julilili42/papers huggingface dataset:
Diagnostic Accuracy of Lung and Abdominal Ultrasound for Tuberculosis in a German Multicenter Cohort of Patients With Presumed Tuberculosis Disease
2024-11-27

Abstract Background There is limited evidence on point-of-care ultrasound for tuberculosis (TB), but studies suggest high sensitivity, especially for lung ultrasound (LUS). However, insufficient data are available on specificity of the examination and its generalizability to a broader patient population. Aims Our study aimed to establish accuracy for lung, chest, and abdominal ultrasound, individually and in combination, for TB diagnosis. Methods We conducted a prospective diagnostic accuracy study among consecutive adult out- and inpatients with probable TB in three German referral hospitals. We applied a comprehensive standardized ultrasound protocol. TB diagnosis was established by a microbiological reference standard including polymerase chain reaction and culture. Results A total of 102 participants originating from 30 different countries were enrolled. HIV prevalence was 7/99 (7%) and 73/102 (72%) had confirmed TB. TB was limited to the lungs in 15/34 (44%) of refugees and 27/39 (69%) in nonrefugees. Focused assessment with sonography for HIV-associated tuberculosis had a sensitivity of 40% (95% confidence interval [CI], 30–52) and specificity of 55% (95% CI, 38–72). Additional findings, such as small subpleural consolidations on LUS had a high sensitivity (88%; 95% CI, 78–93), but a low specificity (17%; 95% CI, 8–35). Larger consolidations in the lung apices had a sensitivity of 19% (95% CI, 12–30) and a specificity of 97% (95% CI, 83–100). Conclusions Our study establishes the first data on LUS performance against a comprehensive reference standard. Overall, our data suggest that ultrasound does not meet the requirements for triage but previously described and novel ultrasound targets in combination could aid in the clinical decision making. Registry: DRKS00026636
Current update on the neurological manifestations of long COVID: more questions than answers
2024-11-27

Since the outbreak of the COVID-19 pandemic, there has been a global surge in patients presenting with prolonged or late-onset debilitating sequelae of SARS-CoV-2 infection, colloquially termed long COVID. This narrative review provides an updated synthesis of the latest evidence on the neurological manifestations of long COVID, discussing its clinical phenotypes, underlying pathophysiology, while also presenting the current state of diagnostic and therapeutic approaches. Approximately one-third of COVID-19 survivors experience prolonged neurological sequelae that persist for at least 12-months post-infection, adversely affecting patients’ quality of life. Core neurological manifestations comprise fatigue, post-exertional malaise, cognitive impairment, headache, lightheadedness ('brain fog'), sleep disturbances, taste or smell disorders, dysautonomia, anxiety, and depression. Some of these features overlap substantially with those reported in post-intensive-care syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, and postural-orthostatic-tachycardia syndrome. Advances in data-driven research utilizing electronic-health-records combined with machine learning and artificial intelligence have propelled the identification of long COVID sub-phenotypes. Furthermore, the evolving definitions reflect the dynamic conceptualization of long COVID in both research and clinical contexts. Although the underlying pathophysiology remains incompletely elucidated, neuroinflammatory responses, endotheliopathy, and metabolic imbalances, rather than direct viral neuroinvasion, are implicated in neurological sequelae. Genetic susceptibility has also emerged as a potential risk factor. While major limitations remain with existing definitions, collaborative strategies to standardize diagnostic approaches are needed. Current therapeutic paradigms advocate for multimodal approaches, integrating pharmacological and non-pharmacological interventions along with comprehensive rehabilitation programs. Although preliminary evidence of therapeutic efficacy has been provided by a number of clinical trials, methodological constraints limit the generalizability of this evidence. Preventive measures, notably vaccination, have proven integral for reducing the global burden of long COVID. Considering the healthcare and socioeconomic repercussions incurred by long COVID worldwide, international collaborative initiatives are warranted to address the remaining challenges in diagnosing and managing patients presenting with neurological sequelae.
Only Infant MLL-Rearranged Leukemia Is Susceptible to an Inhibition of Polo-like Kinase 1 (PLK-1) by Volasertib
2024-11-27

