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OBJECTIVES Intima hyperplasia is a major issue of biological cardiovascular grafts resulting in progressive in vivo degeneration that particularly decreases the durability of coronary and peripheral vascular bypasses. Previously, dichloroacetate (DCA) has been reported to prevent the formation of hyperplastic intima in injured arteries. In this study, the effect of DCA on the neointima formation and degeneration of decellularized small-caliber implants was investigated in a rat model. METHODS Donor rat aortic grafts (n = 22) were decellularized by a detergent-based technique, surface-coated with fibronectin (50 µl ml−1, 24 h incubation) and implanted via anastomoses to the infrarenal aorta of the recipients. Rats in the DCA group (n = 12) received DCA via drinking water during the whole follow-up period (0.75 g l−1), while rats without DCA treatment served as controls (n = 10). At 2 (n = 6 + 5) and 8 (n = 6 + 5) weeks, the grafts were explanted and examined by histology and immunofluorescence. RESULTS Systemic DCA treatment inhibited neointima hyperplasia, resulting in a significantly reduced intima-to-media ratio (median 0.78 [interquartile range, 0.51–1.27] vs 1.49 [0.67–2.39] without DCA, P, Tissue-engineered vascular grafts represent an implant source that promises to overcome the limitations of clinical standard grafts.

There has recently been a keen interest in developing LiDAR systems using SPAD sensors. This has led to a variety of implementations in pixel combining techniques and TDC architectures for such sensors. This paper presents a comparison of these approaches and demonstrates a technique capable of extending the range of LiDAR systems with improved resilience to background conditions. A LiDAR system emulator using a reconfigurable SPAD array and FPGA interface is used to compare these different techniques. A Monte Carlo simulation model leveraging synthetic 3D data is presented to visualize the sensor performance on realistic automotive LiDAR scenes.

This paper presents the design and experimental characterization of a Proton Sound Detector (ProSD), a device that physically captures and senses the weak acoustic signal emitted by the fast energy deposition at the end of the same proton beam range. The measured acoustic signal Time-of-Flight provides a very accurate ( $13~\mu \text{m}$ accuracy) measure of the proton beam penetration depth in water, improving the proton range verification accuracy w.r.t. previous works in pre-clinical scenarios. This suggests interesting possibilities for high-accuracy and real-time beam monitoring and calibration in hadron-therapy for cancer treatment. The detector has been fully characterized and tested with a physical 20 MeV proton beam in a water energy absorber. The ProSD and the water tank have been mounted in front of the exit layer of a 20 MeV 120 ns pulse time-width proton beam. A clear sinusoidal-like acoustic signal of 5 Pa and 2.3 MHz frequency has been detected at 12 dB SNR with 0.8 Gy single shot dose. After averaging 10 beam shots the achieved Signal-to-Noise-Ratio is 22 dB allowing a $\pm 7.5~\mu \text{m}$ precision vs. previously reported $\pm 45~\mu \text{m}$ ionoacoustic precision.

Seit einigen Jahren ist eine stetige Zunahme des Einsatzes von mechanischen extrakorporalen Herz-Kreislauf- und Lungenunterstutzungssystemen (ECLS/ECMO) zu verzeichnen. So wurden seit 2015 in Deutschland jahrlich bei etwa 3000 Patienten ECLS/ECMO-Systeme implantiert. Trotz dieser haufigen Anwendung der passageren Unterstutzungssysteme existieren zurzeit national und international nur Leitlinien zum Einsatz der ECMO/ECLS, die erkrankungsbezogene Teilaspekte komplexer Therapiekaskaden adressieren. Vor diesem Hintergrund erschien es notwendig, evidenzbasierte Empfehlungen zur ECLS/ECMO-Therapie im Hinblick auf Indikationen und das komplexe Patientenmanagement zu verfassen, in denen personelle, prozessuale und infrastrukturelle Anforderungen definiert werden. Aus diesem Grund erfolgte im Juli 2015 durch die Deutsche Gesellschaft fur Thorax‑, Herz- und Gefaschirurgie (DGTHG) die Anmeldung einer diesbezuglichen S3-Leitlinie bei der zustandigen Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF). Im Mittelpunkt der Leitlinie steht die klinische Anwendung der ECLS/ECMO-Therapie; erganzend werden auch strukturelle und okonomische Aspekte adressiert. Unter Federfuhrung der DGTHG wurde mit Einbindung von Experten aus Deutschland, Osterreich und der Schweiz, delegiert aus 11 AWMF-Fachgesellschaften, 5 weiteren Fachgesellschaften sowie der Patientenvertretung, die S3-Leitlinie im Februar 2021 publiziert. Dieser Artikel stellt eine kurze Zusammenfassung des methodischen Konzepts sowie aller konsentierten Empfehlungen fur jede bearbeitete Fragestellung der Leitlinie dar.

