REM sleep before the accumulation of an additional pre-specified amount of NREM sleep., Results: Analyzing spontaneous sleep in mice, we find that, as NREM sleep accumulates between REM bouts, the REM propensity exhibits a peak value and then decays to zero with further NREM accumulation. We show that the REM propensity at REM onset predicts features of the subsequent REM bout under certain conditions. Specifically, during the light phase and for REM propensities occurring before the peak in propensity, the REM propensity at REM onset is correlated with REM bout duration, and with the probability of the occurrence of a short REM cycle called a sequential REM cycle. Further, we also find that proportionally more REM sleep occurs during sequential REM cycles, supporting a correlation between high values of our REM propensity measure and high REM sleep need., Discussion: These results support the theory that a homeostatic need to enter REM sleep accrues during NREM sleep, but only for a limited range of NREM sleep accumulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ginsberg, Cruz, Weber, Booth and Diniz Behn.)

Finding relevant information in the biomedical literature increasingly depends on efficient information retrieval (IR) algorithms. Cross-Encoders, SentenceBERT, and ColBERT are algorithms based on pre-trained language models that use nuanced but computable vector representations of search queries and documents for IR applications. Here we investigate how well these vectorization algorithms estimate relevance labels of biomedical documents for search queries using the OHSUMED dataset. For our evaluation, we compared computed scores to provided labels by using boxplots and Spearman's rank correlations. According to these metrics, we found that Sentence-BERT moderately outperformed the alternative vectorization algorithms and that additional fine-tuning based on a subset of OHSUMED labels yielded little additional benefit. Future research might aim to develop a larger dedicated dataset in order to optimize such methods more systematically, and to evaluate the corresponding functions in IR tools with end-users.

Purpose: To compare the outcomes of fluoroscopic versus portable placement of peripherally inserted central catheters (PICCs) and central venous catheters (CVCs) in pediatric patients., Materials and Methods: This is a single-center, retrospective review of 346 upper-extremity PICC placements (286 fluoroscopic and 60 portable; mean age, 9.83 years [SD ± 5.58]; 49.1% female) and 138 tunneled femoral CVC placements (56 fluoroscopic and 82 portable; mean age, 0.23 years [SD ± 0.36]; 57.0% female). Portable placements used mobile plain-film radiography. All lines were placed by board-certified interventional radiologists., Results: Fluoroscopic PICC placements had a lower procedure time (43.9 vs 57.9 minutes; P < .001), radiation dosage (342 vs 590 mGy·cm 2 ; P < .001), incidence of technical failure (0% vs 3.3%; P = .029), and incidence of catheter malfunction (1.7% vs 12.1%; P < .001) compared with portable PICC placements. Fluoroscopic CVC placements had a lower procedure time (42.6 vs 54.8 minutes; P < .001) and radiation dosage (63.8 vs 405 mGy·cm 2 ; P < .001) compared with portable CVC placements. No technical failures were found in either CVC groups and the difference was nonsignificant for catheter malfunction (0% vs 7.3%; P = .081). Fluoroscopic placements of PICCs and CVCs had a lower incidence rate of central line-associated bloodstream infection compared with portable placements (0.71 vs 2.22 cases per 1,000 line-days; P = .046). Overall, fluoroscopic placements of PICCs and CVCs had fewer adverse events compared with portable placements (3.2% vs 14.8%; P < .001). Portable procedure setting was the only significant factor associated with adverse events (odds ratio, 33.77; 95% CI, 4.56-757.01)., Conclusions: Fluoroscopic placements of PICCs and CVCs are associated with lower procedure time, radiation dose, and risk of adverse events compared with portable placements in pediatric patients., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Medullary thyroid cancer (MTC) is the most frequent manifestation of multiple endocrine neoplasia type 2 (MEN2) that determines the oncological outcome. Germline mutations in the rearranged during transfection (RET) protooncogene, a tumor suppressor gene on chromosome 10q11.2, were identified 30 years ago as the genetic basis of MEN2 and published in 1993 and 1994. These seminal findings gave rise to the concept of prophylactic thyroidectomy for asymptomatic gene mutation carriers based on a positive RET gene test, which has become the standard of care ever since. Clinical genetic investigations showed genotype-phenotype correlations with respect to the individual gene mutation regarding the penetrance and onset of MTC and to a lesser extent also with respect to the other components of MEN2, pheochromocytoma and primary hyperparathyroidism. From this a clinically relevant risk stratification could be derived. Initially, the optimal timing of prophylactic thyroidectomy was primarily based on the RET genotype alone, which was not sufficient for a precise age recommendation and subsequently required additional consideration of calcitonin serum levels for fine tuning. Calcitonin levels first show the risk of lymph node metastasis when they exceed the upper normal limit of the assay independent of carrier age and RET mutation. Routine calcitonin screening of patients with nodular thyroid disease, screening of families on identification of MEN2 index patients, and pre-emptive thyroidectomy in carriers of gene mutations with normal calcitonin levels have led to the fact that nowadays, 30 years after the first description of the gene mutations causing the disease, the life-threatening hereditary MTC has become curable: a shining example for the success of translational transnational medical research for the benefit of patients., (© 2024. The Author(s).)