MLL-rearranged (MLLr) leukemia is characterized by a poor prognosis. Depending on the cell of origin, it differs in the aggressiveness and therapy response. For instance, in adults, volasertib blocking Polo-like kinase 1 (PLK-1) exhibited limited success. Otherwise, PLK-1 characterizes an infant MLLr signature, indicating potential sensitivity. By using our CRISPR/Cas9 MLLr model in CD34+ cells from human cord blood (huCB) and bone marrow (huBM) mimicking the infant and adult patient diseases, we were able to shed light on this phenomenon. The PLK-1 mRNA level was significantly increased in our huCB compared to the huBM model, which was underpinned by analyzing infant and adult MLLr leukemia patients. Importantly, the expression levels correlated with a functional response. Volasertib induced a significant dose-dependent decrease in proliferation and cell cycle arrest, most pronounced in the infant model. Mechanistically, upon volasertib treatment, we uncovered negative feedback only in the huBM model by compensatory upregulation of PLK-1 and related genes like AURKA involved in mitosis. Importantly, the poor response could be overcome by a combinatorial strategy with alisertib, an Aurora kinase A inhibitor. Our study emphasizes the importance of considering the cell of origin in therapeutic decision-making and provides the rationale for evaluating volasertib and alisertib in MLLr leukemia.
Continuous Tuning of Intersystem Crossing Times in Rose Bengal Water/Methanol Solutions
2024-11-27

We use femtosecond transient broadband absorption spectroscopy (TAS) to characterize Rose Bengal in water/methanol solutions and reveal a continuous tunability of intersystem crossing (ISC) times by changing the mole fraction of the solvents. We find that the transients of excited state absorptions (ESAs) in Rose Bengal at ∼430 nm can be attributed to transitions from the singlet state S<sub>1</sub>, with decay times of 74 ps via ISC in pure water and up to 405 ps in pure methanol. TA measurements at near-infrared wavelengths, on the other hand, reveal the rise of an ESA at ∼1080 nm from the triplet state T<sub>1</sub> with time constants of 68 and 491 ps in pure water and methanol, respectively, strongly supporting the associated UV-vis TAS data. Solvent mixtures show a quasi-linear rise of the ISC times with increasing mole fractions of methanol and indicate that Rose Bengal in varying solvent mixtures can be used as a model system to study their influence on excited state photophysics.
Exploring Neural Dynamics in the Auditory Telencephalon of Crows using Functional Ultrasound Imaging
2024-11-27

Abstract Crows, known for advanced cognitive abilities and vocal communication, rely on intricate auditory systems. While the neuroanatomy of corvid auditory pathways is partially explored, the underlying neurophysiological mechanisms are largely unknown. This study used functional ultrasound imaging (fUSi) to investigate sound-induced cerebral blood volume (CBV) changes in the field L complex of the crow’s auditory telencephalon, a functional analogue to the mammalian auditory cortex. FUSi revealed frequency-specific CBV responses, showing a tonotopic organization within the field L complex, with low frequencies in the posterior-dorsal region and high frequencies in the anterior-ventral region, similar to neuronal patterns reported in other songbirds. The responses were more robust when the crows were awake compared to when they were anesthetized. Machine learning analyses showed fUSi signals could be used to classify sound types accurately. Shorter stimuli reliably triggered transient CBV increases, while longer sounds resulted in variable responses, including negative deflections. This variability in CBV responses suggests a delineation of subregions within the field L complex with the central region (L2) as the primary processing hub and outer regions (L1, L3) integrating auditory information. These findings highlight the potential of fUSi for providing high-resolution insights into functional systems in corvids, enabling future exploration of task-related cognitive dynamics.
Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention
2024-11-28

