Search

Abstract Sterile neutrinos with masses at the keV scale and mixing to the active neutrinos offer an elegant explanation of the observed dark matter (DM) density. However, the very same mixing inevitably leads to radiative photon emission and the non-observation of such peaked X-ray lines rules out this minimal sterile neutrino DM hypothesis. We show that in the context of the Standard Model effective field theory with sterile neutrinos (νSMEFT), higher dimensional operators can produce sterile neutrino DM in a broad range of parameter space. In particular, νSMEFT interactions can open the large mixing parameter space due to their destructive interference, through operator mixing or matching, in the X-ray emission. We also find that, even in the zero mixing limit, the DM density can always be explained by νSMEFT operators. The testability of the studied νSMEFT operators in searches for electric dipole moments, neutrinoless double beta decay, and pion decay measurements is discussed.

Abstract In clinical situations, peripheral blood accessible CD3+CD4+CXCR5+ T-follicular helper (TFH) cells may have to serve as a surrogate indicator for dysregulated germinal center responses in tissues. To determine the heterogeneity of TFH cells in peripheral blood versus tonsils, CD3+CD4+CD45RA–CXCR5+ cells of both origins were sorted. Transcriptomes, TCR repertoires and cell-surface protein expression were analysed by single-cell RNA sequencing, flow cytometry and immunohistochemistry. Reassuringly, all blood-circulating CD3+CD4+CXCR5+ T-cell subpopulations also appear in tonsils, there with some supplementary TFH characteristics, while peripheral blood-derived TFH cells display markers of proliferation and migration. Three further subsets of TFH cells, however, with bona fide T-follicular gene expression patterns, are exclusively found in tonsils. One additional, distinct and oligoclonal CD4+CXCR5+ subpopulation presents pronounced cytotoxic properties. Those ‘killer TFH (TFK ) cells’ can be discovered in peripheral blood as well as among tonsillar cells but are located predominantly outside of germinal centers. They appear terminally differentiated and can be distinguished from all other TFH subsets by expression of NKG7 (TIA-1), granzymes, perforin, CCL5, CCR5, EOMES, CRTAM and CX3CR1. All in all, this study provides data for detailed CD4+CXCR5+ T-cell assessment of clinically available blood samples and extrapolation possibilities to their tonsil counterparts.

AbstractSuccessful and efficient emotion regulation (ER) is a key mechanism for mental health. However, acute stress may impact the ability to cognitively regulate negative emotions due to its immediate effects on executive functioning. Based on previous studies, we expected that the time at which ER is tested after a stressor might have a decisive influence, with impairments in ER being more pronounced immediately after stress as compared to a later post-stress phase. To investigate such a time-dependent effect of stress on ER, we investigated 50 healthy adults (26 female) who were exposed to either the Trier Social Stress Test (n = 25) or a control condition (n = 25). Afterwards subjects conducted a cognitive ER task during which they were instructed to either regulate (cognitive reappraisal) or passively view neutral and negative visual stimuli. The ER task was divided into an early (0–20 minutes) and a late post-stress phase (20–40 minutes). Salivary cortisol and α-amylase were assessed as markers of the neuroendocrine stress response. Self-reported emotional state, the mean activity of the late positive potential measured via electroencephalogram (EEG), and corrugator electromyographic activity (EMG) were used as indices of ER. While the groups did not differ in the early post-stress phase, our results suggest a stress-related impairment in ER in the late post-stress phase. This effect was evident in all ER outcome variables (subjective rating, EEG, and EMG data). These results suggest a time-specific stress effect on cognitive reappraisal, which would have implications for reappraisal as a possible stress management technique.

