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Objective: To quantify the variation, triggers and impact on quality of life of symptom flares in women with chronic pelvic pain (CPP)., Design: Cross-sectional questionnaire within the Translational Research in Pelvic Pain clinical cohort study., Setting: Women with CPP, with subgroups of women with endometriosis (EAP), interstitial cystitis/bladder pain syndrome (BPS), comorbid endometriosis and interstitial cystitis/bladder pain syndrome (EABP), and those with pelvic pain without endometriosis or interstitial cystitis/bladder pain syndrome (PP)., Population or Sample: A total of 100 participants., Methods: Descriptive and comparative analysis from flares questionnaire., Main Outcome Measures: The prevalence, characteristics and triggers of short, medium and long symptom flares in CPP., Results: We received 100 responses of 104 questionnaires sent. Seventy-six per cent of women with CPP have ever experienced symptom flares of at least one length (short, medium and/or long). Flares are associated with painful and non-painful symptoms. There is large variation for the frequency, duration, symptoms and triggers for flares. Over 60% of participants reported flares as stopping them from doing things they would usually do, >80% reported thinking about symptoms of flares and >80% reported flares being bothersome., Conclusions: Flares are prevalent and clinically very important in CPP. More research is needed to elucidate the mechanisms and characteristics underlying flares. Clinical practice should include an enquiry into flares with the aim of finding strategies to lessen their burden., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

P2X4 receptors are ATP-gated cation channels that were proposed as novel drug targets due to their role in inflammation and neuropathic pain. Only few potent and selective P2X4 receptor antagonists have been described to date. Labeled tool compounds suitable for P2X4 receptor binding studies are lacking. Here, we present a novel allosteric P2X4 receptor antagonist possessing high potency in the low nanomolar range. We describe its tritium-labeling resulting in the P2X4-selective radiotracer [ 3 H]PSB-OR-2020 with high specific activity (45 Ci/mmol; 1.67 TBq/mmol). A radioligand binding assay was developed using human embryonic kidney (HEK293) cell membranes recombinantly expressing the human P2X4 receptor. Competition binding studies with structurally diverse P2X4 receptor antagonists revealed different allosteric binding sites indicating that the new class of P2X4 receptor antagonists, to which PSB-OR-2020 belongs, interacts with an unprecedented allosteric site. [ 3 H]PSB-OR-2020 may become a useful tool for research on P2X4 receptors and for promoting drug development., Competing Interests: Declarations Ethical approval Not applicable. Competing interests The authors filed a patent on the new class of P2X4 receptor antagonists including the radioligand described in this study., (© 2024. The Author(s).)

Dyspareunia, or pain during sex, is a common and often-debilitating symptom in individuals with endometriosis and/or interstitial cystitis/bladder pain syndrome (IC/BPS). Despite its significant impact on quality of life, it is frequently overlooked in research. This review evaluates how dyspareunia has been addressed in preclinical investigations of these conditions. A systematic search was conducted using EMBASE from 1998 to 2021, identifying original in vivo preclinical studies using female rodents to model (1) endometriosis and (2) IC/BPS. The search aimed to identify studies that assessed dyspareunia. Study quality and risk of bias were evaluated using a modified CAMARADES checklist. Our analysis found 1,286 studies modelling endometriosis and 674 for IC/BPS, but only 18 and 1, respectively, measured dyspareunia. The most common method involved vaginal distention in rats, assessed by either behavioural escape responses or visceromotor reflexes of abdominal muscles. Despite the high prevalence of dyspareunia in these conditions, it is rarely measured in preclinical studies. We identify a significant gap in the literature and offer succinct recommendations for future translational research to address this important symptom.

Background: Liver fibrosis has been recognized as a long-term morbidity associated with Fontan circulation (Fontan-associated liver disease, FALD). The pathophysiology of FALD is not completely understood and abnormal flow dynamics may be associated with this condition. Liver hemodynamics can be quantitatively evaluated with four-dimensional phase-contrast flow magnetic resonance imaging (4D PC flow MRI). The study aimed to evaluate suitability of liver 4D PC flow MRI in Fontan patients and relate flow measurements to normal values and FALD severity., Patients and Methods: Twenty-two Fontan patients were examined by 4D PC flow MRI at 1.5 Tesla to assess mesenteric, portal, splenic, and hepatic venous blood flow. Severity of FALD was graded based on routine screening, including abdominal ultrasound and laboratory tests., Results: Median age was 18.5 (interquartile range, IQR 15.5-20.2) years. FALD was graded as "none or mild" in 16 and as "moderate to severe" in six cases. Ten patients presented at least one feature of portal hypertension (ascites, splenomegaly, or thrombocytopenia). For the entire cohort, blood flow in the superior mesenteric, splenic, and portal vein was lower than reported in the literature. No significant differences were observed in relation to FALD severity. Features of portal hypertension were associated with a higher splenic vein blood flow (0.34 ± 0.17 vs. 0.20 ± 0.07 l/min, p = 0.046). Splenic vein blood flow was negatively correlated to platelet count (r = -0.590, p = 0.005)., Conclusions: 4D PC flow MRI appears suitable to assess liver hemodynamics in Fontan patients and integration into clinical follow-up might help to improve our understanding of FALD., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Higher eukaryotes' life is impossible without copper redox activity and, literally, every breath we take biochemically demonstrates this. However, this dependence comes at a considerable price to ensure target-oriented copper action. Thereto its uptake, distribution but also excretion are executed by specialized proteins with high affinity for the transition metal. Consequently, malfunction of copper enzymes/transporters, as is the case in hereditary Wilson disease that affects the intracellular copper transporter ATP7B, comes with serious cellular damage. One hallmark of this disease is the progressive copper accumulation, primarily in liver but also brain that becomes deadly if left untreated. Such excess copper toxicity may also result from accidental ingestion or attempted suicide. Recent research has shed new light into the cell-toxic mechanisms and primarily affected intracellular targets and processes of such excess copper that may even be exploited with respect to cancer therapy. Moreover, new therapies are currently under development to fight against deadly toxic copper., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Aδ-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., neuropathic pain, and chronic cough. Aiming to develop novel, selective P2X3R antagonists, tetrazolopyrimidine-based hit compound 9 was optimized through structure-activity relationship studies by modifying the tetrazole core as well as side chain substituents. The optimized antagonist 26a , featuring a cyclopropane-substituted triazolopyrimidine core, displayed potent P2X3R-antagonistic activity (IC 50 = 54.9 nM), 20-fold selectivity versus the heteromeric P2X2/3R, and high selectivity versus other P2XR subtypes. Noncompetitive P2X3R blockade was experimentally confirmed by calcium influx assays. Cryo-electron microscopy revealed that 26a stabilizes the P2X3R in its desensitized state, acting as a molecular barrier to prevent ions from accessing the central pore. In vivo studies in a rat neuropathic pain model (spinal nerve ligation) showed dose-dependent antiallodynic effects of 26a , thus presenting a novel, promising lead structure.

