julilili42/papers huggingface dataset:
Safety and efficacy of off-label bulevirtide monotherapy in patients with HDV with decompensated Child-B cirrhosis—A real-world case series
2024-03-13

Background and Aims: Chronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis. Approach and Results: We conducted a retrospective study in patients with HDV with decompensated liver disease at German, Austrian, and Italian centers. We included 19 patients (47% male, mean age: 51 years) with liver cirrhosis Child-Pugh B. The median MELD score was 12 (range 9–17) at treatment initiation. The median observation period was 41 weeks. Virologic response was achieved in 74% and normal alanine aminotransferase was observed in 74%. The combined response was achieved by 42%. The most relevant adverse events included self-limited alanine aminotransferase flares, an asymptomatic increase in bile acids, and the need for liver transplantation. Despite bile acid increases, adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n = 9/19). Improvements in the amount of ascites were observed in 58% of the patients initially presenting with ascites (n = 7/12). Conclusions: This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed in surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm the safety and efficacy of bulevirtide in decompensated HDV cirrhosis.
The high-density lipoprotein binding protein HDLBP is an unusual RNA-binding protein with multiple roles in cancer and disease
2024-03-13

The high-density lipoprotein binding protein (HDLBP) is the human member of an evolutionarily conserved family of RNA-binding proteins, the vigilin protein family. These proteins are characterized by 14 or 15 RNA-interacting KH (heterologous nuclear ribonucleoprotein K homology) domains. While mainly present at the cytoplasmic face of the endoplasmic reticulum, HDLBP and its homologs are also found in the cytosol and nucleus. HDLBP is involved in various processes, including translation, chromosome segregation, cholesterol transport and carcinogenesis. Especially, its association with the latter two has attracted specific interest in the HDLBP's molecular role. In this review, we give an overview of some of the functions of the protein as well as introduce its impact on different kinds of cancer, its connection to lipid metabolism and its role in viral infection. We also aim at addressing the possible use of HDLBP as a drug target or biomarker and discuss its future implications.
Efficient and scalable clarification of Orf virus from HEK suspension for vaccine development
2024-03-13

The Orf virus (ORFV) is a promising vector platform for the generation of vaccines against infectious diseases and cancer, highlighted by its progression to clinical testing phases. One of the critical steps during GMP manufacturing is the clarification of crude harvest because of the enveloped nature and large size of ORFV. This study presents the first description of ORFV clarification process from a HEK suspension batch process. We examined various filter materials, membrane pore sizes, harvest timings, and nuclease treatments. Employing the Ambr® crossflow system for high-throughput, small-volume experiments, we identified polypropylene-based Sartopure® PP3 filters as ideal. These filters, used in two consecutive stages with reducing pore sizes, significantly enhanced ORFV recovery and addressed scalability challenges. Moreover, we demonstrated that the time of harvest and the use of a nuclease play a decisive role to increase ORFV yields. With these findings, we were able to establish an efficient and scalable clarification process of ORFV derived from a suspension production process, essential for advancing ORFV vaccine manufacturing.
Dominant CST3 variants cause adult onset leukodystrophy without amyloid angiopathy
2024-03-13

Abstract Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. This perception has been altered in recent years, as a growing number of leukodystrophies have been described as having an onset in adulthood. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later displayed severe degeneration and loss. In addition, despite the loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level.
Machine learning insights into thrombo-ischemic risks and bleeding events through platelet lysophospholipids and acylcarnitine species
2024-03-13

Abstract Coronary artery disease (CAD) often leads to adverse events resulting in significant disease burdens. Underlying risk factors often remain inapparent prior to disease incidence and the cardiovascular (CV) risk is not exclusively explained by traditional risk factors. Platelets inherently promote atheroprogression and enhanced platelet functions and distinct platelet lipid species are associated with disease severity in patients with CAD. Lipidomics data were acquired using mass spectrometry and processed alongside clinical data applying machine learning to model estimates of an increased CV risk in a consecutive CAD cohort ( n = 595). By training machine learning models on CV risk measurements, stratification of CAD patients resulted in a phenotyping of risk groups. We found that distinct platelet lipids are associated with an increased CV or bleeding risk and independently predict adverse events. Notably, the addition of platelet lipids to conventional risk factors resulted in an increased diagnostic accuracy of patients with adverse CV events. Thus, patients with aberrant platelet lipid signatures and platelet functions are at elevated risk to develop adverse CV events. Machine learning combining platelet lipidome data and common clinical parameters demonstrated an increased diagnostic value in patients with CAD and might improve early risk discrimination and classification for CV events.
Mixed‐effects regression weights for advice taking and related phenomena of information sampling and utilization
2024-03-13