Abstract Introduction Ganglionic local opioid analgesia (GLOA) at the superior cervical ganglion (SCG) is performed for pain control and is known to be an effective procedure. In this study, we evaluated the spread of the injectate in the area of the SCG. Our expectation was that there would be a correlation between the area and volume of the injectate spread and post-procedural outcome measures. Methods This was a retrospective blinded review of magnetic resonance imaging (MRI) scans. Assessors evaluated the anatomical area of fluid spread, the furthermost spread from midline, any hampered spread and contact of contrast fluid with other structures. The efficacy of GLOA and complications were estimated. Results The main solution spread reached from the C1 to C3 vertebrae. The furthest spread in the lateral and sagittal planes was 21.2 and 15.2 mm, respectively. The furthest craniocaudal spread was 63.5 mm. In 53.3% and 33% of interventions, the solution was found in the parapharyngeal space and in its “medial compartment,” respectively. A correlation was found between pain relief and both solution spread and volume of solution spread. No hampered spread was recorded. A negative correlation between pain reduction and number of GLOA was observed. Higher pre-procedural pain intensity was correlated with higher pain reduction. We estimated pain relief in 93% of procedures correctly. No correlation between post-procedural Numerical Rating Scale (NRS) scores and different needle approaches was found. Conclusion For the transoral blocking technique, a strict laterodorsal needle direction is recommended to prevent possible block failures. A total volume of 2 ml injected into the parapharyngeal space and its “medial compartment” is recommended. Higher volumes may lead to uncontrolled distribution patterns. Trial registration Clinicaltrials.gov identifier NCT05257655; date of registration 2022-02-25; patient enrollment date from 2023-01-09 to 2023-08-31.

IntroductionAlthough cardiovascular surgery societies in Europe and the USA constantly strive for the exchange of knowledge and best practices in coronary artery bypass grafting (CABG), the available evidence on whether such efforts result in similar patient outcomes is limited. Therefore, in the present analysis, we sought to compare patient profiles and overall survival outcomes for up to 3 years between large European and US patient cohorts who underwent isolated CABG.MethodsPatients from the European DuraGraft Registry (n = 2,522) who underwent isolated CABG at 45 sites in eight different European countries between 2016 and 2019 were compared to randomly selected patients from the US STS database who were operated during the same period (n = 294,725). Free conduits (venous and arterial grafts) from the DuraGraft Registry patients were intraoperatively stored in DuraGraft, an endothelial damage inhibitor, before anastomosis, whereas grafts from the STS Registry patients in standard-of-care solutions (e.g., saline). Propensity score matching (PSM) models were used to account for differences in patient baseline and surgical characteristics, using a primary PSM with 35 variables (2,400 patients matched) and a secondary PSM with 25 variables (2,522 patients matched, sensitivity analysis). The overall survival for up to 3 years after CABG was assessed as the primary endpoint.ResultsThe comparison of patient profiles showed significant differences between the European and US cohorts. The European patients had more left main disease, underwent more off-pump CABG, and received more arterial grafts together with more complete arterial grafting procedures. In contrast, the US patients received more distal anastomoses with more saphenous vein grafts (SVGs) that were mainly harvested endoscopically. Such differences, however, were well balanced after PSM for the mortality comparison. Mortality comparison at 30 days, 12 months, and 24 months between the European and US patients was 2.38% vs. 1.96%, 4.32% vs. 4.79%, and 5.38% vs. 6.96%, respectively. At 36 months, the mortality was significantly lower in the European patients than that of their US counterparts (7.37% vs. 9.65%; p-value = 0.016). The estimated hazard ratio (HR) was 1.29 (95% CI 1.05–1.59).ConclusionThis large-scale transatlantic comparative analysis shows that there are some significant differences in patient profiles between large cohorts of European and US patients. These differences were adjusted by using PSM for the mortality analysis. No significant difference in mortality was detected between groups through 2 years, but survival was significantly better in the European DuraGraft Registry patients at 3 years post-CABG.