From organs to subcellular organelles, trace element (TE) homeostasis is fundamental for many physiological processes. While often overlooked in early stages, manifested TE disbalance can have severe health consequences, particularly in the context of aging or pathological conditions. Monitoring TE concentrations at the mitochondrial level could identify organelle-specific imbalances, contributing to targeted diagnostics and a healthier aging process. However, mitochondria isolation from frozen tissue is challenging, as it poses the risk of TE losses from the organelles due to cryodamage, but would significantly ease routine laboratory work. To address this, a novel method to isolate an enriched mitochondria fraction (EMF) from frozen tissue was adapted from already established protocols. Validation of manganese (Mn), iron (Fe), and copper (Cu) quantification via inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) showed sufficiently low quantification limits for EMF TE analysis. Successful mitochondrial enrichment from frozen liver samples was confirmed via immunoblots and transmission electron microscopy (TEM) revealed sufficient structural integrity of the EMFs. No significant differences in EMF TEs between frozen and fresh tissue were evident for Mn and Cu and only slight decreases in EMF Fe. Consequently, EMF TEs were highly comparable for isolates from both tissue states. In application, this method effectively detected dietary differences in EMF Fe of a murine feeding study and identified the disease status in a Wilson disease rat model based on drastically increased EMF Cu. In summary, the present method is suitable for future applications, facilitating sample storage and high-throughput analyses of mitochondrial TEs., (© 2024. The Author(s).)

The cyclodepsipeptide FR900359 (FR) and its analogs are able to selectively inhibit the class of G q proteins by blocking GDP/GTP exchange. The inhibitor binding site of G q has been characterized by X-ray crystallography, and various binding and functional studies have determined binding kinetics and mode of inhibition. Here we investigate isotope-labeled FR bound to the membrane-anchored G protein heterotrimer by solid-state nuclear magnetic resonance (ssNMR) and in solution by liquid-state NMR. The resulting data allowed us to identify regions of the inhibitor which show especially pronounced effects upon binding and revealed a generally rigid binding mode in the cis conformation under native-like conditions. The inclusion of the membrane environment allowed us to show a deep penetration of FR into the lipid bilayer illustrating a possible access mode of FR into the cell. Dynamic nuclear polarization (DNP)-enhanced ssNMR was used to observe the structural response of specific segments of the Gα subunit to inhibitor binding. This revealed rigidification of the switch I binding site and an allosteric response in the α5 helix as well as suppression of structural changes induced by nucleotide exchange due to inhibition by FR. Our NMR studies of the FR-G protein complex conducted directly within a native membrane environment provide important insights into the inhibitors access via the lipid membrane, binding mode, and structural allosteric effects., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: Patients with RA treated with Janus kinase inhibitors (JAKis) are at increased risk of herpes zoster (HZ). The objective of this study was to investigate the serological immunogenicity and safety of the HZ subunit (HZ/su) vaccine in RA patients treated with JAKi, for which little is known., Methods: RA patients treated with JAKi (n = 82) at the Department of Rheumatology, Skåne University Hospital, Lund and Malmö, Sweden, and healthy controls (n = 51) received two doses of the HZ/su vaccine (Shingrix). Vaccine-specific antibody responses were analysed using indirect ELISA. Post-vaccination antibody levels were compared between patients and controls using analysis of covariance. Potential predictors for vaccine response were investigated using a multivariable linear regression analysis. Self-reported adverse events (AEs) and changes in RA disease activity were analysed., Results: Following vaccination, vaccine-specific antibody levels increased significantly in both patients and controls (P < 0.0001). A total of 80.5% of patients and 98.0% of controls achieved a ≥4-fold increase in antibody levels. Post-vaccination antibody levels were lower in patients than controls [ratio 0.44 (95% CI 0.31, 0.63)] and lower in patients receiving JAKi + methotrexate than JAKi monotherapy [ratio 0.43 (95% CI 0.24, 0.79)]. AEs, mostly mild/moderate, were common. One patient developed HZ and six patients (6.5%) had increased RA disease activity following vaccination., Conclusion: The HZ/su vaccine was serologically immunogenic in most RA patients treated with JAKi. Moreover, the vaccine had an acceptable safety profile. These results support recommendations for use of the HZ/su vaccine in this vulnerable population., Trial Registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT03886038., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The immobilization of gold nanoparticle (AuNP) linear surface assemblies on polycarbonate (PC) melt surface via molding is investigated. The order of the particle assemblies is preserved during the molding process. The assemblies on PC exhibit plasmonic coupling features and dichroic properties. The structure of the assemblies is quantified based on Scanning Electron Microscopy (SEM) and image analysis data using an orientational order parameter. The transfer process from mold to melt shows high structural fidelity. The order parameter of around 0.98 reflects the orientation of the lines and remains unaffected, independent of the injection direction of the melt relative to the particle lines. This is discussed in the frame of fountain flow during injection molding. The particles were permanently fixed and withstood the injection molding process, detachment of the substrate, and extraction in boiling ethanol. The plasmonic particles coupled strongly within the dense nanoparticle lines to produce anisotropic optical properties, as quantified by dichroic ratios of 0.28 and 0.52 using ultraviolet-visible-near-infrared (UV-Vis-NIR) spectroscopy. AuNP line assemblies on a polymer surface may be a basis for plasmonic devices like surface-enhanced Raman scattering (SERS) sensors or a precursor for nanowires. Their embedding via injection molding constitutes an important link between particle-self-assembly approaches for optically functional surfaces and polymer processing techniques.

Declarative memory retrieval is thought to involve reinstatement of neuronal activity patterns elicited and encoded during a prior learning episode. Furthermore, it is suggested that two mechanisms operate during reinstatement, dependent on task demands: individual memory items can be reactivated simultaneously as a clustered occurrence or, alternatively, replayed sequentially as temporally separate instances. In the current study, participants learned associations between images that were embedded in a directed graph network and retained this information over a brief 8 min consolidation period. During a subsequent cued recall session, participants retrieved the learned information while undergoing magnetoencephalographic recording. Using a trained stimulus decoder, we found evidence for clustered reactivation of learned material. Reactivation strength of individual items during clustered reactivation decreased as a function of increasing graph distance, an ordering present solely for successful retrieval but not for retrieval failure. In line with previous research, we found evidence that sequential replay was dependent on retrieval performance and was most evident in low performers. The results provide evidence for distinct performance-dependent retrieval mechanisms, with graded clustered reactivation emerging as a plausible mechanism to search within abstract cognitive maps., Competing Interests: SK, JN, MG, ÇG, AM, PK, RD, SG, GF No competing interests declared, (© 2023, Kern et al.)

The conduct of clinical trials in paediatrics is essential to improve drug therapy in children. In Europe, paediatric clinical trials have been supported by the European Paediatric Regulation since 2007, but there is still a great need for high-quality clinical trials. The personnel and time required to conduct clinical trials in accordance with EU Regulations 536/2014 and 745/2017 is considerably higher compared to other studies, such as observational studies. It is important that this additional workload for the trial centre is fully compensated, also taking into account EU state aid rules. In paediatric trials, it is necessary to take into account the special requirements of paediatric and adolescent medicine when calculating the additional costs. Within the framework of the pan-European paediatric study network c4c/GermanNetPaeT, a working group dealt with specific aspects of cost calculation in order to support paediatric study centres in internal cost calculation as well as in the subsequent preparation of financing requirements for industrial sponsors or public funders. In several workshops the working group developed a cost calculation template with the content derived from the "Joint recommendations for a total services account as a factor in simplifying contracts" of the Deutsche Hochschulmedizin (DHM, German University Medicine), the Netzwerk der Koordinierungszentren für Klinische Studien (KKS Network, Network of Coordinating Centres for Clinical Trials) and the Verband Forschender Arzneimittelhersteller (vfa, German Association of Research-Based Pharmaceutical Companies). By estimating the specific time required for measures and investigations as part of a sample study, the background to the increased time required was discussed and a list with aspects to be considered for cost calculation was compiled together with the study centres. The paediatrics-specific aspects mentioned in detail are intended to increase understanding of the particular problem of higher costs for clinical trials involving children and adolescents and the need for correspondingly appropriate remuneration. This transparent and comprehensible presentation of the higher financial requirements for both the study centres and the financial supporters is intended to promote the high-quality conduct of clinical trials in paediatric study centres in the long term., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024 Ahne et al.)

