Multicenter, international observational study on quality of life and acceptability of a vaginal contraceptive ring containing etonogestrel/ethinylestradiol 11.00/3.474 mg over six months of use.

OBJECTIVE: The current post-market study aimed at analyzing women's menstrual bleeding intensity, vaginal infections, and quality of life parameters using the contraceptive vaginal ring Ornibel®. PATIENTS AND METHODS: In Germany and Spain, a multicenter study of healthy female adults (n=211) aged 18 to 45 used the vaginal ring Ornibel® for at least six months. Data collection was conducted using a patient questionnaire. The menstrual bleeding intensity was analyzed using visual analog scales (VAS). A Chi-square linear trend test assessed associations between quality-of-life parameters and continuation and recommendation of vaginal ring use. RESULTS: Three out of four women experienced six menstrual bleedings during the first six months of using the vaginal ring, with a median duration of four days during the study. The use of the vaginal ring led to a significant reduction in menstrual flow intensity (from 60 VAS points to 40 VAS points, p<0.001). In the German cohort, it was shown that dysmenorrhea and unscheduled bleeding and spotting were reduced with the use of Ornibel® as well. Most women (93.7%) agreed or strongly agreed that the vaginal ring was easy to insert, and its use was rated as comfortable or very comfortable by 97.5%. Both parameters were significantly associated with the continuation of the ring (easy to insert p=0.01, feeling comfortable: p=0.002) or its recommendation (easy to insert p=0.002, feeling comfortable: p=0.002). CONCLUSIONS: The observational data demonstrate that the contraceptive vaginal ring provides high acceptability and comfort. It is a well-accepted contraceptive method characterized by high efficacy and positive effects on cycle control.

Precision Medicine Approach for Cardiometabolic Risk Factors in Therapeutic Apheresis.

Lipoprotein apheresis (LA) is currently the most powerful intervention possible to reach a maximal reduction of lipids in patients with familial hypercholesterolemia and lipoprotein(a) hyperlipidemia. Although LA is an invasive method, it has few side effects and the best results in preventing further major cardiovascular events. It has been suggested that the highly significant reduction of cardiovascular complications in patients with severe lipid disorders achieved by LA is mediated not only by the potent reduction of lipid levels but also by the removal of other proinflammatory and proatherogenic factors. Here we performed a comprehensive proteomic analysis of patients on LA treatment using intra-individually a set of differently sized apheresis filters with the INUSpheresis system. This study revealed that proteomic analysis correlates well with routine clinical chemistry in these patients. The method is eminently suited to discover new biomarkers and risk factors for cardiovascular disease in these patients. Different filters achieve reduction and removal of proatherogenic proteins in different quantities. This includes not only apolipoproteins, C-reactive protein, fibrinogen, and plasminogen but also proteins like complement factor B (CFAB), protein AMBP, afamin, and the low affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) among others that have been described as atherosclerosis and metabolic vascular diseases promoting factors. We therefore conclude that future trials should be designed to develop an individualized therapy approach for patients on LA based on their metabolic and vascular risk profile. Furthermore, the power of such cascade filter treatment protocols may improve the prevention of cardiometabolic disease and its complications.

Detection and abundance of SARS-CoV-2 in wastewater in Liechtenstein, and the estimation of prevalence and impact of the B.1.1.7 variant.