Abstract Metabolic dysfunction‐associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver model from primary human hepatocytes and non‐parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease‐relevant endpoints, such as steatosis, inflammation and fibrosis, and multi‐omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls. By combining high‐content imaging with scalable biochemical assays and chemogenomic screening, multiple novel targets with anti‐steatotic, anti‐inflammatory, and anti‐fibrotic effects are identified. Among these, activation of the muscarinic M 1 receptor (CHRM1) and inhibition of the TRPM8 cation channel result in strong anti‐fibrotic effects, which are confirmed using orthogonal genetic assays. Strikingly, using biosensors based on bioluminescence resonance energy transfer, a functional interaction along a novel MASH signaling axis in which CHRM1 inhibits TRPM8 via G q/11 and phospholipase C‐mediated depletion of phosphatidylinositol 4,5‐bisphosphate can be demonstrated. Combined, this study presents the first patient‐derived 3D MASH model, identifies a novel signaling module with anti‐fibrotic effects, and highlights the potential of organotypic culture systems for phenotype‐based chemogenomic drug target identification at scale.
Hemorrhage in Pelvic Ring Fractures After Low-Energy Trauma: A Systematic Review
2024-11-28

Background/Objectives: The aim was to investigate diagnostic, treatment and preventive options to establish an overview of the existing evidence on hemorrhage in pelvic fractures in older adults. Methods: A systematic review was conducted. Due to the rarity of this complication, only case reports and series with individuals older than 55 years with a pelvic ring fracture that is caused by a low-energy trauma or no apparent trauma, along with hemorrhage, were eligible. A search was performed on four databases. The CARE checklist was used to investigate the reporting integrity of the included studies. Analysis was performed narratively, and this study was registered on the Open Science Framework. Results: 21 patients from 19 studies were included (17 females and 4 males) with an average age of 82.1 years. The 21 patients suffered a total of 29 fractures. Pubic ramus fractures were present in 48.3% of all fractures. In 42.9%, an active hemorrhage was reported. Arterial vessels were injured in direct anatomical relationship to the fracture. Abdominal pain and hemorrhagic instability were the main red flag symptoms reported. Active arterial hemorrhage was diagnosed by CT with angiogram and treated by embolization with or without additional surgery. Conclusions: Clinically relevant hemorrhage in pelvic fractures due to low-energy trauma is rare. However, these fractures, combined with clinically relevant hemorrhage, account for an increased mortality and morbidity in elderly people. This systematic review was able to create a clinical decision tree for hemorrhage in ramus pubic fractures.
Evaluation of a goalkeeper-specific motor coordination assessment in youth football
2024-11-28

Talent identification and development (TID) in football can be enhanced through objective assessments of talent predictors. Yet, available instruments rarely consider the unique demands of goalkeepers (GKs). During early phases of talent development, considering a GK's giftedness relating to, for example, different abilities (e.g. motor coordination), can complement views on highly specialized GK-specific attributes (e.g. technical skills). Therefore, this study aimed to evaluate a GK-specific motor coordination assessment to support TID in football at early developmental phases. Six tests were designed to assess ball control relevant to GKs. Their content and face validity were confirmed by independent experts (<i>N</i> = 8). The assessment was evaluated with GKs selected for the German Football Association's TID program (U12-U15; <i>N</i> = 120). This study examined the assessment's test-retest reliability and agreement, the structural validity, and the concurrent validity. The overall test score demonstrated good test-retest reliability, although some individual tests showed lower coefficients. Additionally, limited agreement between repeated measurements due to considerable measurement error as well as issues with the structural validity of the test battery were identified. Nevertheless, the findings support the assessment's concurrent validity as higher-rated (i.e. more talented) GKs outperformed lower-rated individuals. Yet, the test battery's diagnostic accuracy is not high enough to justify individual decisions for talent selection. Overall, these findings support the consideration of motor coordination as a talent predictor in youth GKs and emphasize the assessment's potential to enhance coaches' evaluations. The identified psychometric weaknesses in some individual tests provide impetus to further optimize the test battery.
Flow Rate Determination of the Nanoflow Sheath Liquid CE–MS‐Coupling Applying the nanoCEasy Interface
2024-11-28