Rewards paid out for successful retrieval motivate the formation of long-term memory. However, it has been argued that the Motivated Learning Task does not measure reward effects on memory strength but decision-making during retrieval. We report three large-scale online experiments in healthy participants (N = 200, N = 205, N = 187) that inform this debate. In experiment 1, we found that explicit stimulus-reward associations formed during encoding influence response strategies at retrieval. In experiment 2, reward affected memory strength and decision-making strategies. In experiment 3, reward affected decision-making strategies only. These data support a theoretical framework that assumes that promised rewards not only increase memory strength, but additionally lead to the formation of stimulus-reward associations that influence decisions at retrieval., (© 2024. The Author(s).)

Background: Integrated care, in particular the 'Blended Collaborative Care (BCC)' strategy, may have the potential to improve health-related quality of life (HRQoL) in multimorbid patients with heart failure (HF) and psychosocial burden at no or low additional cost. The ESCAPE trial is a randomised controlled trial for the evaluation of a BCC approach in five European countries. For the economic evaluation of alongside this trial, the four main objectives were: (i) to document the costs of delivering the intervention, (ii) to assess the running costs across study sites, (iii) to evaluate short-term cost-effectiveness and cost-utility compared to providers' usual care, and (iv) to examine the budgetary implications., Methods: The trial-based economic analyses will include cross-country cost-effectiveness and cost-utility assessments from a payer perspective. The cost-utility analysis will calculate quality-adjusted life years (QALYs) using the EQ-5D-5L and national value sets. Cost-effectiveness will include the cost per hospital admission avoided and the cost per depression-free days (DFD). Resource use will be measured from different sources, including electronic medical health records, standardised questionnaires, patient receipts and a care manager survey. Uncertainty will be addressed using bootstrapping., Discussion: The various methods and approaches used for data acquisition should provide insights into the potential benefits and cost-effectiveness of a BCC intervention. Providing the economic evaluation of ESCAPE will contribute to a country-based structural and organisational planning of BCC (e.g., the number of patients that may benefit, how many care managers are needed). Improved care is expected to enhance health-related quality of life at little or no extra cost., Trial Registration: The study follows CHEERS2022 and is registered at the German Clinical Trials Register (DRKS00025120)., (© 2024. The Author(s).)

Background: Inpatient beta-lactam allergy labels may increase the unnecessary use of aztreonam and non-beta-lactam antibiotics, which can then lead to more adverse events and increased health care costs, OBJECTIVE: To assess the impact of a novel 2-step process (medication history review followed by risk stratification) on rates of beta-lactam delabeling, aztreonam use, and desensitizations on pediatric, adult, and obstetrics inpatients at a tertiary academic center., Methods: We prospectively collected data on 700 patients who received inpatient consultation from the Beta-Lactam Allergy Evaluation Service between August 2021 and July 2022. Patients were delabeled either by medication review alone, drug challenge alone if with a low-risk history, or penicillin skin test followed by drug challenge if with a high-risk history. Generalized linear regression modeling was used to compare aztreonam days of therapy in the intervention year with the 2 prior years. Drug desensitizations were assessed by electronic chart review., Results: Most of the patients (n = 656 of 700, 94%) had more than or equal to 1 beta-lactam allergy label removed, clarified, or both; 77.9% of these patients (n = 511 of 656) had 587 beta-lactam allergy labels removed. Nearly one-third (n = 149, 27.6%) had 162 allergy labels removed solely by medication history review. All 114 penicillin skin tests performed had negative results, and 98% (8 of 381) of the patients who underwent any drug challenge passed. Only 5.7% of the delabeled patients were relabeled. There was a 27% reduction in aztreonam use (P = .007). Beta-lactam desensitizations were reduced by 80%., Conclusion: A full-time inpatient beta-lactam allergy service using medication history review and risk stratification can safely and effectively remove inpatient beta-lactam allergy labels, reduce aztreonam use, and decrease beta-lactam desensitizations., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

This paper uses a very effective way for surface modification of thermoplastic polymers during moulding. It is based on a grafting reaction between a thin layer of a functional polymer, deposited on a substrate in advance, and a polymer melt. In this paper, a glycol-modified polyethylene terephthalate (PETG) that was brought in contact with a polyethyleneimine layer during fused filament fabrication is investigated. The focus of this paper is the investigation of the reaction product. Grafting was realised by the formation of stable amide bonds by amidation of ester groups in the main chain of a PETG. XPS investigations revealed that the conversion of amino groups was very high, the distribution was even, and the quantity of amino groups per polyester surface area was still very high. The surface properties of the produced polyester part were mainly characterised by polyethyleneimine. The grafting was able to resist several cycles of extraction in alkaline solutions. The stability was only limited by saponification of the polyester. The degree of surface modification was dependent on the molar mass of polyethyleneimine. This could be rationalised, because grafting only occurred with the one polyethyleneimine molecule that is in close vicinity to the polyester surface when both components come in contact. Fused deposition modelling was chosen as the model process with control over each processing step. However, any other moulding process may be applied, particularly injection moulding for mass production.

Bats subject to high rates of fatalities at wind-energy facilities are of high conservation concern due to the long-term, cumulative effects they have, but the impact on broader bat populations can be difficult to assess. One reason is the poor understanding of the geographic source of individual fatalities and whether they constitute migrants or more local individuals. Here, we used stable hydrogen isotopes, trace elements and species distribution models to determine the most likely summer geographic origins of three different bat species ( Lasiurus borealis , L. cinereus , and Lasionycteris noctivagans ) killed at wind-energy facilities in Ohio and Maryland in the eastern United States. In Ohio, 41.6%, 21.3%, 2.2% of all individuals of L. borealis , L. cinereus , and L. noctivagans , respectively, had evidence of movement. In contrast, in Maryland 77.3%, 37.1%, and 27.3% of these same species were classified as migrants. Our results suggest bats killed at a given wind facility are likely derived from migratory as well as resident populations. Finally, there is variation in the proportion of migrants killed between seasons for some species and evidence of philopatry to summer roosts. Overall, these results indicate that the impact of wind-energy facilities on bat populations occurs across a large geographic extent, with the proportion of migrants impacted likely to vary across species and sites. Similar studies should be conducted across a broader geographic scale to understand the impacts on bat populations from wind-energy facilities., Competing Interests: David M. Nelson is an Academic Editor for PeerJ. C.J. Campbell is employed by Bat Conservation International., (©2024 Wieringa et al.)

Competing Interests: Declaration of competing interest There are no conflicts of interest to disclose.

Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry; however, the use of such compounds as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hampered by their rapid in vivo metabolism. Although a successful strategy to address the instability of the monophosphate moiety in oligonucleotide therapeutics has been accomplished by their isosteric replacement with phosphorothioates, no practical methods exist to rapidly and controllably access stereopure di- and triphosphate thioisosteres of both natural and unnatural nucleosides. Here we show how a modular, reagent-based platform can enable the stereocontrolled and scalable synthesis of a library of such molecules. This operationally simple approach provides access to pure stereoisomers of nucleoside α-thiodiphosphates and α-thiotriphosphates, as well as symmetrical or unsymmetrical dinucleoside thiodiphosphates and thiotriphosphates (including RNA cap reagents). We demonstrate that ligand-receptor interactions can be dramatically influenced by P-stereochemistry, showing that such thioisosteric replacements can have profound effects on the potency and stability of lead candidates., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Musculoskeletal diseases affect 1.71 billion people worldwide, impose a high biopsychosocial burden on patients, and are associated with high economic costs. The use of digital health interventions is a promising cost-saving approach for the treatment of musculoskeletal diseases. As physical exercise is the best clinical practice in the treatment of musculoskeletal diseases, digital health interventions that provide physical exercises could have a highly positive impact on musculoskeletal diseases, but evidence is lacking., Objective: This systematic review aims to evaluate the impact of digital physical health exercises on patients with musculoskeletal diseases concerning the localization of the musculoskeletal disease, patient-reported outcomes, and medical treatment types., Methods: We performed systematic literature research using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search was conducted using the PubMed, BISp, Cochrane Library, and Web of Science databases. The Scottish Intercollegiate Guidelines Network checklist was used to assess the quality of the included original studies. To determine the evidence and direction of the impact of digital physical health exercises, a best-evidence synthesis was conducted, whereby only studies with at least acceptable methodological quality were included for validity purposes., Results: A total of 8988 studies were screened, of which 30 (0.33%) randomized controlled trials met the inclusion criteria. Of these, 16 studies (53%) were of acceptable or high quality; they included 1840 patients (1008/1643, 61.35% female; 3 studies including 197 patients did not report gender distribution) with various musculoskeletal diseases. A total of 3 different intervention types (app-based interventions, internet-based exercises, and telerehabilitation) were used to deliver digital physical health exercises. Strong evidence was found for the positive impact of digital physical health exercises on musculoskeletal diseases located in the back. Moderate evidence was found for diseases located in the shoulder and hip, whereas evidence for the entire body was limited. Conflicting evidence was found for diseases located in the knee and hand. For patient-reported outcomes, strong evidence was found for impairment and quality of life. Conflicting evidence was found for pain and function. Regarding the medical treatment type, conflicting evidence was found for operative and conservative therapies., Conclusions: Strong to moderate evidence was found for a positive impact on musculoskeletal diseases located in the back, shoulder, and hip and on the patient-reported outcomes of impairment and quality of life. Thus, digital physical health exercises could have a positive effect on a variety of symptoms of musculoskeletal diseases., (©Johanna Nagel, Florian Wegener, Casper Grim, Matthias Wilhelm Hoppe. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 23.01.2024.)

Abstract: Chronic pelvic pain (CPP), despite its high prevalence, is still relatively poorly understood mechanistically. This study, as part of the Translational Research in Pelvic Pain (TRiPP) project, has used a full quantitative sensory testing (QST) paradigm to profile n = 85 women with and without CPP (endometriosis or bladder pain specifically). We used the foot as a control site and abdomen as the test site. Across 5 diagnostically determined subgroups, we found features which are common across different aetiologies, eg, gain of function in pressure pain threshold (PPT) when assessing responses from the lower abdomen or pelvis (referred pain site). However, disease-specific phenotypes were also identified, eg, greater mechanical allodynia in endometriosis, despite there being large heterogeneities within diagnostic groups. The most common QST sensory phenotype was mechanical hyperalgesia (>50% across all the groups). A "healthy' sensory phenotype was seen in <7% of CPP participants. Specific QST measures correlated with sensory symptoms assessed by the painDETECT questionnaire (pressure-evoked pain [painDETECT] and PPT [QST] [ r = 0.47, P < 0.001]; mechanical hyperalgesia (painDETECT) and mechanical pain sensitivity [MPS from QST] [ r = 0.38, P = 0.009]). The data suggest that participants with CPP are sensitive to both deep tissue and cutaneous inputs, suggesting that central mechanisms may be important in this cohort. We also see phenotypes such as thermal hyperalgesia, which may be the result of peripheral mechanisms, such as irritable nociceptors. This highlights the importance of stratifying patients into clinically meaningful phenotypes, which may have implications for the development of better therapeutic strategies for CPP., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Forests cover about one-third of Europe's surface and their growth is essential for climate protection through carbon sequestration and many other economic, environmental, and sociocultural ecosystem services. However, reports on how climate change affects forest growth are contradictory, even for same regions. We used 415 unique long-term experiments including 642 plots across Europe covering seven tree species and surveys from 1878 to 2016, and showed that on average forest growth strongly accelerated since the earliest surveys. Based on a subset of 189 plots in Scots pine (the most widespread tree species in Europe) and high-resolution climate data, we identified clear large-regional differences; growth is strongly increasing in Northern Europe and decreasing in the Southwest. A less pronounced increase, which is probably not mainly driven by climate, prevails on large areas of Western, Central and Eastern Europe. The identified regional growth trends suggest adaptive management on regional level for achieving climate-smart forests., (© 2023. Springer Nature Limited.)