Especially for pediatric patients, proxies of mucosal inflammation are needed. The Pediatric Ulcerative Colitis Activity Index (PUCAI) has been established to predict clinical and endoscopic disease activity. However, histologic inflammation might persist. We applied a special variable selection technique to predict histologic healing in pediatric ulcerative colitis (UC) as parsimoniously (but still as precisely) as possible. The retrospective analysis included data from two study cohorts, comprising 91 visits from 59 pediatric patients with UC. A Bayesian ordinal regression model was used in combination with a projection-predictive feature selection (PPFS) to identify a minimal subset of clinical and laboratory parameters sufficient for the prediction of histologic disease activity. Following the PPFS, CEDATA-GPGE patient registry data were analyzed to investigate the relevance of the selected predictors in relation to PUCAI and Physician Global Assessment (PGA) in up to 6697 patient visits. Fecal calprotectin (FC) and platelet count were identified as the minimal subset of predictors sufficient for prediction of histologic disease activity in pediatric UC. FC and platelet count also appeared to be associated with increasing disease activity as measured by PUCAI and PGA in the CEDATA-GPGE registry. Based on the selected model, predictions can be performed with a Shiny web app.  Conclusion: Our statistical approach constitutes a reproducible and objective tool to select a minimal subset of the most informative parameters to predict histologic inflammation in pediatric UC. A Shiny app shows how physicians may predict the histologic activity in a user-friendly way using FC and platelet count. To generalize the findings, further prospective studies will be needed. What is Known: • Histologic healing is a major endpoint in the therapy of ulcerative colitis (UC). • The PUCAI score has been established to predict disease activity in pediatric UC but is not suitable for the prediction of histologic healing. What is New: • Our Bayesian ordinal regression model in combination with a projection-predictive feature selection is a reproducible and objective tool to select the minimal subset of clinical and laboratory parameters to predict histologic inflammation in pediatric UC. • Histologic inflammation in pediatric UC can be non-invasively predicted based on the combination of fecal calprotectin levels and platelet count., (© 2024. The Author(s).)

Bats are ecologically diverse vertebrates characterized by their ability to host a wide range of viruses without apparent illness and the presence of numerous endogenous viral elements (EVEs). EVEs are well preserved, expressed, and may affect host biology and immunity, but their role in bat immune system evolution remains unclear. Among EVEs, endogenous bornavirus-like elements (EBLs) are bornavirus sequences integrated into animal genomes. Here, we identified a novel EBL in the microbat Myotis daubentonii , EBLL-Cultervirus.10-MyoDau (short name is CV.10-MyoDau) that shows protein-level conservation with the L-protein of a Cultervirus (Wuhan sharpbelly bornavirus). Surprisingly, we discovered a transcript on the antisense strand comprising three exons, which we named AMCR-MyoDau. The active transcription in Myotis daubentonii tissues of AMCR-MyoDau, confirmed by RNA-Seq analysis and RT-PCR, highlights its potential role during viral infections. Using comparative genomics comprising 63 bat genomes, we demonstrate nucleotide-level conservation of CV.10-MyoDau and AMCR-MyoDau across various bat species and its detection in 22 Yangochiropera and 12 Yinpterochiroptera species. To the best of our knowledge, this marks the first occurrence of a conserved EVE shared among diverse bat species, which is accompanied by a conserved antisense transcript. This highlights the need for future research to explore the role of EVEs in shaping the evolution of bat immunity.

Competing Interests: Competing interests: None declared.