The new coronavirus 2 (SARS-CoV-2) is known to be also shed through feces, which makes wastewater-based surveillance possible, independent of symptomatic cases and unbiased by any testing strategies and frequencies. We investigated the entire population of the Principality of Liechtenstein with samples from the wastewater treatment plant Bendern (serving all 39,000 inhabitants). Twenty-four-hour composite samples were taken once or twice a week over a period of 6 months from September 2020 to March 2021. Viral RNA was concentrated using the PEG centrifugation method followed by reverse transcription quantitative PCR. The aim of this research was to assess the suitability of SARS-CoV-2 fragments to relate the viral wastewater signal to the incidences and assess the impact of the emerging B.1.1.7. variant. The viral load in the wastewater peaked at almost 9 × 108 viral fragments per person equivalent (PE) and day on October 25, and showed a second peak on December 22 reaching a viral load of approximately 2 × 108 PE-1d-1. Individual testing showed a lag of 4 days and a distinct underestimation of cases at the first peak when testing frequency was low. The wastewater signal showed an immediate response to the implementation of non-pharmaceutical interventions. The new virus variant B.1.1.7. was first detected in wastewater on December 23, while it was first observed with individual testing on January 13, 2021. Further, our data indicate that the emergence of new virus variant may change the wastewater signal, probably due to different shedding patterns, which should be considered in future models.

Methods for extremely sparse-angle proton tomography.

Proton radiography is a widely fielded diagnostic used to measure magnetic structures in plasma. The deflection of protons with multi-MeV kinetic energy by the magnetic fields is used to infer their path-integrated field strength. Here the use of tomographic methods is proposed for the first time to lift the degeneracy inherent in these path-integrated measurements, allowing full reconstruction of spatially resolved magnetic field structures in three dimensions. Two techniques are proposed which improve the performance of tomographic reconstruction algorithms in cases with severely limited numbers of available probe beams, as is the case in laser-plasma interaction experiments where the probes are created by short, high-power laser pulse irradiation of secondary foil targets. A new configuration allowing production of more proton beams from a single short laser pulse is also presented and proposed for use in tandem with these analytical advancements.

Fermentation profile, cholesterol-reducing properties and chemopreventive potential of ß-glucans from Levilactobacillus brevis and Pediococcus claussenii - a comparative study with ß-glucans from different sources.

The aim of the present study was to investigate whether ß-glucans obtained from the lactic acid bacteria (LAB) Levilactobacillus (L.) brevis and Pediococcus (P.) claussenii exhibit similar physiological effects such as cholesterol-binding capacity (CBC) as the structurally different ß-glucans from oat, barley, and yeast as well as curdlan. After in vitro fermentation, fermentation supernatants (FSs) and/or -pellets (FPs) were analyzed regarding the concentrations of short-chain fatty acids (SCFAs), ammonia, bile acids, the relative abundance of bacterial taxa and chemopreventive effects (growth inhibition, apoptosis, genotoxicity) in LT97 colon adenoma cells. Compared to other glucans, the highest CBC was determined for oat ß-glucan (65.9 ± 8.8 mg g-1, p < 0.05). Concentrations of SCFA were increased in FSs of all ß-glucans (up to 2.7-fold). The lowest concentrations of ammonia (down to 0.8 ± 0.3 mmol L-1) and bile acids (2.5-5.2 µg mL-1) were detected in FSs of the ß-glucans from oat, barley, yeast, and curdlan. The various ß-glucans differentially modulated the relative abundance of bacteria families and reduced the Firmicutes/Bacteroidetes ratio. Treatment of LT97 cells with the FSs led to a significant dose-dependent growth reduction and increase in caspase-3 activity without exhibiting genotoxic effects. Though the different ß-glucans show different fermentation profiles as well as cholesterol- and bile acid-reducing properties, they exhibit comparable chemopreventive effects.

The transCampus Metabolic Training Programme Explores the Link of SARS-CoV-2 Virus to Metabolic Disease.

Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society. A modern training programme in diabetes and metabolism does not only involve a thorough understanding of classical physiology, biology and clinical diabetology but has to bring together an interdisciplinary team. With the arrival of the coronavirus pandemic, this prestigious and unique metabolic training programme is facing new challenges but also new opportunities. The consortium of the training programme has recognized early on the need for a guidance and for practical recommendations to cope with the COVID-19 pandemic for the community of patients with metabolic disease, obesity and diabetes. This involves the optimal management from surgical obesity programmes to medications and insulin replacement. We also established a global registry analyzing the dimension and role of metabolic disease including new onset diabetes potentially triggered by the virus. We have involved experts of infectious disease and virology to our faculty with this metabolic training programme to offer the full breadth and scope of expertise needed to meet these scientific challenges. We have all learned that this pandemic does not respect or heed any national borders and that we have to work together as a global community. We believe that this transCampus metabolic training programme provides a prime example how an international team of established experts in the field of metabolism can work together with students from all over the world to address a new pandemic.

