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Objective: Liver transplant (LT) evaluation is a complex process for patients involving multi-step and parallel medical, surgical, and psychosocial assessments of a patient's appropriateness for transplant. Patients may experience difficulties in navigating the evaluation process, potentially leading to disengagement and resulting in further health decline or death prior to completing evaluation. We aimed to identify and characterize patients' perceptions of undergoing LT evaluation., Methods: We performed fourteen 30-45 min, semi-structured interviews between 3/2021-5/2021 with patients at a large LT center. Using the constant comparison method, we individually noted themes within and across interviews and codes., Results: Our analysis generated 5 thematic dimensions related to patient engagement (i.e., patient involvement/activation): (1) psychological impact of evaluation on patients' lives; (2) information received during evaluation; (3) prior medical experience of the patient; 4) communication between patients and transplant providers; and (5) support system of the patients. Among these dimensions, we identified 8 themes., Conclusion: LT patient engagement is a multi-dimensional component of LT evaluation that incorporates the psychological impact, information received, prior medical experience, communication, and support systems of patients., Practical Implications: This work can inform targeted interventions for increasing patient engagement during the LT evaluation process., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Alexandra Strauss reports financial support was provided by National Institute of Diabetes and Digestive and Kidney Diseases. Dorry Segev reports financial support was provided by National Institute of Allergy and Infectious Diseases. 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 Elsevier B.V. All rights reserved.)

Background: Pulmonary embolism (PE) is a potentially life-threatening condition. Admission and treatment in the intensive care unit (ICU) is an important element in critically ill PE patients., Objectives: We aimed to identify risk factors for ICU admission and differences in patient profiles regarding risk factors and comorbidities between PE patients who had to be admitted to an ICU and those who were treated in a normal ward without ICU., Methods: We used the German nationwide inpatient sample to analyze all hospitalizations of PE patients in Germany from 2016 to 2020 stratified for ICU admission., Results: Overall, 484,859 hospitalized PE patients were treated in German hospitals from 2016 to 2020. Among these, 92,313 (19.0%) were admitted to ICU. Patients treated in ICU were younger (69.0 [IQR, 58.0-78.0] vs 72.0 [IQR, 60.0-80.0] years; P  < .001) and had higher prevalence of cardiovascular risk factors and comorbidities. In-hospital case fatality rate was elevated in PE patients treated in ICU (22.7% vs 10.7%; P  < .001), and ICU admission was independently associated with increased in-hospital case fatality (odds ratio [OR], 2.54; 95% CI, 2.49-2.59; P  < .001). Independent risk factors for ICU admission comprised PE with imminent or present decompensation (OR, 3.30; 95% CI, 3.25-3.35; P  < .001), hemodynamic instability (OR, 4.49; 95% CI, 4.39-4.59; P  < .001), arterial hypertension (OR, 1.20; 95% CI, 1.18-1.22; P  < .001), diabetes mellitus (OR, 1.16; 95% CI, 1.14-1.18; P  < .001), obesity (OR, 1.300; 95% CI, 1.27-1.33; P  < .001), surgery (OR, 2.55; 95% CI, 2.50-2.59; P  < .001), stroke (OR, 2.86; 95% CI, 2.76-2.96; P  < .001), pregnancy (OR, 1.45; 95% CI, 1.21-1.74; P  < .001), heart failure (OR, 1.74; 95% CI, 1.71-1.77; P  < .001), atrial fibrillation/flutter (OR, 1.69; 95% CI, 1.66-1.73; P  < .001), chronic obstructive pulmonary disease (OR, 1.21; 95% CI, 1.18-1.24; P  < .001), and renal failure (OR, 1.92; 95% CI, 1.88-1.95; P  < .001)., Conclusion: ICU treatment is an important element in the treatment of PE patients. Besides hemodynamic compromise, cardiovascular risk factors, stroke, pregnancy, and cardiopulmonary as well as renal comorbidities were independent predictors of ICU admission. Necessity of ICU admission was afflicted by increased case fatality., (© 2024 The Author(s).)