The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen, abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. HER4 differentially affects the cellular response to tamoxifen and abemaciclib treatment. Most conspicuous is the increased sensitivity of MCF-7 in vitro upon HER4 knockout and the inhibition of cell proliferation by NRG1. Additionally, we assessed tumor growth and immunological effects as responses to tamoxifen and abemaciclib therapy in humanized tumor mice (HTM) based on MCF-7 HER4-wildtype and the corresponding HER4-knockout cells. Without any treatment, the enhanced MCF-7 tumor growth in HTM upon HER4 knockout suggests a tumor-suppressive effect of HER4 under preclinical but human-like conditions. This phenomenon is associated with an increased HER2 expression in MCF-7 in vivo. Independent of HER4, abemaciclib and tamoxifen treatment considerably inhibited tumor growth in these mice. However, abemaciclib-treated hormone receptor-positive breast cancer patients with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is associated with unfavorable outcomes in abemaciclib-treated patients.

Background: An acute abdomen is a medical emergency that requires early diagnosis and treatment. In pregnancy, this process is significantly more challenging, and radiological findings are sometimes unclear due to the enlarged uterus displacing other structures. Moreover, endometriosis-related complications are rare, and the disease is often undiagnosed., Case Presentation: We report a case of acute perforation of the cecum and appendix during pregnancy (35 weeks of gestation) caused by a previously unknown, deep infiltrating endometriosis with focal ulceration of the affected bowel wall, which sonographically seemed to be acute appendicitis., Conclusion: Despite the relatively low risk, clinicians should be aware of possible endometriosis-associated complications in pregnancy with potentially life-threatening events, even in previously unknown endometriosis. Further studies should evaluate intestinal complications during pregnancy in relation to previous treatment of intestinal endometriosis (conservative vs. surgical)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Stiegler, Kapitza, Weber, Patalakh and Schäfer.)

The long-term stability of red wine color depends on the formation of polymeric pigments from anthocyanins. Although there is still a lot of uncertainty about the specific structure of this diverse group of pigments, there is consensus that they are reaction products of anthocyanins and other polyphenols. Interactions between anthocyanins and pectic polysaccharides have been suggested to stabilize anthocyanins. This study explores the impact of such interactions by adding pectin during red winemaking. The results demonstrate that these interactions induce the formation of additional polymeric pigments which enhance the pigment stability during fermentation and aging. While initial pigment formation is higher in wines with added pectin, a notable proportion of the complexes degrades in the later stages of fermentation. Presumably, tannins form insoluble complexes with pectin, reducing tannin concentration by more than 300 mg/L. Anthocyanin concentrations decrease by over 400 mg/L, and polymeric pigments double. Anthocyanins that form polymeric pigments with pectic polysaccharides expand the range of pigments in red wines with possible consequences for the sensory properties of the wine. These findings highlight the complex interactions between pectin, anthocyanins, and tannins, and their influence on pigment formation and wine composition during fermentation and aging., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hensen, Jan-Peter reports financial support was provided by German Ministry for Economic Affairs and Energy (via AiF) and the FEI (Forschungskreis der Ernährungsindustrie e.V., Bonn). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Skip metastases, node metastases in the lateral neck sparing the ipsilateral central neck, challenge the current concept of central-to-lateral lymphatic spread. This study sought to delineate patterns of central and lateral neck involvement in unilateral papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC). Methods: This was a retrospective correlative analysis of nodal patterns in surgical specimens from patients with unilateral PTC or MTC who had undergone thyroidectomy with at least ipsilateral central neck dissection between November 1994 and January 2024 at a tertiary referral center. Results: Included were 833 patients with unilateral PTC and 640 patients with unilateral MTC. Simultaneous presence or absence of node metastases was noted in ipsilateral central and lateral neck compartments in 76.6-78.1% of patients with PTC (both node positive in 27.0-54.7% and both node negative in 23.4-49.6%) and 77.3-80.0% of patients with MTC (both node positive in 26.6-33.2% and both node negative in 44.1-53.4%). Only one ipsilateral neck compartment was node positive in 21.9-23.4% of patients with PTC and 20.0-22.7% of patients with MTC. The ipsilateral central, but not the ipsilateral lateral compartment, was node positive in 8.8-16.9% with PTC and 8.6-8.8% of patients with MTC, whereas the ipsilateral lateral, but not the ipsilateral central compartment, was node positive in 6.5-13.1% with PTC and 11.3-14.1% with MTC. Ipsilateral lateral neck involvement sparing the ipsilateral central neck was 1.5-2 times more frequent in patients with node positive MTC than patients with node positive PTC (24.2-25.2% vs. 12.9-17.1%). Greater numbers of node metastases in the ipsilateral central neck compartment were associated with more frequent involvement of the ipsilateral lateral, contralateral central, and contralateral lateral neck compartments. Thyroid tumor diameter intensified nodal spread without changing nodal spread patterns. Conclusions: These histopathological findings, which need to be interpreted in light of the respective tumor biology, offer an unprecedented glimpse at the metastatic patterns of unilateral PTC and MTC. Customizing neck dissection to the patterns of nodal spread, considering operative status (initial vs. reoperative surgery) and experience with neck dissection, may require more frequent concomitant dissections of ipsilateral central and ipsilateral lateral neck compartments.