Background & Aims: Excess copper causes hepatocyte death in hereditary Wilson's disease (WD). Current WD treatments by copper-binding chelators may gradually reduce copper overload; they fail, however, to bring hepatic copper close to normal physiological levels. Consequently, lifelong daily dose regimens are required to hinder disease progression. This may result in severe issues due to nonadherence or unwanted adverse drug reactions and also due to drug switching and ultimate treatment failures. This study comparatively tested bacteria-derived copper binding agents-methanobactins (MBs)-for efficient liver copper depletion in WD rats as well as their safety and effect duration., Methods: Copper chelators were tested in vitro and in vivo in WD rats. Metabolic cage housing allowed the accurate assessment of animal copper balances and long-term experiments related to the determination of minimal treatment phases., Results: We found that copper-binding ARBM101 (previously known as MB-SB2) depletes WD rat liver copper dose dependently via fecal excretion down to normal physiological levels within 8 days, superseding the need for continuous treatment. Consequently, we developed a new treatment consisting of repetitive cycles, each of ∼1 week of ARBM101 applications, followed by months of in-between treatment pauses to ensure a healthy long-term survival in WD rats., Conclusions: ARBM101 safely and efficiently depletes excess liver copper from WD rats, thus allowing for short treatment periods as well as prolonged in-between rest periods., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Escape: Evaluation of a patient-centred biopsychosocial blended collaborative care pathway for the treatment of multimorbid elderly patients., Therapeutic Area: Healthcare interventions for the management of older patients with multiple morbidities., Aims: Multi-morbidity treatment is an increasing challenge for healthcare systems in ageing societies. This comprehensive cohort study with embedded randomized controlled trial tests an integrated biopsychosocial care model for multimorbid elderly patients., Hypothesis: A holistic, patient-centred pro-active 9-month intervention based on the blended collaborative care (BCC) approach and enhanced by information and communication technologies can improve health-related quality of life (HRQoL) and disease outcomes as compared with usual care at 9 months., Methods: Across six European countries, ESCAPE is recruiting patients with heart failure, mental distress/disorder plus ≥2 medical co-morbidities into an observational cohort study. Within the cohort study, 300 patients will be included in a randomized controlled assessor-blinded two-arm parallel group interventional clinical trial (RCT). In the intervention, trained care managers (CMs) regularly support patients and informal carers in managing their multiple health problems. Supervised by a clinical specialist team, CMs remotely support patients in implementing the treatment plan-customized to the patients' individual needs and preferences-into their daily lives and liaise with patients' healthcare providers. An eHealth platform with an integrated patient registry guides the intervention and helps to empower patients and informal carers. HRQoL measured with the EQ-5D-5L as primary endpoint, and secondary outcomes, that is, medical and patient-reported outcomes, healthcare costs, cost-effectiveness, and informal carer burden, will be assessed at 9 and ≥18 months., Conclusions: If proven effective, the ESCAPE BCC intervention can be implemented in routine care for older patients with multiple morbidities across the participating countries and beyond., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Chronic pelvic pain (CPP) is a common condition affecting up to 26.6% of women, with many suffering for several years before diagnosis and/or treatment. Its clinical presentation is varied and there are frequently comorbid conditions both within and outside the pelvis. We aim to explore whether specific subgroups of women with CPP report different clinical symptoms and differing impact of pain on their quality of life (QoL)., Methods: The study is part of the Translational Research in Pelvic Pain (TRiPP) project which is a cross-sectional observational cohort study. The study includes 769 female participants of reproductive age who completed an extensive set of questions derived from standardised WERF EPHect questionnaires. Within this population we defined a control group (reporting no pelvic pain, no bladder pain syndrome, and no endometriosis diagnosis, N  = 230) and four pain groups: endometriosis-associated pain (EAP, N  = 237), interstitial cystitis/bladder pain syndrome (BPS, N  = 72), comorbid endometriosis-associated pain and BPS (EABP, N  = 120), and pelvic pain only (PP, N  = 127)., Results: Clinical profiles of women with CPP (13-50 years old) show variability of clinical symptoms. The EAP and EABP groups scored higher than the PP group ( p  < 0.001) on the pain intensity scales for non-cyclical pelvic pain and higher than both the BPS and PP groups ( p  < 0.001) on the dysmenorrhoea scale. The EABP group also had significantly higher scores for dyspareunia ( p  < 0.001), even though more than 50% of sexually active participants in each pain group reported interrupting and/or avoiding sexual intercourse due to pain in the last 12 months. Scores for the QoL questionnaire (SF-36) reveal that CPP patients had significantly lower QoL across all SF-36 subscales ( p  < 0.001). Significant effects were also observed between the pain groups for pain interference with their work ( p  < 0.001) and daily lives ( p  < 0.001), with the EABP suffering more compared to the EAP and PP groups ( p  < 0.001)., Discussion: Our results demonstrate the negative impact that chronic pain has on CPP patients' QoL and reveal an increased negative impact of pain on the comorbid EABP group. Furthermore, it demonstrates the importance of dyspareunia in women with CPP. Overall, our results demonstrate the need for further exploration of interventions targeting QoL more broadly and suggest that novel approaches to classifying women with CPP are needed., Competing Interests: AWH: reports grant funding from the MRC, NIHR, CSO, Wellbeing of Women, Roche Diagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust and Standard Life. His employer has received consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma and Ferring, outside the submitted work. In addition, AWH has a patent for a serum biomarker for endometriosis pending. AH: Employee of Bayer AG, Germany. EPZ: received financial support from Grunenthal and Mundipharma for research activities and advisory and lecture fees from Grünenthal, Novartis and Mundipharma. In addition, she receives scientific support from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), the German Federal Joint Committee (G-BA) and the Innovative Medicines Initiative (IMI) 2 Joint Undertaking under grant agreement No 777500. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA All money went to the institution EMP.-Z is working for RDT: Ad board for BAYER, IASP task force on chronic pain classification. CMB: Research Grants from Bayer Healthcare, MDNA Life Sciences, Roche Diagnostics, European Commission, NIH His employer has received consulancy fees from Myovant and ObsEva for work outside of this project. FC: Consultant and/or investigator for Allergan (Abbvie), Astellas, Bayer, Ipsen and Recordati. SAM: has been an advisory board member for AbbVie and Roche and receives research funding from the National Institutes of Health, the US Department of Defense, the J Willard and Alice S Marriott Foundation, and AbbVie; none are related to the presented work; the J Willard and Alice S Marriott Foundation supported enrollment of and data collection from the A2A cohort in Boston from which TRiPP data were sampled. KTZ: reports grant funding from EU Horizon 2020, NIH US, Wellbeing of Women, Bayer AG, Roche Diagnostics, Evotec-Lab282, MDNA Life Sciences, outside the submitted work. JN: Employee and shareholder of Bayer AG, Germany. KV: declares research funding from Bayer Healthcare and UKRI and honoraria for consultancy and talks and associated travel expenses from Bayer Healthcare, Grunenthal GmBH, AbbVie and Eli Lilly. The remaining 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, (© 2023 Demetriou, Krassowski, Abreu Mendes, Garbutt, Vitonis, Wilkins, Coxon, Arendt-Nielsen, Aziz, Birch, Horne, Hoffman, Hummelshoj, Lunde, Meijlink, Perro, Rahmioglu, Terry, Pogatzki-Zahn, Sieberg, Treede, Becker, Cruz, Missmer, Zondervan, Nagel and Vincent.)

Monoclonal antibodies for COVID-19 are authorized in high-risk patients aged ≥12 years, but evidence in pediatric patients is limited. In our cohort of 142 patients treated at seven pediatric hospitals between 12/1/20 and 7/31/21, 9% developed adverse events, 6% were admitted for COVID-19 within 30 days, and none received ventilatory support or died., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Endometriosis is a chronic, hormone-dependent, inflammatory disease, characterized by the presence and growth of endometrial tissue outside the uterine cavity. It is associated with moderate to severe pelvic and abdominal pain symptoms, subfertility and a marked reduction in health-related quality of life. Furthermore, relevant co-morbidities with affective disorders like depression or anxiety have been described. These conditions have a worsening effect on pain perception in patients and might explain the negative impact on quality of life observed in those suffering from endometriosis-associated pain. Whereas several studies using rodent models of endometriosis focused on biological and histopathological similarities with the human situation, the behavioral characterization of these models was never performed. This study investigated the anxiety-related behaviors in a syngeneic model of endometriosis. Using elevated plus maze and the novel environment induced feeding suppression assays we observed the presence of anxiety-related behaviors in endometriosis-induced mice. In contrast, locomotion or generalized pain did not differ between groups. These results indicate that the presence of endometriosis lesions in the abdominal cavity could, similarly to patients, induce profound psychopathological changes/impairments in mice. These readouts might provide additional tools for preclinical identification of mechanisms relevant for development of endometriosis-related symptoms., Competing Interests: PN-B, JN, and TZ were employees and shareholders of Bayer AG. AL-B was a former employee and shareholder of Bayer AG and was employed by Evotec. MH and OB were employed by Taconic Biosciences., (Copyright © 2023 Nunez-Badinez, Laux-Biehlmann, Hayward, Buiakova, Zollner and Nagel.)