Abstract Advice taking and related research is dominated by deterministic weighting indices, specifically ratio‐of‐differences‐based formulas for investigating informational influence. Their arithmetic is intuitively simple, but they pose several measurement problems and restrict research to a particular paradigmatic approach. As a solution, we propose to specify how strongly peoples' judgments are influenced by externally provided evidence by fitting corresponding mixed‐effects regression models. Our approach explicitly distinguishes between endogenous components, such as updated beliefs, and exogenous components, such as independent initial judgments and advice. Crucially, mixed‐effects regression coefficients of various exogenous sources of information also reflect individual weighting but are based on a conceptually consistent representation of the endogenous judgment process. The formal derivation of the proposed weighting measures is accompanied by a detailed elaboration on their most important technical and statistical subtleties. We use this modeling approach to revisit empirical findings from several paradigms investigating algorithm aversion, sequential collaboration, and advice taking. In summary, we replicate and extend the original finding of algorithm appreciation and initially demonstrate a lack of evidence for both systematic order effects in sequential collaboration as well as differential weighting of multiple pieces of advice. In addition to opening new avenues for innovative research, appropriate modeling of information sampling and utilization has the potential to increase the reproducibility and replicability of behavioral science. Furthermore, the proposed method is relevant beyond advice taking, as mixed‐effects regression weights can also inform research on related cognitive phenomena such as multidimensional belief updating, anchoring effects, hindsight bias, or attitude change.
Twelve-hour normothermic liver perfusion in a rat model: characterization of the changes in the ex-situ bio-molecular phenotype and metabolism
2024-03-13

Abstract The partial understanding of the biological events that occur during normothermic machine perfusion (NMP) and particularly during prolonged perfusion might hinder its deployment in clinical transplantation. The aim of our study was to implement a rat model of prolonged NMP to characterize the bio-molecular phenotype and metabolism of the perfused organs. Livers (n = 5/group) were procured and underwent 4 h (NMP4h) or 12 h (NMP12h) NMP, respectively, using a perfusion fluid supplemented with an acellular oxygen carrier. Organs that were not exposed to any procedure served as controls (Native). All perfused organs met clinically derived viability criteria at the end of NMP. Factors related to stress-response and survival were increased after prolonged perfusion. No signs of oxidative damage were detected in both NMP groups. Evaluation of metabolite profiles showed preserved mitochondrial function, activation of Cori cycle, induction of lipolysis, acetogenesis and ketogenesis in livers exposed to 12 h-NMP. Increased concentrations of metabolites involved in glycogen synthesis, glucuronidation, bile acid conjugation, and antioxidant response were likewise observed. In conclusion, our NMP12h model was able to sustain liver viability and function, thereby deeply changing cell homeostasis to maintain a newly developed equilibrium. Our findings provide valuable information for the implementation of optimized protocols for prolonged NMP.
Coherent interface between optical and microwave photons on an integrated superconducting atom chip
2024-03-13

Abstract Sub-wavelength arrays of atoms exhibit remarkable optical properties, analogous to those of phased array antennas, such as collimated directional emission or nearly perfect reflection of light near the collective resonance frequency. We propose to use a single-sheet sub-wavelength array of atoms as a switchable mirror to achieve a coherent interface between propagating optical photons and microwave photons in a superconducting coplanar waveguide resonator. In the proposed setup, the atomic array is located near the surface of the integrated superconducting chip containing the microwave cavity and optical waveguide. A driving laser couples the excited atomic state to Rydberg states with strong microwave transition. Then the presence or absence of a microwave photon in the superconducting cavity makes the atomic array transparent or reflective to the incoming optical pulses of proper frequency and finite bandwidth.
Electrophysiological signatures of a developmental delay in a stem cell model ofKCNQ2developmental and epileptic encephalopathy
2024-03-13