Head and neck squamous cell carcinoma (HNSCC) is a global cancer burden with a 5-year overall survival rate of around 50%, stagnant for decades. A tumour-induced immunosuppressive microenvironment contributes to HNSCC progression, with the adenosine (ADO) pathway and an upregulated expression of inhibitory immune checkpoint regulators playing a key role in this context. The correlation between high neutrophil-to-lymphocyte ratio (NLR) with advanced tumour staging suggests involvement of neutrophils (NØ) in cancer progression. Interestingly, we associated a high NLR with an increased intracellular PD-L1 localization in primary HNSCC samples, potentially mediating more aggressive tumour characteristics and therefore synergistically favouring tumour progression. Still, further research is needed to harness this knowledge for effective treatments and overcome resistance. Since it is hypothesized that the tumour microenvironment (TME) may be influenced by small extracellular vesicles (sEVs) secreted by tumours (TEX), this study aims to investigate the impact of HNSCC-derived TEX on NØ and blockade of ADO receptors as a potential strategy to reverse the pro-tumour phenotype of NØ. UMSCC47-TEX exhibited CD73 enzymatic activity involved in ADO signalling, as well as the immune checkpoint inhibitor PD-L1. Data revealed that TEX induce chemotaxis of NØ and the sustained interaction promotes a shift into a pro-tumour phenotype, dependent on ADO receptors (P1R), increasing CD170 high subpopulation, CD73 and PD-L1 expression, followed by an immunosuppressive secretome. Blocking A3R reduced CD73 and PD-L1 expression. Co-culture experiments with HNSCC cells demonstrated that TEX-modulated NØ increase the CD73/PD-L1 axis, through Cyclin D-CDK4/6 signalling. To support these findings, the CAM model with primary tumour was treated with NØ supernatant. Moreover, these NØ promoted an increase in migration, invasion, and reduced cell death. Targeting P1R on NØ, particularly A3R, exhibited potential therapeutic strategy to counteract immunosuppression in HNSCC. Understanding the TEX-mediated crosstalk between tumours and NØ offers insights into immunomodulation for improving cancer therapies., (© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Rapid eye movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically regulated, ensuring that any loss of REMs is compensated by a subsequent increase in its amount. However, the neural mechanisms underlying the homeostatic control of REMs are largely unknown. Here, we show that GABAergic neurons in the preoptic area of the hypothalamus projecting to the tuberomammillary nucleus (POA GAD2 →TMN neurons) are crucial for the homeostatic regulation of REMs in mice. POA GAD2 →TMN neurons are most active during REMs, and inhibiting them specifically decreases REMs. REMs restriction leads to an increased number and amplitude of calcium transients in POA GAD2 →TMN neurons, reflecting the accumulation of REMs pressure. Inhibiting POA GAD2 →TMN neurons during REMs restriction blocked the subsequent rebound of REMs. Our findings reveal a hypothalamic circuit whose activity mirrors the buildup of homeostatic REMs pressure during restriction and that is required for the ensuing rebound in REMs., Competing Interests: JM, AL, XJ, JH, NS, RC, AO, AL, FW, SC No competing interests declared, (© 2023, Maurer et al.)

The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891).There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5-50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.