BackgroundSocietal measures to contain the spread of COVID-19 (eg, lockdown and contact restrictions) have been associated with decreased health and well-being. A multitude of prepandemic studies identified the beneficial effects of physical exercise on both physical and mental health. ObjectiveWe report on the feasibility of a remote physical exercise intervention and its stress-buffering potential in 2 untrained cohorts: a pre–COVID-19 cohort that completed the intervention in 2019 and a lockdown cohort that started the intervention shortly before pandemic-related restrictions were implemented. MethodsIn a randomized controlled trial, participants were assigned to either an intervention group (IG; pre–COVID-19 cohort: n=7 and lockdown cohort: n=9) or a control group (CG; pre–COVID-19 cohort: n=6 and lockdown cohort: n=6). IG participants received weekly individualized training recommendations delivered via web-based support. The intervention period was initially planned for 8 weeks, which was adhered to in the pre–COVID-19 cohort (mean 8.3, SD 0.5 weeks) but was extended to an average of 17.7 (SD 2.0) weeks in the lockdown cohort. Participants’ health parameters were assessed before and after the intervention: aerobic capacity was measured as peak oxygen uptake (VO2peak) via cardiopulmonary exercise testing. Depressive symptoms were scored via the depression subscale of the Brief Symptom Inventory-18. ResultsDropout rates were low in both cohorts in the IG (pre–COVID-19 cohort: n=0, 0% and lockdown cohort: n=2, 16.7%) and the CG (pre–COVID-19 cohort: n=0, 0% and lockdown cohort: n=2, 20%). The mean adherence to the training sessions of the IG for both cohorts was 84% (pre–COVID-19 cohort: SD 5.5% and lockdown cohort: SD 11.6%). Aligned rank transform ANOVAs in the lockdown cohort indicated deterioration of VO2peak and depressive symptoms from before to after the intervention in the CG but no longitudinal changes in the IG. Analyses in the pre–COVID-19 cohort revealed significant increases in VO2peak for the IG compared to the CG (P=.04) but no intervention effects on depressive symptoms. ConclusionsWith low dropout rates and high adherence, the remote intervention was feasible for healthy adults under regular conditions and in the face of pandemic-related stressors. Moreover, our results hint at a stress-buffering effect as well as a buffering of a lockdown-induced deconditioning of remote physical exercise interventions in the pandemic scenario, which can be used in future studies to overcome equally stressful periods of life. However, due to limited statistical power, these findings should be replicated in similar scenarios. Trial RegistrationGerman Clinical Trials Register DRKS00018078; https://drks.de/search/en/trial/DRKS00018078

Günther Sandner fasst in seinem zeithistorischen Beitrag die Biografie und das politische Wirken Otto Neuraths zusammen, um damit eine maßgebliche intellektuelle Linie nachzuzeichnen, die zutiefst mit dem Roten Wien verbunden ist. Auch 100 Jahre später sind die Leistungen von Neurath und die Positionen des Austromarxismus – so etwa die Forderung nach einer „Vollsozialisierung“ von Wirtschaft und Gesellschaft – angesichts des neofeudalen Kapitalismus von beeindruckender Aktualität.

Introduction: Patients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of “trial-ineligible” and “potentially trial-eligible” patients. Methods: Data from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either “potentially trial-eligible” or “trial-ineligible” according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042). Results: Of 746 patients included, 343 patients (46.0%) were classified as “trial-ineligible” and had significantly worse outcomes compared with “potentially trial-eligible” patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2–8.4) versus 10.3 (95% CI: 8.4–13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19–1.72), p less than 0.001; median overall survival: 15.9 (95% CI: 11.4–20.3) versus 25.3 (95% CI: 19.8–30.4) months, hazard ratio of 1.36 (95% CI: 1.10–1.67), p equals 0.004. Conclusions: Our data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses.

Ex vivo genetically-modified cellular immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapies, have generated significant clinical and commercial outcomes due to their unparalleled response rates against relapsed and refractory blood cancers. However, the development and scalable manufacture of these novel therapies remains challenging and further process understanding and optimisation is required to improve product quality and yield. In this study, we employ a quality-by-design (QbD) approach to systematically investigate the impact of critical process parameters (CPPs) during the expansion step on the critical quality attributes (CQAs) of CAR-T cells. Utilising the design of experiments (DOE) methodology, we investigated the impact of multiple CPPs, such as number of activations, culture seeding density, seed train time, and IL-2 concentration, on CAR-T CQAs including, cell yield, viability, metabolism, immunophenotype, T cell differentiation, exhaustion and CAR expression. Initial studies undertaken in G-Rex® 24 multi-well plates demonstrated that the combination of a single activation step and a shorter, 3-day, seed train resulted in significant CAR-T yield and quality improvements, specifically a 3-fold increase in cell yield, a 30% reduction in exhaustion marker expression and more efficient metabolism when compared to a process involving 2 activation steps and a 7-day seed train. Similar findings were observed when the CPPs identified in the G-Rex® multi-well plates studies were translated to a larger-scale automated, controlled stirred-tank bioreactor (Ambr® 250 High Throughput) process. The single activation step and reduced seed train time resulted in a similar, significant improvement in CAR-T CQAs including cell yield, quality and metabolism in the Ambr® 250 High Throughput bioreactor, thereby validating the findings of the small-scale studies and resulting in significant process understanding and improvements. This study provides a methodology for the systematic investigation of CAR-T CPPs and the findings demonstrate the scope and impact of enhanced process understanding for improved CAR-T production.