In an experimental setting a laboratory analysis of substances migrating from UV prints under mechanical stress into sweat and saliva simulant was performed. The influence of paper type and curing degree on UV prints was investigated. Five substances were identified at concentrations above the limit of detection in the simulants PPG-3 glyceryl triacrylate, ethoxylated trimethylolpropane triacrylate, trimethylolpropane triacrylate, 2/4-isopropylthioxanthone (ITX), and 2,4-diethylthioxanthone (DETX). Migration of the acrylates and photoinitiators into saliva and sweat simulants were increased when the UV inks were printed on uncoated paper in comparison to coated paper. With an exposure scenario considering a person to leaf through 80 pages of UV-printed paper per day while touching each page with a licked fingertip, Risk Characterisation Ratios (RCR) for oral exposure well below 1 were obtained for all five substances indicating no risk for the general population. The three acrylates are classified for skin sensitisation. The migrated amounts per skin surface area of these three were compared with the EC3 value for a hypothetical substance that could be categorised as strong sensitiser (EC3 = 0.1%). The results show that the risk of skin sensitisation even under worst case conditions can be considered as negligible., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To localise and characterise changes in cognitive networks in Amyotrophic Lateral Sclerosis (ALS) using source analysis of mismatch negativity (MMN) waveforms., Rationale: The MMN waveform has an increased average delay in ALS. MMN has been attributed to change detection and involuntary attention switching. This therefore indicates pathological impairment of the neural network components which generate these functions. Source localisation can mitigate the poor spatial resolution of sensor-level EEG analysis by associating the sensor-level signals to the contributing brain sources. The functional activity in each generating source can therefore be individually measured and investigated as a quantitative biomarker of impairment in ALS or its sub-phenotypes., Methods: MMN responses from 128-channel electroencephalography (EEG) recordings in 58 ALS patients and 39 healthy controls were localised to source by three separate localisation methods, including beamforming, dipole fitting and exact low resolution brain electromagnetic tomography., Results: Compared with controls, ALS patients showed significant increase in power of the left posterior parietal, central and dorsolateral prefrontal cortices (false discovery rate = 0.1). This change correlated with impaired cognitive flexibility (rho = 0.45, 0.45, 0.47, p = .042, .055, .031 respectively). ALS patients also exhibited a decrease in the power of dipoles representing activity in the inferior frontal (left: p = 5.16 × 10 -6 , right: p = 1.07 × 10 -5 ) and left superior temporal gyri (p = 9.30 × 10 -6 ). These patterns were detected across three source localisation methods. Decrease in right inferior frontal gyrus activity was a good discriminator of ALS patients from controls (AUROC = 0.77) and an excellent discriminator of C9ORF72 expansion-positive patients from controls (AUROC = 0.95)., Interpretation: Source localization of evoked potentials can reliably discriminate patterns of functional network impairment in ALS and ALS subgroups during involuntary attention switching. The discriminative ability of the detected cognitive changes in specific brain regions are comparable to those of functional magnetic resonance imaging (fMRI). Source analysis of high-density EEG patterns has excellent potential to provide non-invasive, data-driven quantitative biomarkers of network disruption that could be harnessed as novel neurophysiology-based outcome measures in clinical trials., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The determination of regional blood flow via the accumulation of fluorescent microspheres is a concept regularly used in medical research. Typically, the microbeads get extracted from the tissue of interest and are then quantified by measuring the absorption or fluorescence of the incorporated dyes without further separation from the medium. However, in that case the absorption spectra of different dyes can overlap when used simultaneously, leading to an overestimation of the concentration. Additionally, background absorption from the medium can be problematic. Therefore, a high performance liquid chromatography method for the simultaneous detection of four dyes (orange, crimson, yellow-green and red) incorporated in different microbeads in samples from biological media such as organ tissue (brain, heart and kidneys) was developed. Since for biological samples often a large sample size is required for sufficient statistics, the method was optimized to yield very short run times. With this method it was possible to detect very low concentrations of only one microsphere per gram of organ tissue. By applying this sensitive quantification technique, it was demonstrated that the application of microbeads for perfusion measurements might not be reliable due to different organ distributions in each animal., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Fluorescently labelled proteins are often used to study processes in vitro, e.g. the binding of proteins to cell surfaces or the adsorption of plasma proteins on drug nanocarriers. However, the fact that the fluorescent labelling may affect the protein properties is frequently neglected. On the example of a simple model system, we reiterate the importance of this issue by showing that even a single label may perturb interactions between hydrophilic starch-based nanocapsules and serum albumin and thus prevent binding., (Copyright © 2016 Elsevier B.V. All rights reserved.)