In recent years, several noncanonical RNA caps derived from cofactors and metabolites have been identified. Purine-containing RNA caps have been extensively studied, with multiple decapping enzymes identified and efficient capture and sequencing protocols developed for nicotinamide adenine dinucleotide (NAD)-RNA, which allowed for a stepwise elucidation of capping functions. Despite being identified as an abundant noncanonical RNA-cap, UDP-sugar-capped RNA remains poorly understood, which is partly due to its complex in vitro preparation. Here, we describe a scalable synthesis of sugar-capped uridine-guanosine dinucleotides from readily available protected building blocks and their enzymatic conversion into several cell wall precursor-capped dinucleotides. We employed these capped dinucleotides in T7 RNA polymerase-catalyzed in vitro transcription reactions to efficiently generate RNAs capped with uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), its N-azidoacetyl derivative UDP-GlcNAz, and various cell wall precursors. We furthermore identified four enzymes capable of processing UDP-GlcNAc-capped RNA in vitro: MurA, MurB and MurC from Escherichia coli can sequentially modify the sugar-cap structure and were used to introduce a bioorthogonal, clickable moiety, and the human Nudix hydrolase Nudt5 was shown to efficiently decap UDP-GlcNAc-RNA. Our findings underscore the importance of efficient synthetic methods for capped model RNAs. Additionally, we provide useful enzymatic tools that could be utilized in the development and application of UDP-GlcNAc capture and sequencing protocols. Such protocols are essential for deepening our understanding of the widespread yet enigmatic GlcNAc modification of RNA and its physiological significance., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Potential alcohol, as obtained by grape maturity, affects the extraction of phenolics during winemaking. The extent to which potential alcohol is correlated to phenolic and sensory characteristics of red wine was investigated. Decoupling of the ripening kinetics of grape constituents due to climate change emphasizes this question. The impact of potential alcohol, as naturally obtained by grape maturity or adjusted by sugar addition, representing high sugar but low phenolic maturity, on wine characteristics was investigated for two varieties over two vintages. Enhancement of potential alcohol to late harvest conditions did not achieve the sensory characteristics of wine made from phenolic mature grapes. An experimental model was developed revealing the contribution of potential alcohol to phenolic and sensory characteristics. In Pinot noir, anthocyanins correlated well with natural potential alcohol but were not influenced by enhanced potential alcohol. In Cabernet Sauvignon, polymeric pigments provided the most accurate information about grape maturity perception in wine.

Little is known about axillary node metastasis of medullary thyroid cancer (MTC). To address this, a comparative study of patients with and without axillary node metastases of MTC was conducted. Among 1215 consecutive patients with MTC, 482 patients had node-negative MTC and 733 patients node-positive MTC. Among the 733 patients with node-positive MTC, 4 patients (0.5%) had axillary node metastases, all of which were ipsilateral. Patients with axillary node metastases had 5.7-6.9-fold more node metastases removed, both at the authors' institution (medians of 34.5 vs. 5 metastases; p=0.011) and in total (medians of 57 vs. 10 metastases; p=0.013), developed more frequently distant metastases (3 of 4 vs. 178 of 729 patients, or 75 vs. 24%; p=0.049), specifically to bone (2 of 4 vs. 67 of 729 patients, or 50 vs. 9%; p=0.046) and brain (1 of 4 vs. 4 of 729 patients, or 25 vs. 0.5%; p=0.027), and more often succumbed to cancer-specific death (3 of 4 vs. 52 of 729 patients, or 75 vs. 14%; p=0.005). Altogether, patients with axillary node metastases revealed 4-8-fold more node metastases in the ipsilateral lateral neck (medians of 11 vs. 3 metastases; p=0.021) and in the ipsilateral central neck (medians of 8 vs. 1 metastases; p=0.079) patients without axillary node metastases. Cancer-specific survival of patients with vs. patients without axillary node metastases of MTC was significantly shorter (means of 41 vs. 224 months; p log-rank <0.001). These findings show that patients with axillary node metastases of MTC have massive metastatic dissemination with poor survival., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Definitions of aggressive MS employ clinical and MR imaging criteria to identify highly active, rapidly progressing disease courses. However, the degree of overlap between clinical and radiological parameters and biochemical markers of CNS injury is not fully understood. Aim of this cross-sectional study was to match clinical and MR imaging hallmarks of aggressive MS to serum/CSF markers of neuroaxonal and astroglial injury (neurofilament light chain (sNfL, cNfL), and glial fibrillary acidic protein (sGFAP, cGFAP))., Methods: We recruited 77 patients with relapsing-remitting MS (RRMS) and 22 patients with clinically isolated syndrome. NfL and GFAP levels in serum and CSF were assessed using a single-molecule-array HD-1-analyzer. A general linear model with each biomarker as a dependent variable was computed. Clinical and imaging criteria of aggressive MS, as recently proposed by the ECTRIMS Consensus Group, were modeled as independent variables. Other demographic, clinical or laboratory parameters, were modeled as covariates. Analyses were repeated in a homogenous subgroup, consisting only of newly diagnosed, treatment-naïve RRMS patients presenting with an acute relapse., Results: After adjusting for covariates and multiplicity of testing, sNfL and cNfL concentrations were strongly associated with the presence of ≥2 gadolinium-enhancing lesions (p sNfL  = 0.00008; p cNfL  = 0.004) as well as the presence of infratentorial lesions on MRI (p sNfL  = 0.0003; p cNfL  < 0.004). No other clinical and imaging criteria of aggressive MS correlated significantly with NfL or GFAP in serum and CSF. In the more homogeneous subgroup, sNfL still was associated with the presence of ≥2 gadolinium-enhancing lesions (p sNfL  = 0.001), presence of more than 20 T2-lesions (p sNfL  = 0.049) as well as the presence of infratentorial lesions on MRI (p sNfL  = 0.034), while cNfL was associated with the presence of ≥2 gadolinium-enhancing lesions (p sNfL  = 0.011) and presence of more than 20 T2-lesions (p sNfL  = 0.029)., Conclusions: Among proposed risk factors for an aggressive disease course, MRI findings but not clinical characteristics correlated with sNfL and cNfL as a marker of neuroaxonal injury and should be given appropriate weight considering MS prognosis and therapy. No significant correlation was detected for GFAP alone., (© 2024. The Author(s).)