Abstract Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs.

Abstract We consider the generation of a baryon asymmetry in an extension of the Standard Model with two singlet Majorana fermions that are degenerate above the electroweak phase transition. The model can explain neutrino masses as well as the observed matter-antimatter asymmetry, for masses of the heavy singlets below the electroweak scale. The only physical CP violating phases in the model are those in the PMNS mixing matrix, i.e. the Dirac phase and a Majorana phase that enter light neutrino observables. We present an accurate analytic approximation for the baryon asymmetry in terms of CP flavour invariants, and derive the correlations with neutrino observables. We demonstrate that the measurement of CP violation in neutrino oscillations as well as the mixings of the heavy neutral leptons with the electron, muon and tau flavours suffice to pin down the matter-antimatter asymmetry from laboratory measurements.

Abstract The cosmic microwave background (CMB) has proven to be an invaluable tool for studying the properties and interactions of neutrinos, providing insight not only into the sum of neutrino masses but also the free streaming nature of neutrinos prior to recombination. The CMB is a particularly powerful probe of new eV-scale bosons interacting with neutrinos, as these particles can thermalize with neutrinos via the inverse decay process, $$\nu \bar{\nu } \rightarrow X$$ ν ν ¯ → X , and suppress neutrino free streaming near recombination – even for couplings as small as $$\lambda _{\nu } \sim {\mathcal {O}}(10^{-13})$$ λ ν ∼ O ( 10 - 13 ) . Here, we revisit CMB constraints on such bosons, improving upon a number of approximations previously adopted in the literature and generalizing the constraints to a broader class of models. This includes scenarios in which the boson is either spin-0 or spin-1, the number of interacting neutrinos is either $$N_{\textrm{int}} = 1,2 $$ N int = 1 , 2 or 3, and the case in which a primordial abundance of the species is present. We apply these bounds to well-motivated models, such as the singlet majoron model or a light $$U(1)_{L_{\mu }-L_{\tau }}$$ U ( 1 ) L μ - L τ gauge boson, and find that they represent the leading constraints for masses $$m_X\sim 1\, {\textrm{eV}}$$ m X ∼ 1 eV . Finally, we revisit the extent to which neutrino-philic bosons can ameliorate the Hubble tension, and find that recent improvements in the understanding of how such bosons damp neutrino free streaming reduces the previously found success of this proposal.

The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) pathway plays a key role in the pathogenesis of pulmonary hypertension (PH). Targeted treatments include phosphodiesterase type 5 inhibitors (PDE5i) and sGC stimulators. The sGC stimulator riociguat is approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). sGC stimulators have a dual mechanism of action, enhancing the sGC response to endogenous NO and directly stimulating sGC, independent of NO. This increase in cGMP production via a dual mechanism differs from PDE5i, which protects cGMP from degradation by PDE5, rather than increasing its production. sGC stimulators may therefore have the potential to increase cGMP levels under conditions of NO depletion that could limit the effectiveness of PDE5i. Such differences in mode of action between sGC stimulators and PDE5i could lead to differences in treatment efficacy between the classes. In addition to vascular effects, sGC stimulators have the potential to reduce inflammation, angiogenesis, fibrosis and right ventricular hypertrophy and remodelling. In this review we describe the evolution of treatments targeting the NO–sGC–cGMP pathway, with a focus on PH.

While suggested, surgery is not always possible as a first-line treatment of Cushing’s Disease (CD). In such cases, patients require medical therapy in order to prevent complications resulting from hypercortisolism. Although there has been a wide expansion in pharmacological options in recent years, mitotane was the agent of choice for treating hypercortisolism decades ago. Due to the introduction of other therapies, long-term experience with mitotane remains limited. Here, we report the case of a woman with CD who was treated with mitotane for 37 years. During the treatment period, biochemical and clinical disease control was achieved and the patient had two uncomplicated pregnancies. Drug-related side effects remained moderate and could be controlled by several dose adjustments. Our case highlights the ability of mitotane to allow an effective control of hypercortisolism and to represent a safe treatment option in special situations where CD requires an alternative therapeutic approach. Furthermore, we provide a literature review of the long-term use of mitotane and reported cases of pregnancy in the context of mitotane therapy.