Preparations for a European R&D roadmap for an inertial fusion demo reactor.

A European consortium of 15 laboratories across nine nations have worked together under the EUROFusion Enabling Research grants for the past decade with three principle objectives. These are: (a) investigating obstacles to ignition on megaJoule-class laser facilities; (b) investigating novel alternative approaches to ignition, including basic studies for fast ignition (both electron and ion-driven), auxiliary heating, shock ignition, etc.; and (c) developing technologies that will be required in the future for a fusion reactor. A brief overview of these activities, presented here, along with new calculations relates the concept of auxiliary heating of inertial fusion targets, and provides possible future directions of research and development for the updated European Roadmap that is due at the end of 2020. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

Whole-beam self-focusing in fusion-relevant plasma.

Fast ignition inertial confinement fusion requires the production of a low-density channel in plasma with density scale-lengths of several hundred microns. The channel assists in the propagation of an ultra-intense laser pulse used to generate fast electrons which form a hot spot on the side of pre-compressed fusion fuel. We present a systematic characterization of an expanding laser-produced plasma using optical interferometry, benchmarked against three-dimensional hydrodynamic simulations. Magnetic fields associated with channel formation are probed using proton radiography, and compared to magnetic field structures generated in full-scale particle-in-cell simulations. We present observations of long-lived, straight channels produced by the Habara-Kodama-Tanaka whole-beam self-focusing mechanism, overcoming a critical barrier on the path to realizing fast ignition. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

One-dimensional hydrodynamic simulations of low convergence ratio direct-drive inertial confinement fusion implosions.

Indirect drive inertial confinement fusion experiments with convergence ratios below 17 have been previously shown to be less susceptible to Rayleigh-Taylor hydrodynamic instabilities, making this regime highly interesting for fusion science. Additional limitations imposed on the implosion velocity, in-flight aspect ratio and applied laser power aim to further reduce instability growth, resulting in a new regime where performance can be well represented by one-dimensional (1D) hydrodynamic simulations. A simulation campaign was performed using the 1D radiation-hydrodynamics code HYADES to investigate the performance that could be achieved using direct-drive implosions of liquid layer capsules, over a range of relevant energies. Results include potential gains of 0.19 on LMJ-scale systems and 0.75 on NIF-scale systems, and a reactor-level gain of 54 for an 8.5 MJ implosion. While the use of 1D simulations limits the accuracy of these results, they indicate a sufficiently high level of performance to warrant further investigations and verification of this new low-instability regime. This potentially suggests an attractive new approach to fusion energy. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

Orbital Angular Momentum Coupling in Elastic Photon-Photon Scattering.

In this Letter, we investigate the effect of orbital angular momentum (OAM) on elastic photon-photon scattering in a vacuum for the first time. We define exact solutions to the vacuum electromagnetic wave equation which carry OAM. Using those, the expected coupling between three initial waves is derived in the framework of an effective field theory based on the Euler-Heisenberg Lagrangian and shows that OAM adds a signature to the generated photons thereby greatly improving the signal-to-noise ratio. This forms the basis for a proposed high-power laser experiment utilizing quantum optics techniques to filter the generated photons based on their OAM state.

A multiphysics approach for modeling early atherosclerosis.