Immunotoxicology/immunosafety science is rapidly evolving, with novel modalities and immuno-oncology among the primary drivers of new tools and technologies. The Immunosafety Working Group of IQ/DruSafe sought to better understand some of the key challenges in immunosafety evaluation, gaps in the science, and current limitations in methods and data interpretation. A survey was developed to provide a baseline understanding of the needs and challenges faced in immunosafety assessments, the tools currently being applied across the industry, and the impact of feedback received from regulatory agencies. This survey also focused on current practices and challenges in conducting the T-cell-dependent antibody response (TDAR) and the cytokine release assay (CRA). Respondents indicated that ICH S8 guidance was insufficient for the current needs of the industry portfolio of immunomodulators and novel modalities and should be updated. Other challenges/gaps identified included translation of nonclinical immunosafety assessments to the clinic, and lack of relevant nonclinical species and models in some cases. Key areas of emerging science that will add future value to immunotoxicity assessments include development of additional in vitro and microphysiological system models, as well as application of humanized mouse models. Efforts are ongoing in individual companies and consortia to address some of these gaps and emerging science., Competing Interests: Declaration of competing 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Climate change and population densities accelerated transmission of highly pathogenic viruses to humans, including the Crimean-Congo haemorrhagic fever virus (CCHFV). Here we report that the Low Density Lipoprotein Receptor (LDLR) is a critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in cell culture and blood vessel organoids. The interaction between CCHFV and LDLR is highly specific, with other members of the LDLR protein family failing to bind to or neutralize the virus. Biosensor experiments demonstrate that LDLR specifically binds the surface glycoproteins of CCHFV. Importantly, mice lacking LDLR exhibit a delay in CCHFV-induced disease. Furthermore, we identified the presence of Apolipoprotein E (ApoE) on CCHFV particles. Our findings highlight the essential role of LDLR in CCHFV infection, irrespective of ApoE presence, when the virus is produced in tick cells. This discovery holds profound implications for the development of future therapies against CCHFV., (© 2024. The Author(s).)

Sleep disturbances are prevalent in children with autism spectrum disorder (ASD) and have a major impact on the quality of life. Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is highly fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. Exposure to a novel environment further exacerbates sleep disturbances in 16p11.2 deletion mice by fragmenting NREMs and decreasing rapid eye movement sleep (REMs). In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine reverse sleep fragmentation. Furthermore, inhibiting LC-NE neurons restores memory. Rabies-mediated unbiased screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory regulatory brain regions in 16p11.2 deletion mice. Our findings demonstrate that heightened activity of LC-NE neurons and altered brain-wide connectivity underlies sleep fragmentation in 16p11.2 deletion mice and identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD., Competing Interests: CONFLICT OF INTEREST The authors declare no competing financial interests.