High atmospheric deposition of nitrogen (N) impacts functions and structures of N limited ecosystems. Due to filtering and related canopy drip effects forests are particularly exposed to N deposition. Up to now, this was proved by many studies using technical deposition samplers but there are only some few studies analysing the canopy drip effect on the accumulation of N in moss and related small scale atmospheric deposition patterns. Therefore, we investigated N deposition and related accumulation of N in forests and in (neighbouring) open fields by use of moss sampled across seven European countries. Sampling and chemical analyses were conducted according to the experimental protocol of the European Moss Survey. The ratios between the measured N content in moss sampled inside and outside of forests were computed and used to calculate estimates for non-sampled sites. Potentially influencing environmental factors were integrated in order to detect their relationships to the N content in moss. The overall average N content measured in moss was 20.0mgg(-1) inside and 11.9mgg(-1) outside of forests with highest N values in Germany inside of forests. Explaining more than 70% of the variance, the multivariate analyses confirmed that the sampling site category (site with/without canopy drip) showed the strongest correlation with the N content in moss. Spatial variances due to enhanced dry deposition in vegetation stands should be considered in future monitoring and modelling of atmospheric N deposition., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In spite of the crucial role of heterotrimeric G proteins as molecular switches transmitting signals from G protein-coupled receptors, their selective manipulation with small molecule, cell-permeable inhibitors still remains an unmet challenge. Here, we report that the small molecule BIM-46187, previously classified as pan-G protein inhibitor, preferentially silences Gαq signaling in a cellular context-dependent manner. Investigations into its mode of action reveal that BIM traps Gαq in the empty pocket conformation by permitting GDP exit but interdicting GTP entry, a molecular mechanism not yet assigned to any other small molecule Gα inhibitor to date. Our data show that Gα proteins may be "frozen" pharmacologically in an intermediate conformation along their activation pathway and propose a pharmacological strategy to specifically silence Gα subclasses with cell-permeable inhibitors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Muscarinic acetylcholine receptors belong to Class Aseven transmembrane helical receptors and serve as important drug targets in the treatment of various diseases such as chronic obstructive pulmonary disease, overactive bladder, bronchial asthma and glaucoma. Despite intensive research the discovery of experimental ligands which activate or block specific muscarinic receptor subtypes has only been successful for the M1 and M4 subtypes but remains a challenging task at the other subtypes. In recent years, ligands have been introduced which bind simultaneously to the acetylcholine binding site, that is, the orthosteric site, and to an allosteric binding site. These so-called dualsteric ligands display M2 subtype preference due to the addressing of the allosteric binding site. As proven recently, dualsteric receptor activation goes along with a pronounced signaling bias which follows clear structure–bias-relationships. Dualsteric receptor targeting might represent a common strategy to generate functional selectivity.