This work is devoted to the development of a mathematical model of the early stages of atherosclerosis incorporating processes of all time scales of the disease and to show their interactions. The cardiovascular mechanics is modeled by a fluid-structure interaction approach coupling a non-Newtonian fluid to a hyperelastic solid undergoing anisotropic growth and a change of its constitutive equation. Additionally, the transport of low-density lipoproteins and its penetration through the endothelium is considered by a coupled set of advection-diffusion-reaction equations. Thereby, the permeability of the endothelium is wall-shear stress modulated resulting in a locally varying accumulation of foam cells triggering a novel growth and remodeling formulation. The model is calibrated and applied to an murine-specific case study, and a qualitative validation of the computational results is performed. The model is utilized to further investigate the influence of the pulsatile blood flow and the compliance of the artery wall to the atherosclerotic process. The computational results imply that the pulsatile blood flow is crucial, whereas the compliance of the aorta has only a minor influence on atherosclerosis. Further, it is shown that the novel model is capable to produce a narrowing of the vessel lumen inducing an adaption of the endothelial permeability pattern.

Vascular proteomics in metabolic and cardiovascular diseases.

The vasculature is essential for proper organ function. Many pathologies are directly and indirectly related to vascular dysfunction, which causes significant morbidity and mortality. A common pathophysiological feature of diseased vessels is extracellular matrix (ECM) remodelling. Analysing the protein composition of the ECM by conventional antibody-based techniques is challenging; alternative splicing or post-translational modifications, such as glycosylation, can mask epitopes required for antibody recognition. By contrast, proteomic analysis by mass spectrometry enables the study of proteins without the constraints of antibodies. Recent advances in proteomic techniques make it feasible to characterize the composition of the vascular ECM and its remodelling in disease. These developments may lead to the discovery of novel prognostic and diagnostic markers. Thus, proteomics holds potential for identifying ECM signatures to monitor vascular disease processes. Furthermore, a better understanding of the ECM remodelling processes in the vasculature might make ECM-associated proteins more attractive targets for drug discovery efforts. In this review, we will summarize the role of the ECM in the vasculature. Then, we will describe the challenges associated with studying the intricate network of ECM proteins and the current proteomic strategies to analyse the vascular ECM in metabolic and cardiovascular diseases.

Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767): Perioperative and Long-term Results of a Multicenter Randomized Controlled Trial.

OBJECTIVES: To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial. BACKGROUND: PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications. METHODS: A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up. RESULTS: From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters. CONCLUSIONS: The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.

Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport.

Transactive response DNA-binding protein 43 (TDP-43) is a predominantly nuclear, ubiquitously expressed RNA and DNA-binding protein. It recognizes and binds to UG repeats and is involved in pre-mRNA splicing, mRNA stability and microRNA metabolism. TDP-43 is essential in early embryonic development but accumulates in cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal lobar degeneration (FTLD). It is not known yet whether cytoplasmic aggregates of TDP-43 are toxic or protective but they are often associated with a loss of TDP-43 from the nucleus and neurodegeneration may be caused by a loss of normal TDP-43 function or a gain of toxic function. Here we present a proteomic study to analyze the effect of loss of TDP-43 on the proteome. MS data are available via ProteomeXchange with identifier PXD001668. Our results indicate that TDP-43 is an important regulator of RNA metabolism and intracellular transport. We show that Ran-binding protein 1 (RanBP1), DNA methyltransferase 3 alpha (Dnmt3a) and chromogranin B (CgB) are downregulated upon TDP-43 knockdown. Subsequently, transportin 1 level is increased as a result of RanBP1 depletion. Improper regulation of these proteins and the subsequent disruption of cellular processes may play a role in the pathogenesis of the TDP-43 proteinopathies ALS and FTLD.

Lung assist devices influence cardio-energetic parameters: Numerical simulation study.