BackgroundRigorous research trials have demonstrated that early childhood interventions can reach socially disadvantaged families and can have a lasting impact on the healthy development of their children. However, little is known about the internal and contextual factors that contribute to the long-term implementation of such interventions. In this study, we investigated the development of the home visiting program Pro Kind. The program was adapted from the evidence-based US-American Nurse-Family Partnership program and was implemented in Germany in 2006. Using an exploratory approach, we examined factors contributing to the long-term implementation of this program.MethodsQualitative interviews with program implementers (midwives, social workers, program managers) of the Pro Kind program and key stakeholders in two cities in Germany were conducted. Interview guides were developed to assess participants' perceptions and experiences on how the program had developed over time internally and in the interaction with its environment. Data were collected between March and September 2021. Drawing on the Consolidated Framework for Implementation Research (CFIR), data was coded according to the principles of thematic analysis.ResultsA total of 25 individuals (11 program implementers, 14 key stakeholders) were interviewed. The identified factors related to three out of five domains of the CFIR model in our analysis. First, regarding the intervention characteristics, the evidence of effectiveness and the relative advantage of the implementation of the program compared to similar interventions were viewed as contributors to long-term implementation. However, the program's adaptability was discussed as a constraining factor for reaching the target group. Second, concerning the inner setting, stakeholders and program implementers perceived the implementation climate, the leadership engagement and the program's size as relevant factors for networking strategies and program visibility. Third, as part of the outer setting, the degree of networking with external stakeholders was highlighted of great importance for the program.ConclusionsWe identified several factors of particular importance for the long-term implementation and sustainability of an early childhood intervention at the practice level, particularly in the local context in Germany. These findings should inform the design of impactful, scalable, and sustainable early childhood interventions targeting disadvantaged families.

Background C reactive protein (CRP) kinetics have recently been suggested as predictive biomarkers for the efficacy of immune checkpoint inhibitor (ICI) therapy in selected cancer types. The aim of this study was to characterize early CRP kinetics as a tumor-agnostic biomarker for ICI treatment outcomes.Methods In this multicenter retrospective cohort study, two independent cohorts of patients with various cancer types undergoing palliative ICI treatment at Austrian academic centers served as the discovery (n=562) and validation cohort (n=474). Four different patterns of CRP kinetics in the first 3 months of ICI therapy were defined (CRP-flare responders, CRP-responders, CRP non-responders, patients with all-normal CRP). Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were defined as coprimary endpoints. Univariable and multivariable logistic regression, landmark analysis and Cox regression including CRP kinetics as time-dependent variable were performed.Results The ORR in patients with all-normal CRP, CRP responders, CRP flare-responders and CRP non-responders was 41%, 38%, 31% and 12%, respectively. The median OS and PFS estimates were 24.5 months (95% CI 18.5 to not reached) and 8.2 months (95% CI 5.9 to 12.0) in patients with all-normal CRP, 16.1 months (95% CI 12.6 to 19-8) and 6.1 months (95% CI 4.9 to 7.2) in CRP-responders, 14.0 months (95% CI 8.5 to 19.4) and 5.7 months (95% CI 4.1 to 8.5) in CRP flare-responders and 8.1 months (95% CI 5.8 to 9.9) and 2.3 months (95% CI 2.2 to 2.8) in CRP non-responders (log-rank p for PFS and OS

Vascular cognitive impairment (VCI) describes neurodegenerative disorders characterized by a vascular component. Pathologically, it involves decreased cerebral blood flow (CBF), white matter lesions, endothelial dysfunction, and blood-brain barrier (BBB) impairments. Molecularly, oxidative stress and inflammation are two of the major underlying mechanisms. Nitric oxide (NO) physiologically stimulates soluble guanylate cyclase (sGC) to induce cGMP production. However, under pathological conditions, NO seems to be at the basis of oxidative stress and inflammation, leading to a decrease in sGC activity and expression. The native form of sGC needs a ferrous heme group bound in order to be sensitive to NO (Fe(II)sGC). Oxidation of sGC leads to the conversion of ferrous to ferric heme (Fe(III)sGC) and even heme-loss (apo-sGC). Both Fe(III)sGC and apo-sGC are insensitive to NO, and the enzyme is therefore inactive. sGC activity can be enhanced either by targeting the NO-sensitive native sGC (Fe(II)sGC), or the inactive, oxidized sGC (Fe(III)sGC) and the heme-free apo-sGC. For this purpose, sGC stimulators acting on Fe(II)sGC and sGC activators acting on Fe(III)sGC/apo-sGC have been developed. These sGC agonists have shown their efficacy in cardiovascular diseases by restoring the physiological and protective functions of the NO-sGC-cGMP pathway, including the reduction of oxidative stress and inflammation, and improvement of vascular functioning. Yet, only very little research has been performed within the cerebrovascular system and VCI pathology when focusing on sGC modulation and its potential protective mechanisms on vascular and neural function. Therefore, within this review, the potential of sGC as a target for treating VCI is highlighted.