Chronic pain induced by endometriosis is a maladaptive pain experienced by half of women with this disease. The lack of pharmacological treatments suitable for the long-term relief of endometriosis-associated pain, without an impact on fertility, remains an urgent unmet need. Progress has been slowed by the absence of a reproducible rodent endometriosis model that fully replicates human physiopathological characteristics, including pain symptoms. Although pain assessment in rodents is a complicated task requiring qualified researchers, the choice of the behavioral test is no less important, since selecting inappropriate tests can cause erroneous data. Pain is usually measured with reflex tests in which hypersensitivity is evaluated by applying a noxious stimulus, yet this ignores the associated emotional component that could be evaluated via non-reflex tests. We conducted a systematic review of endometriosis models used in rodents and the number of them that studied pain. The type of behavioral test used was also analyzed and classified according to reflex and non-reflex tests. Finally, we determined the most used reflex tests for the study of endometriosis-induced pain and the main non-reflex behavioral tests utilized in visceral pain that can be extrapolated to the study of endometriosis and complement traditional reflex tests.

Background: To examine rates of serious pneumococcal infections up to 10 years after vaccination with 7-valent conjugated pneumococcal vaccine (PCV7) in patients with arthritis compared to non-vaccinated arthritis patients., Methods: In total, 595 adult arthritis patients (rheumatoid arthritis; RA = 342, 80 % women and spondylarthropathy; SpA = 253, 45 % women) received one dose of PCV7. Mean age/disease duration were 62/16 and 51/14 years, respectively. For each patient, 4 matched reference subjects were identified. At vaccination, 420 patients received bDMARDs (anti-TNF = 330, tocilizumab = 15, abatacept = 18, anakinra = 1, rituximab = 56). Methotrexate was given as monotherapy (n = 86) or in combination with bDMARD (n = 220). 89 SpA patients received NSAIDs without DMARD. The Skåne Healthcare Register was searched for ICD-10 diagnostic codes for pneumococcal infections (pneumonia, lower respiratory tract infection, septicemia, meningitis, septic arthritis) between January 2000 and December 2018. Frequency of infections after vs before vaccination were calculated (relative risks). Relative risk ratio (RRR) and relative risk reduction (1-RRR) were calculated comparing patients vs non-vaccinated references. Kaplan-Meier and Cox regression were used to investigate time to first event and predictors of infections., Results: Among vaccinated RA and SpA patients, there was a significant relative risk reduction of pneumonia and all serious infections; 53% and 46%, respectively. There was no significant difference in time to first pneumonia or all serious infections after vaccination between patients and references. Higher age, RA diagnosis and concomitant prednisolone were associated with infections., Conclusion: One dose of pneumococcal conjugate vaccine may decrease risk of serious pneumococcal infection up to 10 years in patients with arthritis receiving immunomodulating treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Meliha Kapetanovic reports equipment, drugs, or supplies was provided by Wyeth Pharmaceuticals.]., (Copyright © 2022. Published by Elsevier Ltd.)

Aims: P2X receptors are ATP-gated ion channels which play a role in many pathophysiological conditions. They are considered as novel drug targets, particularly in the fields of pain, (neuro) inflammation, and cancer. Due to difficulties in developing drug-like orthosteric ligands that bind to the highly polar ATP binding site, the design of positive and negative allosteric modulators (PAMs and NAMs) is a promising strategy. The P2X4 receptor was proposed as a novel target for neuropathic and inflammatory pain (antagonists), and for the treatment of alcoholism (PAMs). So far, little is known about the allosteric binding site(s) of P2X4 receptors. The aim of this study was to identify the binding site(s) of the macrocyclic natural product ivermectin, the urea derivative BX430, and the antidepressant drug paroxetine that act as allosteric modulators of P2X4 receptors., Material and Methods: We generated chimeric receptors in which extracellular sequences of the human P2X4 receptor were exchanged for corresponding residues of the human P2X2 receptor, complemented by specific single amino acid residue mutants. Chimeric and mutated receptors were stably expressed in 1321N1 astrocytoma cells, and characterized by fluorimetric measurement of ATP-induced Ca 2+ -influx. In addition, docking studies utilizing a homology model of the human P2X4 receptor were performed., Key Findings: Our results suggest a common binding site for ivermectin and BX430 in an extracellular receptor domain, while paroxetine might bind to the cation pore., Significance: The obtained results provide a basis for the development of positive and negative allosteric P2X4 modulators with improved properties and will support future drug development efforts., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Asynchronous virtual patient care is increasingly used; however, the effectiveness of virtually delivering guideline-concordant care in conjunction with antibiotic stewardship initiatives remains uncertain. We developed a bundled stewardship intervention to improve antibiotic use in E-visits for upper respiratory tract infections (URTIs)., Methods: In this before-and-after study, adult patients who completed E-visits for "cough," "flu," or "sinus symptoms" at Michigan Medicine between January 1, 2018, and September 30, 2020, were included. Patient demographics, diagnoses, and antibiotic details were collected. The multifaceted intervention occurred over 6 months. Segmented linear regression was performed to estimate the effect of the intervention on appropriate antibiotic use for URTI diagnoses (defined as no antibiotic prescribed) and sinusitis (defined as guideline-concordant antibiotic selection and duration). Regression lines were fit to data before the bundled intervention (January 2019) and after the bundled intervention (May 2019)., Results: In total, 5,151 E-visits were included. The intervention decreased the number of visits for flu, cough, or sinus symptoms prescribed antibiotics from 43.2% to 28.9% ( P < .001). Guideline concordance of antibiotic prescriptions improved following the intervention: first-line amoxicillin-clavulanate rose from 37.9% of prescriptions to 66.1% of prescriptions ( P < .001), second-line doxycycline rose from 13.8% to 22.7% ( P < .001); and median duration of antibiotics decreased from 10 days to 5 days ( P < .001)., Conclusions: A multifaceted stewardship bundle for E-visits involving both changes in the EMR and audit and feedback improved guideline-concordant antibiotic use for URTIs. This approach can aid stewardship efforts in the ambulatory care setting with regard to telemedicine.

The 2022 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Austin, Texas at the Society of Toxicologic Pathology's 40th annual meeting during a half-day session on Sunday, June 19. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and topics covered during the symposium included induced and spontaneous neoplastic and nonneoplastic lesions in the mouse lung, spontaneous lesions in the reproductive tract of a female cynomolgus macaque, induced vascular lesions in a mouse asthma model and interesting case studies in a rhesus macaque, dog and genetically engineered mouse model.

Self-heating nanocomposites with a positive temperature coefficient (PTC) provide outstanding potential for a broad range of engineering applications in automobile, spacecraft, or smart building. Therefore, extensive studies have been carried out to understand thermo-electrical behavior. However, some controversies remain, especially on the material composition, to clarify influencing factors on the PTC performance. In this study, the thermo-electrical behaviors of injection molded carbon black (CB)/polyamide (PA) nanocomposites have been investigated. Three types of CB with well-defined specific surface area and polyamides with high and low crystallinity were selected to provide a guideline for self-heating devices including PTC-Effects. Significantly reduced specific resistances up to 2.7 Ω·cm were achieved by incorporating CB with a high specific surface area into a highly crystalline PA. Noticeable PTC-Effects of ~53% and average surface temperatures up to 147 °C have been observed due to self-heating, which confirms a promising material performance as a heating device.

Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis.