Rapid eye movement (REM) sleep is known to facilitate fear extinction and play a protective role against fearful memories. 1 , 2 Consequently, disruption of REM sleep after a traumatic event may increase the risk for developing PTSD. 3 , 4 However, the underlying mechanisms by which REM sleep promotes extinction of aversive memories remain largely unknown. The infralimbic cortex (IL) is a key brain structure for the consolidation of extinction memory. 5 Using calcium imaging, we found in mice that most IL pyramidal neurons are intensively activated during REM sleep. Optogenetically suppressing the IL specifically during REM sleep within a 4-h window after auditory-cued fear conditioning impaired extinction memory consolidation. In contrast, REM-specific IL inhibition after extinction learning did not affect the extinction memory. Whole-cell patch-clamp recordings demonstrated that inactivating IL neurons during REM sleep depresses their excitability. Together, our findings suggest that REM sleep after fear conditioning facilitates fear extinction by enhancing IL excitability and highlight the importance of REM sleep in the aftermath of traumatic events for protecting against traumatic memories., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dimeric naphthopyranones are known to be biologically active, however, for the corresponding monomeric naphthopyranones this information is still elusive. Here the first enantioselective total synthesis of semi-viriditoxic acid as well as the synthesis of semi-viriditoxin and derivatives is reported. The key intermediate in the synthesis of naphthopyranones is an α,β-unsaturated δ-lactone, which we synthesized in two different ways (Ghosez-cyclization and Grubbs ring-closing metathesis), while the domino-Michael-Dieckmann reaction of the α,β-unsaturated δ-lactone with an orsellinic acid derivative is the key reaction. A structure-activity relationship study was performed measuring the cytotoxicity in Burkitt B lymphoma cells (Ramos). The dimeric structure was found to be crucial for biological activity: Only the dimeric naphthopyranones showed cytotoxic and apoptotic activity, whereas the monomers did not display any activity at all., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Background: Hip and knee osteoarthritis (OA) are highly prevalent worldwide. The guidelines recommend physical activity and education as the core treatments for osteoarthritis. Digital health has the potential to engage people in physical activity and disease management. Therefore, we conducted a pilot trial to assess the usability and preliminary effectiveness of an app-based physical activity and education program (Join2Move) compared to usual care for people with hip and/or knee OA in Germany., Methods: A randomized controlled pilot study was conducted. Individuals with diagnosed or self-reported knee and hip OA were included. Allocation to the intervention or control group was randomized. The intervention group received the Join2Move program. The Join2Move program was previously developed as a website and evaluated in the Netherlands. For the current study, the program was translated and adapted to the German context and adjusted from a website to an app. The control group received usual care. The primary outcomes were usability and preliminary effectiveness (pain and physical functioning). Measurements were taken at baseline and at twelve weeks. The data analysis was performed using SPSS (IBM SPSS Statistics 29.0)., Results: Sixty participants, with a mean age of 61.9 (SD ± 7.2) years, were allocated to the intervention (n = 32) or the control group (n = 28) and included in the analysis. The majority of participants had knee OA (68%), and 12% had hip and knee OA. The dropout rate was n = 11 (18%). No adverse events were reported. Usability was rated as acceptable (mean System Usability Scale = 71.3/100) with a wide range (32.5 to 100). Statistically significant between-group differences were found only for pain (mean difference 8.52 (95% CI 1.01 to 16.04), p = 0.027)., Conclusions: Join2Move demonstrated acceptable usability. The preliminary results of the pilot trial indicate the potential of a stand-alone app for the treatment of patients with hip or knee OA. However, the acceptable usability of Join2Move limits its recommendation for everyone. There appears to be room for improvement in app usability and in identifying patients for whom the app is suitable and the right time to use a stand-alone app., Trial Registration: German Clinical Trials Register DRKS00027164 ., (© 2024. The Author(s).)

Purpose and Methods: We present an unusual case of an HIV-negative patient with postpartum pulmonary cryptococcosis and cryptococcemia., Results: The diagnostic methods and treatment of cryptococcosis in a postpartum patient are presented in this case report. Due to anaphylaxis to liposomal amphotericin B, desensitisation to the drug was performed., Conclusion: We would like to raise awareness about rare infections such as cryptococcosis in pregnancy and the postpartum period. In addition, we were able to document a successful desensitisation to liposomal amphotericin B., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

We introduce a method, single-particle profiler, that provides single-particle information on the content and biophysical properties of thousands of particles in the size range 5-200 nm. We use our single-particle profiler to measure the messenger RNA encapsulation efficiency of lipid nanoparticles, the viral binding efficiencies of different nanobodies, and the biophysical heterogeneity of liposomes, lipoproteins, exosomes and viruses., (© 2023. The Author(s).)