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are known to have a rather high affinity for the allosteric site of muscarinic M2 receptors. In order to get more insight into the contribution of the lateral substituents for alloster binding affinity, a series of compounds with unilaterally varying imide substituents were synthesized and tested for their ability to retard allosterically the dissociation of [3H]N-methylscopolamine from the receptor protein (control t1/2 = 2 min; 3 mM MgHCO4, 50 mM Tris, pH 7.3, 37 degrees C). Among the test compounds, the naphthalimide containing agent (half maximum effect at ECs5,diss = 60 nM) revealed the highest potency. Apparently, its affinity for the allosteric site in NMS-occupied receptors is 20fold higher compared with the phthalimide containing parent compound W 84. Analysis of quantitative structure-activity relationships yielded a parabolic correlation between the volume of the lateral substituents and the allosteric potency. The maximal volume was determined to be approximately 600 A3 suggesting that the allosteric binding site contains a binding pocket of a defined size for the imide moiety.

Elbow injuries in throwing athletes can be challenging from the diagnostic and management perspectives. The stress of repetitive throwing does predispose athletes to certain conditions with which treating clinicians need to be familiar. An understanding of the anatomy of the elbow and the biomechanics of throwing is essential to making the correct diagnosis and instituting proper care. Failure of nonoperative measures often requires surgical intervention. A thorough understanding of the anatomy and the spectrum of conditions that can occur is needed before decisions regarding surgical management can be made. The operative approach to elbow pathology, whether performed open or arthroscopically, should be completed by orthopedists who have experience with the clinical conditions and the appropriate technical facility to provide comprehensive care. This article has reviewed the anatomy, biomechanics, and spectrum of conditions that affect throwing athletes' elbows as well as the potential complications that can be associated with surgical management.

Phthalimide-containing heptane-bisammonium-type compounds retard the dissociation of the antagonist [3H]-N-methylscopolamine ([3H]NMS) from muscarinic M2-receptor allosterically with high potency. To study the contribution of the lateral substituents to this effect, a series of derivatives was synthesized in which the phthalimide moiety was truncated. The potency of the compounds to delay [3H]NMS dissociation was measured in porcine heart homogenates (50 mM Tris-HCl, 3 mM MgHPO4, pH 7.3, 37 degrees C). Potency declined with diminuition of the lateral substituents, e.g. loss of the aromatic ring of the phthalimide resulted in a 400fold reduction in potency. In the hexahydrophthalimide derivatives, the cis-stereoisomer was about fivefold more potent than the trans-isomer. In conclusion, almost flat hydrophobic lateral moieties appear to be pivotal for high allosteric potency, suggesting a hydrophobic interaction of these parts of the molecule with the [3H]NMS occupied receptor protein.

Several bispyridinium compounds have been shown to be potent allosteric modulators of ligand binding to muscarinic M2-receptors. ,,Uno compounds" are benzyl derivatives of the bispyridinium "TMB4" (trimethylene-bis-[4-hydroxy-iminomethyl-pyridinium]). To gain more insight into structure activity relationships, eleven derivatives with varying structure of the oxime-linked aromatic substituent were tested for their ability to inhibit the equilibrium-binding of [3H]N-methylscopolamine ([3H]NMS) in guinea pig cardiac membranes and to retard [3H]NMS-dissociation allosterically. At a concentration of 3 microM, all compounds reduced [3H]NMS-binding to about 40 % of the control level, indicating a similar potency to inhibit the association of [3H]NMS. Allosteric retardation of [3H]NMS-dissociation required higher concentrations. Comparing the effects of the compounds at 30 and 300 microM, respectively, revealed considerable differences in potency. Therefore, the concentration-dependency of the delay of [3H]NMS-dissociation was determined for selected compounds. The results indicate that introduction of a benzyl-moiety into TMB4 leads to a 20-fold increase in allosteric potency. A further increment by a factor of 10 is obtained with the 2,6-dichlorobenzyl-substitution and with the naphthyl-derivative. The other compounds were less potent. An inverse correlation was found between the rotational freedom of the aromatic substituent and the allosteric potency. In conclusion, the aromatic moiety of non-symmetric bispyridinium-type modulators does not seem to be part of the pharmacophore involved in the inhibitory effect on the association of [3H]NMS. In contrast, a rigid aromatic lateral moiety appears to be essential for the interaction with the recognition site mediating the allosteric delay of [3H]NMS dissociation from muscarinic M2-receptors.