White-nose syndrome (WNS) is an emerging fungal epizootic disease that has caused large-scale mortality in several species of North American bats. The fungus that causes WNS, Pseudogymnoascus destructans (Pd), has also been detected in bat species without diagnostic signs of WNS. Although these species could play a role in WNS spread, understanding of the spatial and temporal extents of Pd occurrence on WNS-resistant species is limited. This study evaluated the presence of Pd on 272 individuals of three species of migratory tree-roosting bats: hoary (Lasiurus cinereus), eastern red (Lasiurus borealis), and silver-haired (Lasionycteris noctivagans) bats, obtained opportunistically during summer and autumn from throughout much of their ranges in North America. We also compared tissue sampling protocols (i.e., tissue swabbing, fur swabbing, and DNA extraction of excised wing tissue). We detected Pd on three eastern red bats from Illinois and Ohio, US, one silver-haired bat from West Virginia, US, and one hoary bat from New York, US, all via DNA extracted from wing tissue of carcasses. These results document the first publicly reported detections of Pd on a hoary bat and on migratory bats during the autumn migratory period, and demonstrate the potential for using carcasses salvaged at wind-energy facilities to monitor for Pd., (© Wildlife Disease Association 2022.)

Objectives: Patients undergoing coronary artery bypass graft (CABG) surgery are exposed to multiple treatment-related stressors, which can impact coping and health-related quality of life (HRQoL). The objective of this trial was to analyse the feasibility and preliminary efficacy of a multi-component intervention that combines psychological support and reduction of hospital-specific stressors on HRQoL, length of hospital and intensive care unit stay, self-efficacy, and plasma interleukin (IL)-6 and -8 levels in CABG patients., Methods: This three-arm, randomized controlled, single-centre pilot trial assessed the Intervention for CABG to Optimize Patient Experience in 88 patients undergoing elective CABG. Standard medical care (SMC, n = 29) was compared with 2 intervention groups: (i) psychological interventions to optimize treatment expectations (IA group, n = 30) and (ii) multi-component intervention (IB group, n = 29) with psychological interventions plus an additional treatment package (light therapy, noise reduction, music, and if desired, 360° images delivered via virtual reality)., Results: The implementation of psychological interventions in routine medical treatment was feasible (91.5% of participants completed all intervention sessions). Both interventions were associated with significantly shorter hospital stay compared to SMC (IA/IB 9.8/9.3 days vs SMC 12.5 days). Self-efficacy expectations at post-surgery were significantly higher compared to SMC both in the IA group (P = 0.011) and marginally in the IB group (P = 0.051). However, there were no treatment effects of the interventions on HRQoL and plasma levels of IL-6 or IL-8 after CABG., Conclusions: A perioperative multi-component intervention may lead to shorter hospital stay and higher self-efficacy after CABG. Further studies are needed to determine its impact on HRQoL and inflammation., Clinical Trial Registration Number: Ethical approval (# 21/2/18) for the study was obtained from the Research Ethics Committee of the University of Göttingen Medical Center, and the trial was registered in the German Clinical Trials Register (DRKS00015309, https://www.drks.de/drks&#95;web/setLocale&#95;EN.do)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

In collaboration with the American College of Veterinary Pathologists.

Demand for direct chemical modification of functional material on a surface is increasing in various fields. A new approach for a functionalized surface is investigated by applying a conventional laser in order to generate chemical activation by photothermal energy. Poly(ethyleneimine) (PEI), with a high density of amino groups, is chemically grafted on poly(methyl methacrylate) (PMMA) by irradiation of a CO 2 laser (10.6 μm). Laser parameters such as power, scan rate, and focal length are observed to play an important role in order to introduce effective photothermal energy for the chemical reaction between PEI and PMMA. By optimization of laser parameters, the amide compound is produced as a result of the reaction of amine from PEI and the ester of PMMA successfully. The PMMA surface modified with PEI is analyzed by XPS and TOF-SIMS to identify the functional groups. Furthermore, the surface is characterized in terms of wettability, adhesion force, and surface charge for various applications. Finally, reaction with dye and metal on the amine-terminated PMMA shows promising results in supplying a selective and reliable functional substrate.

Self-powered tactile module-based electronic skins incorporating triboelectric nanogenerator (TENG) appears to be a worthwhile alternative for smart monitoring devices in terms of sustainable energy harvesting. On top of it, ultra-stretchability and detection sensitivity are imperative to mimic human skin. We report, for the first time, a metal-free single electrode TENG-based self-powered tactile module comprising of microwells (diameters 2 μm and 200 nm, respectively) on fluoroelastomer (FKM) and laser induced graphene (LIG) electrodes by in situ simultaneous transfer printing method. Direct imprinting of both the active surface and LIG electrode on a tribonegative FKM has not been attempted before. The resulting triboelectric module exhibits impressive maximum power density of 715 mW m -2 , open circuit voltage and maximum output current of 148 V and 9.6 μA respectively for a matching load of 10 MΩ. Moreover, the TENG unit is very robust and sustained high electrical output even at 200% elongation. A dielectric-to-dielectric TENG-based tactile sensor is also constructed using FKM (negative tribolayer) and TiO 2 deposited micropatterned PDMS. Resulting tribo-sensor demonstrates remarkable motion and force sensitivity. It can also distinguish subtle human contact force that can simulate skin with high sensitivity and therefore, can be utilized for potential e-skin/bionic skin applications in health and human-machine interfaces.

Periventricular nodular heterotopia (PVNH) is an X-linked disease caused by loss-of-function variants in the filamin A ( FLNA ) gene. FLNA-PVNH is a heterogeneous disorder, and the phenotype is associated with neurological and non-neurological features including cardiovascular, gastrointestinal, pulmonary, haematological, cutaneous and skeletal manifestations. No clear definition of the FLNA-PVNH phenotype has been established, but the patients are predominantly females with seizures, cardiovascular manifestations, and normal intelligence or mild intellectual disability. Herein, we describe a PVNH patient diagnosed with a novel heterozygous missense variant in FLNA after an atypical presentation of deep vein thrombosis and thrombocytopenia. Clinical evaluation found hypermobility, cardiovascular and skin manifestations. Moreover, we conducted a literature review of 186 FLNA-PVNH patients to describe the phenotypic spectrum. In conclusion, our patient highlights the importance of thorough clinical evaluation to identify manifestations in this very heterogeneous disorder. The phenotypic review may guide clinicians in the assessment and follow-up of FLNA-PVNH patients., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Augmented aortic systolic blood pressure (SBP) and wave reflection via sympathetic-mediated vasoconstriction elevates the risk for adverse cardiovascular events in older adults. L-citrulline (L-CIT) supplementation has shown to reduce aortic SBP and pulse pressure (PP) responses to cold pressor test (CPT) induced sympathoactivation in young men. The aim of this study was to elucidate the efficacy of L-CIT supplementation to attenuate aortic hemodynamic responses to CPT in older adults., Methods and Results: Sixteen older adults were randomly assigned to placebo or L-CIT (6 g/day) for 14-days in a crossover, double-blind, placebo-controlled design. Brachial SBP and aortic SBP, PP, augmented pressure (AP), augmentation index standardized at 75 bpm (AIx@75), and pressure of the forward (Pf) and reflected (Pb) waves were evaluated at rest and during CPT pre- and post-intervention. Although no hemodynamic changes at rest, brachial SBP (Δ-12 ± 18 vs. Δ4 ± 14 mmHg; P = 0.008) and aortic SBP (Δ-10 ± 14 vs. Δ4 ± 12 mmHg; P = 0.005), PP (Δ-10 ± 12 vs. Δ4 ± 11 mmHg; P = 0.002), AP (Δ-4 ± 4 vs. Δ2 ± 7 mmHg; P = 0.004), AIx@75 (Δ-3.2 ± 7.2 vs. Δ2.2 ± 6.9%; P = 0.038), Pf (Δ-6 ± 10 vs. Δ3 ± 9 mmHg; P = 0.019), and Pb (Δ-4 ± 6 vs. Δ2 ± 6 mmHg; P = 0.008) responses to the CPT were significantly attenuated following L-CIT supplementation vs. placebo., Conclusions: L-CIT supplementation attenuated aortic pulsatile pressure and pressure wave reflection responses to CPT in older adults, providing possible cardioprotection during cold-induced sympathoactivation in older adults., (Published by Elsevier Inc.)