BackgroundPostoperative nausea and vomiting (PONV) is an unpleasant complication after surgery that commonly co-occurs with pain. Considering the high prevalence among pediatric patients, it is important to explore the main risk factors leading to PONV in order to optimize treatment strategies. The objectives of this study are as follows: (1) to determine the prevalence of PONV on the day of surgery by conducting interviews with pediatric patients, (2) to assess PONV prevalence in the recovery room and on the ward by analyzing nursing records, and (3) to collect information on PONV risk factors on the day of surgery and the following postoperative days. We wanted to investigate real-life scenarios rather than relying on artificially designed studies.MethodsA prospective analysis [according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines] of PONV on the day of surgery and the following postoperative days was conducted by evaluating demographic and procedural parameters, as well as conducting interviews with the children under study. A total of 626 children and adolescents, ranging in age from 4 to 18 years, were interviewed on the ward following their surgery. The interviews were conducted using a questionnaire, as children aged 4 and above can participate in an outcome-based survey.ResultsOn the day of surgery, several multivariable independent predictors were identified for PONV. The type of surgery was found to be a significant factor (p = 0.040) with the highest odds ratio (OR) in patients with procedural investigations [OR 5.9, 95% confidence interval (CI): 1.8–19.2], followed by abdominal surgery (OR 3.1, 95% CI: 0.9–11.1) when inguinal surgery was used as the reference category. In addition, the study identified several predictors, including the amount of fentanyl administered during anesthesia (µg/kg body weight) (OR 1.4, 95% CI: 1.1–1.8), intraoperative use of piritramide (OR 2.6, 95% CI: 1.5–4.4) and diclofenac (OR 2.0, 95% CI: 1. 3–3.1), opioid administration in the recovery room (OR 3.0, 95% CI: 1.9–4.7), and piritramide use on the ward (OR 4.5, 95% CI: 1.7–11.6).ConclusionsThe main risk factors for PONV include the intraoperative administration of opioids during the recovery room stay and at the ward, the intraoperative use of non-opioids (diclofenac), and the specific type of surgical procedure. Real-life data demonstrated that in clinical praxis, there is a gap between the adherence to established guidelines and the use of antiemetic prophylaxis in surgeries that are generally not associated with a high PONV prevalence. Further efforts are needed to improve the existing procedures and thus improve the overall outcome.

Plant phenology, i. e. the timing of life cycle events, is related to individual fitness and species distribution ranges. Temperature is one of the most important drivers of plant phenology together with day length. The adaptation of their phenology may be important for the success of invasive plant species. The present study aims at understanding how the performance and the phenology of the invasive legume Lupinus polyphyllus vary with latitude. We sampled data across a >2000 km latitudinal gradient from Central to Northern Europe. We quantified variation in phenology of flowering and fruiting of L. polyphyllus using >1600 digital photos of inflorescences from 220 individual plants observed weekly at 22 sites. The day of the year at which different phenological phases were reached, increased 1.3–1.8 days per degree latitude, whereas the growing degree days (gdd) required for these phenological phases decreased 5–16 gdd per degree latitude. However, this difference disappeared, when the day length of each day included in the calculation of gdd was considered. The day of the year of the earliest and the latest climatic zone to reach any of the three studied phenological phases differed by 23–30 days and temperature requirements to reach these stages differed between 62 and 236 gdd. Probably, the invasion of this species will further increase in the northern part of Europe over the next decades due to climate warming. For invasive species control, our results suggest that in countries with a large latitudinal extent, the mowing date should shift by ca. one week per 500 km at sites with similar elevations.