We aim at an analysis of the effects mechanical ventilators (MVs) and thoracic artificial lungs (TALs) will have on the cardiovascular system, especially on important quantities, such as left and right ventricular external work (EW), pressure-volume area (PVA) and cardiac mechanical efficiency (CME). Our analyses are based on simulation studies which were carried out by using our CARDIOSIM(©) software simulator. At first, we carried out simulation studies of patients undergoing mechanical ventilation (MV) without a thoracic artificial lung (TAL). Subsequently, we conducted simulation studies of patients who had been provided with a TAL, but did not undergo MV. We aimed at describing the patient's physiological characteristics and their variations with time, such as EW, PVA, CME, cardiac output (CO) and mean pulmonary arterial/venous pressure (PAP/PVP). We were starting with a simulation run under well-defined initial conditions which was followed by simulation runs for a wide range of mean intrathoracic pressure settings. Our simulations of MV without TAL showed that for mean intrathoracic pressure settings from negative (-4 mmHg) to positive (+5 mmHg) values, the left and right ventricular EW and PVA, right ventricular CME and CO decreased, whereas left ventricular CME and the PAP increased. The simulation studies of patients with a TAL, comprised all the usual TAL arrangements, viz. configurations "in series" and in parallel with the natural lung and, moreover, hybrid configurations. The main objective of the simulation studies was, as before, the assessment of the hemodynamic response to the application of a TAL. We could for instance show that, in case of an "in series" configuration, a reduction (an increase) in left (right) ventricular EW and PVA values occurred, whereas the best performance in terms of CO can be achieved in the case of an in parallel configuration.

[Cytoreductive surgery for malignant peritoneal tumors]. / Zytoreduktive Chirurgie für maligne Tumoren des Peritoneums.

Cytoreductive surgery is an essential part of a multimodality treatment concept for peritoneal metastases. Indications are primary peritoneal tumors like peritoneal mesothelioma or secondaries from colorectal cancer or pseudomyxoma peritonei. Patients with gastric or ovarian carcinoma or abdominal sarcoma with peritoneal seedings can be treated within studies. Tumor entity, tumor load, and tumor distribution are the most critical issues for patient selection. Complete macroscopic cytoreduction is the strongest prognostic factor and can be achieved by parietal and visceral peritonectomy. The operation should be performed in a standardized manner. Due to possible tumor manifestation in all four quadrants of the abdomen and extensive extraperitoneal dissection, extensive surgical and oncological expertise is prerequisite. Treatment in specialized surgical oncology centers is recommended to minimize morbidity and mortality. The German Society for General and Visceral Surgery is certifying centers of competence for surgical treatment of peritoneal malignancies. Data of all patients are documented in the HIPEC register. The inclusion of patients in studies is recommended.

Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up.

Chronic renal failure is a well-known long-term complication of methylmalonic aciduria (MMA-uria), occurring even under apparently optimal metabolic management. The onset of renal dysfunction seems to be dependent on the type of defect and vitamin B12-responsiveness. We report on a patient with a vitamin B12-responsive cobalamin A type (cblA) MMA-uria caused by a homozygous stop mutation (p.R145X) in the cobalamin A gene (MMAA). She was diagnosed with chronic kidney disease (CKD) stage III at the age of 12 years. Following re-evaluation, the patient received vitamin B12 (hydroxocobalamin) treatment, resulting in a significant decrease in the concentration of methylmalonic acid (MMA) in urine and plasma. Until age 29 years glomerular filtration rate remained stable probably due to hydroxocobalamin treatment slowing down progression to end-stage renal failure. Kidney biopsies showed non-specific manifestations of chronic interstitial inflammation. The patient received a renal transplant at age 35 years. Under continuous treatment with hydroxocobalamin there is no evidence of kidney damage due to MMA-uria until the last follow-up 6 years after transplantation. This case report illustrates (i) a long-term follow-up of a patient with MMA-uria due to cblA deficiency, (ii) the involvement of the kidney as a target organ and (iii) the importance of early and adequate vitamin B12 substitution in responsive patients. Further investigation will be necessary to prove the protective effect of hydroxocobalamin in the kidney in vitamin B12-responsive patients.