Paspalum dilatatum (common name dallisgrass), a productive C4 grass native to South America, is an important pasture grass found throughout the temperate warm regions of the world. It is characterized by its tolerance to frost and water stress and a higher forage quality than other C4 forage grasses. P. dilatatum includes tetraploid (2 n = 40), sexual, and pentaploid (2 n = 50) apomictic forms, but is predominantly cultivated in an apomictic monoculture, which implies a high risk that biotic and abiotic stresses could seriously affect the grass productivity. The obtention of reproducible and efficient protocols of regeneration and transformation are valuable tools to obtain genetic modified grasses with improved agronomics traits. In this review, we present the current regeneration and transformation methods of both apomictic and sexual cultivars of P. dilatatum , discuss their strengths and limitations, and focus on the perspectives of genetic modification for producing new generation of forages. The advances in this area of research lead us to consider Paspalum dilatatum as a model species for the molecular improvement of C4 perennial forage species., Competing Interests: LV was employed by company BASF Argentina SA. The remaining 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. The handling editor declared a shared affiliation with one of the authors GS at the time of review., (Copyright © 2022 Schrauf, Voda, Zelada, García, Giordano, Roa, Guitian, Rebori, Ghio, Couso, Castro, Musacchio, Rush, Nagel, Wang, Cogan and Spangenberg.)

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with impaired health-related quality of life (HRQoL), high symptom severity, and poor cardiovascular outcomes. Both clinical and psychological factors may contribute to symptom severity and HRQoL in AF., Methods: Using data from the observational Atrial Fibrillation Rhine-Neckar Region (ARENA) trial, we identified medical and psychosocial factors associated with AF-related symptom severity using European Heart Rhythm Association symptom classification and HRQoL using 5-level EuroQoL- 5D., Results: In 1218 AF patients (mean age 71.1 ± 10.5 years, 34.5% female), female sex (OR 3.7, p < 0.001), preexisting coronary artery disease (CAD) (OR 1.7, p = 0.020), a history of cardioversion (OR 1.4, p = 0.041), cardiac anxiety (OR 1.2; p < 0.001), stress from noise (OR 1.4, p = 0.005), work-related stress (OR 1.3, p = 0.026), and sleep disturbance (OR 1.2, p = 0.016) were associated with higher AF-related symptom severity. CAD (β = -0.23, p = 0.001), diabetes mellitus (β = -0.25, p < 0.001), generalized anxiety (β = -0.30, p < 0.001), cardiac anxiety (β = -0.16, p < 0.001), financial stress (β = -0.11, p < 0.001), and sleep disturbance (β = 0.11, p < 0.001) were associated with impaired HRQoL., Conclusions: Psychological characteristics, preexisting CAD, and diabetes may play an important role in the identification of individuals at highest risk for impaired HRQoL and high symptom severity in patients with AF.

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis ( HCA ). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing.

Background: There is minimal data evaluating the safety of antibiotic de-escalation in patients with acute myeloid leukemia (AML) with fever and ongoing neutropenia. Therefore, this study evaluated antibiotic prescribing, infection-related outcomes, and patient outcomes of an antibiotic de-escalation initiative., Patients and Methods: This pre-post quasiexperimental study included adult patients with AML hospitalized with febrile neutropenia. An antibiotic de-escalation guideline was implemented in January 2017, which promoted de-escalation or discontinuation of intravenous antipseudomonal β-lactams. The primary outcome assessment was the incidence of bacterial infection in a historical control group before guideline implementation compared with an intervention group after guideline implementation., Results: A total of 93 patients were included. Antibiotic de-escalation occurred more frequently in the intervention group (71.7% vs 7.5%; P<.001), which resulted in fewer days of therapy for intravenous antipseudomonal β-lactams (14 vs 25 days; P<.001). Thirty-day all-cause mortality and length of hospitalization were not different between groups. However, the intervention group had significantly fewer episodes of Clostridioides difficile colitis (5.7% vs 27.5%; P=.007)., Conclusions: Implementation of an antibiotic de-escalation guideline resulted in decreased use of intravenous antipseudomonal β-lactams and fewer episodes of C difficile colitis, without adversely impacting patient outcomes. Additional studies are needed, preferably in the form of randomized controlled trials, to confirm these results.

Because knowledge entails true belief, it can be hard to explain why a given action is naturally seen as driven by one of these states as opposed to the other. A simpler and more radical characterization of knowledge helps to solve this problem while also shedding some light on what is special about social learning.

We present a protocol for the design, fabrication and characterisation of laser-induced ultrasound transmitters with a specific, user-defined frequency response for the purpose of ultrasound tomography of large-volume biomedical samples. Using an analytic solution to the photoacoustic equation and measurements of the optical and acoustic properties of the materials used in the transmitters, we arrive at a required mixture of carbon black and polydimethylsiloxane to achieve the desired frequency response. After an in-depth explanation of the fabrication and characterisation approaches we show the performance of the fabricated transmitter, which has a centre frequency of 0.9 MHz, 200% bandwidth and 45.8 ∘ opening angle, multi-kPa pressures over a large depth range in water., Competing Interests: 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., (© 2021 The Authors.)

G proteins represent intracellular switches that transduce signals relayed from G protein-coupled receptors. The structurally related macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM) are potent, selective inhibitors of the Gα q protein family. We recently discovered that radiolabeled FR and YM display strongly divergent residence times, which translates into significantly longer antiasthmatic effects of FR. The present study is aimed at investigating the molecular basis for this observed disparity. Based on docking studies, we mutated amino acid residues of the Gα q protein predicted to interact with FR or YM, and recombinantly expressed the mutated Gα q proteins in cells in which the native Gα q proteins had been knocked out by CRISPR-Cas9. Both radioligands showed similar association kinetics, and their binding followed a conformational selection mechanism, which was rationalized by molecular dynamics simulation studies. Several mutations of amino acid residues near the putative binding site of the "lipophilic anchors" of FR, especially those predicted to interact with the isopropyl group present in FR but not in YM, led to dramatically accelerated dissociation kinetics. Our data indicate that the long residence time of FR depends on lipophilic interactions within its binding site. The observed structure-kinetic relationships point to a complex binding mechanism of FR, which likely involves snap-lock- or dowel-like conformational changes of either ligand or protein, or both. These experimental data will be useful for the design of compounds with a desired residence time, a parameter that has now been recognized to be of utmost importance in drug development., (Copyright © 2021. Published by Elsevier Ltd.)