Introduction: Propofol and sevoflurane have a long history in pediatric anesthesia. Combining both drugs at low dose levels offers new opportunities. However, monitoring the hypnotic effects of this drug combination in children is challenging, because the currently available processed EEG-based systems are insufficiently validated in young children and the co-administration of anesthetics. This study investigated electroencephalographic density spectral array monitoring during propofol/sevoflurane coadministration with fixed sevoflurane- and variable propofol dosages., Patients and Methods: We analyzed the density spectral array pattern recorded during propofol/sevoflurane anesthesia in pediatric patients from birth to 11 years of age. Data from 78 patients were suitable for analysis. The primary outcome parameter of this study was the correlation between variable propofol dosages and the expression of the four electroencephalogram frequency bands β, α, θ, and δ. The main secondary outcome parameters were the intra-operative total EEG power and the prevalence of burst suppression., Results: In patients above the age of 1 year, a dose-dependent correlation between the propofol dosage and the relative percentage of β (-12.2%, p < 0.001) and δ (5.1%, p < 0.001) was found. There was an age-dependent trend toward increasing mean EEG power, with the most significant increase in the first year of life. In 14.1% of our patients, at least one episode of burst suppression occurred., Conclusion: DSA-guided augmentation of propofol anesthesia with sevoflurane provides sufficient depth of anesthesia at doses usually considered sub-anesthetic in children, leading to less anesthetic drug exposure for the individual child., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The radionuclides 43 Sc, 44g/mSc, and 47 Sc can be produced cost-effectively in sufficient yield for medical research and applications by irradiating natTi and natV target materials with protons. Maximizing the production yield of the therapeutic 47 Sc in the highest cross section energy range of 24-70 MeV results in the co-production of long-lived, high-γ-ray-energy 46 Sc and 48 Sc contaminants if one does not use enriched target materials. Mass separation can be used to obtain high molar activity and isotopically pure Sc radionuclides from natural target materials; however, suitable operational conditions to obtain relevant activity released from irradiated natTi and natV have not yet been established at CERN-MEDICIS and ISOLDE. The objective of this work was to develop target units for the production, release, and purification of Sc radionuclides by mass separation as well as to investigate target materials for the mass separation that are compatible with high-yield Sc radionuclide production in the 9-70 MeV proton energy range. In this study, the in-target production yield obtained at MEDICIS with 1.4 GeV protons is compared with the production yield that can be reached with commercially available cyclotrons. The thick-target materials were irradiated at MEDICIS and comprised of metallic natTi, natV metallic foils, and natTiC pellets. The produced radionuclides were subsequently released, ionized, and extracted from various target and ion source units and mass separated. Mono-atomic Sc laser and molecule ionization with forced-electron-beam-induced arc-discharge ion sources were investigated. Sc radionuclide production in thick natTi and natV targets at MEDICIS is equivalent to low- to medium-energy cyclotron-irradiated targets at medically relevant yields, furthermore benefiting from the mass separation possibility. A two-step laser resonance ionization scheme was used to obtain mono-atomic Sc ion beams. Sc radionuclide release from irradiated target units most effectively could be promoted by volatile scandium fluoride formation. Thus, isotopically pure 44g/mSc, 46 Sc, and 47 Sc were obtained as mono-atomic and molecular ScF 2+ ion beams and collected for the first time at CERN-MEDICIS. Among all the investigated target materials, natTiC is the most suitable target material for Sc mass separation as molecular halide beams, due to high possible operating temperatures and sustained release.

Post-surgical reproductive performance following ovine caesarean section has not been well studied. To assess any direct effects of surgical delivery in the absence of confounders such as dystocia or underlying diseases, we studied elective surgery performed in healthy animals for teaching purposes. Four hundred and eleven paired breeding records following vaginal delivery ( n = 233), elective caesarean section ( n = 122), and subsequent further vaginal deliveries in animals with a history of one prior elective caesarean operation ( n = 56) were evaluated retrospectively. The overall subsequent pregnancy rate was 95%. Multivariable statistical analyses did not reveal any significant influence of planned caesarean surgery on subsequent conception, stillbirth, perinatal lamb mortality, lamb birth weights, or the incidence of premature foetal death (mummification and abortion). A significantly higher number of mating attempts was, however, necessary. Also, a significant reduction in litter size was seen in the first pregnancy immediately following a surgical delivery in comparison to animals which had previously only delivered vaginally ( p = 0.001), but litter size returned to pre-caesarean levels in further follow-up pregnancies in animals with a history of one elective caesarean section ( p = 0.436). Subsequent long-term reproductive performance of sheep following elective caesarean section is thus excellent, and the results encourage retention for breeding.