ABSTRACT In recent years, nanoflow sheath liquid (nanoSL) interfaces have been used more commonly for capillary electrophoresis–mass spectrometry (CE–MS) coupling due to their high sensitivity combined with flexibility in CE separation conditions. So far, the exact amount of sheath liquid (SL) and, thus, the dilution effect remain unknown due to the self‐supplying type of the nanoSL interfaces. To quantify the SL flow rates, we present here an approach for the determination of the flow rate based on isotopically labeled standards using the nanoCEasy interface. SL and pumped CE flow are spiked with atrazine and d5‐atrazine, respectively, enabling the determination of the total flow rate for different electrospray (ES) conditions. Generally, flow rates increase with higher ES voltages. Only at high ES voltages, larger emitter sizes lead to higher flow rates; for low voltages, flow rates are independent of emitter size. Additionally, smaller emitter sizes can generally be operated at lower ES voltages. Visualizing the ES, higher flow rates lead to a larger spray angle. Higher flow rates may decrease the signal intensity by diluting the CE‐separated analytes. Indeed, this effect is observed for the flow‐injected atrazine analytes and in the CE–MS analysis of an amino acid standard mix under aqueous acidic separation conditions. Therefore, lower flow rates are preferred for low electroosmotic flow (EOF) applications. However, in high EOF applications, higher voltages are required to prevent the accumulation of aqueous background electrolyte (BGE) at the emitter tip, which otherwise leads to peak broadening and inefficient ionization. Overall, the presented data enable the selection of stable and sensitive settings for nanoSL interfaces.
Graph Product Structure for $h$-Framed Graphs
2024-11-28

Graph product structure theory expresses certain graphs as subgraphs of the strong product of much simpler graphs. In particular, an elegant formulation for the corresponding structural theorems involves the strong product of a path and of a bounded treewidth graph, and allows to lift combinatorial results for bounded treewidth graphs to graph classes for which the product structure holds, such as to planar graphs [Dujmović et al., J. ACM, 67(4), 22:1-38, 2020]. In this paper, we join the search for extensions of this powerful tool beyond planarity by considering the -framed graphs, a graph class that includes -planar, optimal -planar, and -map graphs (for appropriate values of ). We establish a graph product structure theorem for -framed graphs stating that the graphs in this class are subgraphs of the strong product of a path, of a planar graph of treewidth at most , and of a clique of size . This allows us to improve over the previous structural theorems for -planar and -map graphs. Our results lead to significant progress over the previous bounds on the queue number, non-repetitive chromatic number, and -centered chromatic number of these graph classes, e.g., we lower the currently best upper bound on the queue number of -planar graphs and -map graphs from to and from to , respectively. We also employ the product structure machinery to improve the current upper bounds on the twin-width of -planar graphs from to . All our structural results are constructive and yield efficient algorithms to obtain the corresponding decompositions.
Sex Differences in Insulin-Induced Hippocampus Functional Connectivity During Visual Food-Cue Presentation
2024-11-28

Abstract Context Central insulin has been shown to regulate eating behavior and cognitive processes in a sex-specific manner. Besides memory, the hippocampus is pivotal in the control of appetite. Objective This work aimed to investigate how insulin interacts with the hippocampal food-cue response and evaluate the potential role of sex hormones. Methods Using functional magnetic resonance imaging, we evaluated task-based functional connectivity (FC) of the hippocampus during food-cue presentation in 60 participants (age: 21-69 years; 30 women) after intranasal insulin or placebo administration, in a randomized within-subject design. In an exploratory analysis, we investigated whether hippocampal FC after intranasal insulin administration is related to estradiol and progesterone levels during the follicular and luteal phase of the menstrual cycle in 13 premenopausal women (age: 20-28 years). Results Intranasal insulin increased hippocampal FC with the prefrontal cortex compared to placebo, regardless of sex. This correlated with stronger reduction in subjective feeling of hunger and food craving. Moreover, we observed an interaction between sex and nasal spray condition with higher hippocampal FC to the calcarine gyrus after insulin compared to placebo in men, while women showed a lower response. In premenopausal women, the centrally mediated effect of insulin on hippocampus to calcarine gyrus FC negatively correlated with the estradiol/progesterone ratio in the luteal phase. Conclusion Central insulin influences hippocampal FC to regions vital for inhibitory control during high-caloric food-cue presentation, implying a potential role of the hippocampal network in modulating insulin's anorexic effects. The observed sex differences between the hippocampus and visual cortex might be influenced by sex hormone action.
Hegel as a ‘backward-looking prophet’?: Kierkegaard’s critique of Hegel’s philosophy of history
2024-11-28