Abstract Background KCNQ2 , encoding K V 7.2 ion channels, has emerged as one of the prominent genes causing early onset seizures with developmental delay ( KCNQ2 developmental and epileptic encephalopathy; KCNQ2 -DEE). KCNQ2 de novo loss-of-function (LOF) and associated neuronal hyperexcitability have been accepted as mechanisms contributing to seizures. To investigate the developmental impact of KCNQ2 LOF, we generated patient iPSC-derived models for two previously reported de novo variants, p.(Arg325Gly) and p.(Gly315Arg), linked to severe congenital DEE. Methods Functional investigation of the two variants was initially performed in Xenopus laevis oocyte system. Patient-derived iPSC lines were differentiated using NGN2- and embryoid body-based protocols yielding neurons roughly corresponding to mid- and mid-late gestational stages, respectively. K V 7- mediated M-current, passive neuronal properties, action potential generation and spontaneous oscillatory network activities were analysed with whole-cell patch clamping. Findings Studied KCNQ2 variants showed LOF with a dominant-negative effect in the heterologous system. Reduced M-currents in patient iPSC-derived neurons corroborated a LOF as the main pathomechanism. Interestingly, this led to the reduced neuronal firing of the early neurons and to a disruption of complex oscillatory activity, with significantly reduced duration and amplitude of these events in patient iPSC-derived neurons. Interpretation We provide experimental evidence for changing roles of the M-current throughout development and place disease variant-mediated M-current reduction in the context of the neuronal maturation in the prenatal brain. Based on the reduced neuronal firing and disrupted oscillatory activity seen in patient iPSC-derived neurons, we propose that a delayed/impaired maturation of neuronal and network properties underlies KCNQ -DEE caused by LOF variants.
Impact of COVID‐19 on paediatric chronic intestinal failure: A tertiary care children's hospital experience
2024-03-13

Abstract Objectives Paediatric patients with intestinal failure (IF) are at risk for both gastrointestinal (GI) and systemic complications, thus depending on a functioning network of multidisciplinary care. Data on the clinical impact of coronavirus disease 2019 (COVID‐19) or the pandemic‐related restrictions are limited. We aimed to analyse the clinical course of COVID‐19 in children with IF, and to evaluate the perceived impact of the COVID‐19 pandemic on IF patients and their caregivers by analysing quality of life (QoL), health‐related QoL (HRQoL) and health care. Methods Children with IF presenting at our intestinal rehabilitation centre were enrolled and interviewed about test‐proven COVID‐19 infection. A standardised questionnaire was offered to all caregivers of IF patients and to two control groups (children with inflammatory bowel disease and gastrointestinal healthy children). Results Between December 2020 and November 2022, 25 out of 127 patients with IF contracted COVID‐19. Forty‐eight per cent had GI symptoms, 32% required additional intravenous fluids and 20% were hospitalized. Only 25% of vaccinated children showed signs of GI dysfunction, compared to 52% of unvaccinated children. Analysis of 93 questionnaires showed a negative impact on QoL and HRQoL (&gt;66.7% and &gt;27.8%, respectively). IF patients frequently experienced restrictions in health care, including appointments, services and supply of parenteral nutrition or medications. Caregiver burden increased significantly more often in caregivers of children with IF ( p = 0.007). Conclusions Paediatric patients with IF contracting COVID‐19 have an increased risk for GI dysfunction which may be alleviated by vaccination. Children and their caregivers were highly burdened by pandemic‐related restrictions and reductions in health care provision.
Physical and mental effects of different radical prostatectomy techniques on urologic surgeons
2024-03-13