Abstract We revisit the generation of a matter-antimatter asymmetry in the minimal extension of the Standard Model with two singlet heavy neutral leptons (HNL) that can explain neutrino masses. We derive an accurate analytical approximation to the solution of the complete linearized set of kinetic equations, which exposes the non-trivial parameter dependencies in the form of parameterization-independent CP invariants. The identification of various washout regimes relevant in different regions of parameter space sheds light on the relevance of the mass corrections in the interaction rates and clarifies the correlations of baryogenesis with other observables. In particular, by requiring that the measured baryon asymmetry is reproduced, we derive robust upper or lower bounds on the HNL mixings depending on their masses, and constraints on their flavour structure, as well as on the CP-violating phases of the PMNS mixing matrix, and the amplitude of neutrinoless double-beta decay. We also find certain correlations between low and high scale CP phases. Especially emphasizing the testable part of the parameter space we demonstrate that our findings are in very good agreement with numerical results. The methods developed in this work can help in exploring more complex scenarios.

Abstract Background Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential. Methods We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592). Results Mosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model. Conclusion Inhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.

Diabetes mellitus (DM) is an independent risk factor for micro- and macrovascular complications such as nephropathy and atherosclerosis respectively, which are the major causes of premature morbidity and mortality in Type 1 and Type 2 diabetic patients. Endothelial dysfunction is the critical first step of vascular disease and is characterized by reduced bioavailability of the essential endothelial vasodilator, nitric oxide (NO), coupled with an elevation in inflammation and oxidative stress. A novel pathway to bolster NO activity is to upregulate soluble guanylate cyclase (sGC), an enzyme responsible for mediating the protective actions of NO. Two classes of sGC modulators exist, activators and stimulators, with differing sensitivity to oxidative stress. In this study, we investigated the therapeutic effects of the sGC stimulator BAY 41-2272 (Bay 41) and the sGC activator BAY 60-2770 (Bay 60) on endpoints of atherosclerosis and renal disease as well as inflammation and oxidative stress in diabetic Apolipoprotein E knockout (ApoE-/-) mice. We hypothesized that under oxidative conditions known to accompany diabetes, sGC activation might be more efficacious than sGC stimulation in limiting diabetic vascular complications. We demonstrate that Bay 60 not only significantly decreased nitrotyrosine staining (P

ObjectiveAcyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is dysregulated in catabolic/malnutrition states like sepsis or systemic inflammation. However, regulation of ACBP has not been investigated in conditions with impaired kidney function, so far.Design/methodsSerum ACBP concentrations were investigated by enzyme-linked immunosorbent assay i) in a cohort of 60 individuals with kidney failure (KF) on chronic haemodialysis and compared to 60 individuals with a preserved kidney function; and ii) in a human model of acute kidney dysfunction (AKD). In addition, mACBP mRNA expression was assessed in two CKD mouse models and in two distinct groups of non-CKD mice. Further, mRNA expression of mACBP was measured in vitro in isolated, differentiated mouse adipocytes - brown and white - after exposure to the uremic agent indoxyl sulfate.ResultsMedian [interquartile range] serum ACBP was almost 20-fold increased in KF (514.0 [339.3] µg/l) compared to subjects without KF (26.1 [39.1] µg/l) (p

Experiments in a tunable graphene superlattice show that the unusual 1/B periodic resistance oscillations at high temperatures in the energy spectrum of electrons in a 2D periodic potential, known as the Hofstadter butterfly, coexist with oscillations due to commensurability between the electron cyclotron radius and the superlattice’s period.

Abstract Successful therapy of heart failure with preserved ejection fraction (HFpEF) remains a major unmet clinical need. Device-based treatment approaches include the interatrial shunt device (IASD), conventional assist devices pumping blood from the left ventricle (LV-VAD) or the left atrium (LA-VAD) towards the aorta, and a valveless pulsatile assist device with a single cannula operating in co-pulsation with the native heart (CoPulse). Hemodynamics of two HFpEF subgroups during rest and exercise condition were translated into a lumped parameter model of the cardiovascular system. The numerical model was applied to assess the hemodynamic effect of each of the four device-based therapies. All four therapy options show a reduction in left atrial pressure during rest and exercise and in both subgroups (> 20%). IASDs concomitantly reduce cardiac output (CO) and shift the hemodynamic overload towards the pulmonary circulation. All three mechanical assist devices increase CO while reducing sympathetic activity. LV-VADs reduce end-systolic volume, indicating a high risk for suction events. The heterogeneity of the HFpEF population requires an individualized therapy approach based on the underlying hemodynamics. Whereas phenotypes with preserved CO may benefit most from an IASD device, HFpEF patients with reduced CO may be candidates for mechanical assist devices.