Abstract Kierkegaard presents his critique of a Hegelian philosophy of history in the works of his Climacus pseudonym, the Philosophical Fragments and the corresponding Concluding Unscientific Postscript . It has been contested whether he addressed his arguments toward Hegel directly. In this paper, I argue that these arguments are systematically pertinent to central issues both of Hegel’s as well as any other philosophical engagement with history. To make this point I proceed in three steps. First, the basic outlines of Hegel’s philosophy of history are given concerning its exact subject matter, what the aim of history is, and whether the reason inherent in it allows us to conceive of historical events as necessary. Second, I will show that, though agreeing with Hegel on some points, Climacus holds that we can ascribe neither a determinist nor a conceptual kind of necessity to historical events. Finally, I will expand on Climacus’s account of radical metaphysical contingency and its ethical implications which prompt some objections against philosophy of history in general.
Comprehensive evaluation of EEG spatial sampling, head modeling, and parcellation effects on network alterations in idiopathic generalized epilepsy
2024-11-28

Abstract Idiopathic generalized epilepsy (IGE) is characterized by marked brain network alterations as assessed using electrophysiology. Logistical challenges and the need for a volumetric MRI often hinder the clinical application of high-density EEG or MEG. This study investigates the influence of EEG channel density and the head model on brain metrics derived from 256-channel EEG and 19-channel routine EEG in two samples balanced for age and sex. First, we evaluated resting-state data from 35 individuals with IGE and 54 healthy controls collected using the 256-channel setup. Data were analyzed at full density and then iteratively down-sampled to lower densities. Source reconstruction was performed either using individual MRI data or a standard brain template and dynamic imaging of coherent sources (DICS). We assessed EEG power and connectivity (imaginary part of coherency) group differences at all channel compositions, head model types, and parcellations (cortical vertices, anatomical and network parcellations). Second, a routine sample recorded with 19 channels was analyzed to validate findings in a real epilepsy monitoring scenario (71 patients, 43 controls). We found that lower-density arrays reliably identified global group differences for both power and connectivity and in frequency bands for which the strongest effects were observed. The spatial similarity of the results for the 256 channels set and those with fewer channels were good to moderate for power (r spin ∼0.97 to 0.33), but dropped for connectivity with fewer than 64 channels (r spin ∼0.78 to-0.12). Comparing individual and canonical head models revealed consistent effects (r spin ∼0.77 to 0.5), with coarser brain parcellations increasing stability for low-density maps. In sum, low-density EEG arrays suffice for detecting global alterations in IGE, particularly in signal power. Our findings advocate for leveraging clinical EEG for brain-wide analyses in IGE while emphasizing the need for high-density coverage if spatial precision is needed. Canonical head models are a viable alternative if no individual MRI is available, especially for regional-or network-level assessments.
The membrane domains of mammalian adenylyl cyclases are lipid receptors
2024-11-29

The biosynthesis of cyclic 3′,5′-adenosine monophosphate (cAMP) by mammalian membrane-bound adenylyl cyclases (mACs) is predominantly regulated by G-protein-coupled receptors (GPCRs). Up to now the two hexahelical transmembrane domains of mACs were considered to fix the enzyme to membranes. Here, we show that the transmembrane domains serve in addition as signal receptors and transmitters of lipid signals that control Gsα-stimulated mAC activities. We identify aliphatic fatty acids and anandamide as receptor ligands of mAC isoforms 1–7 and 9. The ligands enhance (mAC isoforms 2, 3, 7, and 9) or attenuate (isoforms 1, 4, 5, and 6) Gsα-stimulated mAC activities in vitro and in vivo. Substitution of the stimulatory membrane receptor of mAC3 by the inhibitory receptor of mAC5 results in a ligand inhibited mAC5–mAC3 chimera. Thus, we discovered a new class of membrane receptors in which two signaling modalities are at a crossing, direct tonic lipid and indirect phasic GPCR–Gsα signaling regulating the biosynthesis of cAMP.