Abstract Oblective In this web-based international survey study, we aimed to show association between physical exhaustion, and patient, relatives, and employers-related mental stress on surgeons performing open radical prostatectomy (ORP), laparoscopic radical prostatectomy (LRP), and robot-assisted laparoscopic prostatectomy (RALP) . Methods A ten-question survey was sent to the urologists performing ORP, LRP, and RALP via e-mail and social media platforms. The techniques preferred by the participants and their possible associations with physical exhaustion, musculoskeletal complaints and stress caused by patients’ or patients’ relatives or employers’ expectations as well as regular exercise or sportive activities were investigated. Results A total of 160 urologists completed the survey. RALP group showed lower physical exhaustion rate and increased eye-strain (p &lt; 0.001 and p = 0.002, respectively). Although walking was the most preferred sportive activity, no correlation was found between regular sport or exercise and musculoskeletal complaints (p &gt; 0.05). Conclusion Lower physical exhaustion was achieved in RALP technique compared to ORP and LRP. Although the number of participants limited, regular exercise weakly improved physical exhaustion and musculoskeletal complaints. We believe that encouraging the urologists dealing with LRP and RALP to force regular sportive activities would help to improve physical discomfort.
Whole-body simulation of realistic fruit fly locomotion with deep reinforcement learning
2024-03-14

Abstract The body of an animal influences how the nervous system produces behavior. Therefore, detailed modeling of the neural control of sensorimotor behavior requires a detailed model of the body. Here we contribute an anatomically-detailed biomechanical whole-body model of the fruit fly Drosophila melanogaster in the MuJoCo physics engine. Our model is general-purpose, enabling the simulation of diverse fly behaviors, both on land and in the air. We demonstrate the generality of our model by simulating realistic locomotion, both flight and walking. To support these behaviors, we have extended MuJoCo with phenomenological models of fluid forces and adhesion forces. Through data-driven end-to-end reinforcement learning, we demonstrate that these advances enable the training of neural network controllers capable of realistic locomotion along complex trajectories based on high-level steering control signals. We demonstrate the use of visual sensors and the re-use of a pre-trained general-purpose flight controller by training the model to perform visually guided flight tasks. Our project is an open-source platform for modeling neural control of sensorimotor behavior in an embodied context.
Physiologically based pharmacokinetic modeling of imatinib and N‐desmethyl imatinib for drug–drug interaction predictions
2024-03-14

Abstract The first‐generation tyrosine kinase inhibitor imatinib has revolutionized the development of targeted cancer therapy and remains among the frontline treatments, for example, against chronic myeloid leukemia. As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug–drug interactions (DDIs) when co‐administered with corresponding perpetrator drugs. Additionally, imatinib and its main metabolite N ‐desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co‐medications. This work presents the development of a parent–metabolite whole‐body physiologically based pharmacokinetic (PBPK) model for imatinib and NDMI used for the investigation and prediction of different DDI scenarios centered around imatinib as both a victim and perpetrator drug. Model development was performed in PK‐Sim® using a total of 60 plasma concentration–time profiles of imatinib and NDMI in healthy subjects and cancer patients. Metabolism of both compounds was integrated via CYP2C8 and CYP3A4, with imatinib additionally transported via P‐glycoprotein. The subsequently developed DDI network demonstrated good predictive performance. DDIs involving imatinib and NDMI were simulated with perpetrator drugs rifampicin, ketoconazole, and gemfibrozil as well as victim drugs simvastatin and metoprolol. Overall, 12/12 predicted DDI area under the curve determined between first and last plasma concentration measurements (AUC last ) ratios and 12/12 predicted DDI maximum plasma concentration ( C max ) ratios were within twofold of the respective observed ratios. Potential applications of the final model include model‐informed drug development or the support of model‐informed precision dosing.
Charged hadron fragmentation functions at high energy colliders
2024-03-14

We update our extraction of parton-to-charged hadron fragmentation functions at next-to-leading order accuracy in quantum chromodynamics (QCD), focusing on the wealth of data collected at the Large Hadron Collider over the past decade. We obtain an accurate description of single-inclusive processes involving unidentified charged hadrons produced at different rapidities and transverse momenta in proton-proton collisions in a wide range of center-of-mass system energies between 0.9 and 13 TeV, along with measurements performed in proton-antiproton collisions at the Tevatron Collider in the past. Next-to-leading order estimates of charged hadron production rates agree best with data when the theoretical factorization scales are selected similar to those optimized for identified pions, kaons, and protons in a recent global QCD analysis.