Finding a sustainable mobility solution for the future is one of the most competitive challenges in the logistics and mobility sector at present. Policymakers, researchers, and companies are working intensively to provide novel options that are environmentally friendly and sustainable. While autonomous car-sharing services have been introduced as a very promising solution, an innovative alternative is arising: the use of self-driving bikes. Shared autonomous cargo-bike fleets are likely to increase the livability and sustainability of the city, as the use of cargo-bikes in an on-demand mobility service can replace the use of cars for short-distance trips and enhance connectivity to public transportation. However, more research is needed to develop this new concept. In this paper, we investigate different rebalancing strategies for an on-demand, shared-use, self-driving cargo-bikes service (OSABS). We simulate a case study of the system in the inner city of Magdeburg using AnyLogic. The simulation model allows us to evaluate the impact of rebalancing on service level, idle mileage, and energy consumption. We conclude that the best proactive rebalancing strategy for our case study is to relocate bikes only between neighboring regions. We also acknowledge the importance of bike relocation to improve service efficiency and reduce fleet size.

Selection of the ideal surgical procedure for coronary revascularization in patients with severe cardiac dysfunction at times may represent a challenge. In recent years, with the advent of surgical large microaxial pumps, e.g., Impella 5.0 (Abiomed Inc., Boston, USA), specific support and effective unloading of the left ventricle has become available. In the interventional field, good results have been achieved with smaller microaxial pumps in the setting of so-called protected percutaneous coronary intervention. In this study, we would like to share our early experience with surgical coronary revascularization under the sole support of Impella 5.0, omitting the use of heart–lung machine in three cases of severe cardiac dysfunction due to complex ischemic heart disease. Effective circulatory support intraoperatively and postoperatively speaks in favor of this technique in selected patients.

Ascertainment bias is a well-recognized source of bias in research, but few studies have systematically analyzed sources of ascertainment bias in randomized trials in which blinding is not possible and endpoint assessment is not protocolized. In the current study, we sought to evaluate differences in the clinical practice patterns of trial investigators with respect to bias in the ascertainment of pre-revascularization patient risk and the incidence of secondary endpoints post-revascularization. We conducted a cross-sectional survey of active investigators ( n = 936) from the Best Endovascular Versus Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST-CLI) trial. The total survey response rate was 19.6% (183/936). Vascular surgeons were more likely than nonsurgical interventionalists to order tests for cardiac complications after both surgical bypass ( p < 0.001) and endovascular revascularization ( p = 0.038). Post-procedure, investigators were more likely to order additional testing for cardiac complications in open surgery versus endovascular cases (7% vs 16% never, 41% vs 65% rarely, 43% vs 17% sometimes, 9% vs 2% always, respectively; p < 0.0001). Significant variation in practice patterns exist in the pre- and post-procedure assessment of cardiac risk and events for patients with CLI undergoing revascularization. Variation in the ascertainment of risk and outcomes according to the type of revascularization procedure and physician specialty should be considered when interpreting the results of clinical studies, such as the BEST-CLI trial. ClinicalTrials.gov Identifier: NCT02060630

Objective Conventional sacral neuromodulation (SNM) has shown to be an effective treatment for lower urinary tract and bowel dysfunction, but improvements of clinical outcome are still feasible. Currently, in preclinical research, new stimulation parameters are being investigated to achieve better and longer effects. This systematic review summarizes the status of SNM stimulation parameters and its effect on urinary tract and bowel dysfunction in preclinical research. Materials and Methods The literature search was conducted using three databases: Ovid (Medline, Embase) and PubMed. Articles were included if they reported on stimulation parameters in animal studies for lower urinary tract or bowel dysfunction as a primary outcome. Methodological quality assessment was performed using the SYRCLE Risk of Bias (RoB) tool for animal studies. Results Twenty‐two articles were eligible for this systematic review and various aspects of stimulation parameters were included: frequency, intensity, pulse width, stimulation signal, timing of stimulation, and unilateral vs. bilateral stimulation. In general, all experimental studies reported an acute effect of SNM on urinary tract or bowel dysfunction, whereas at the same time, various stimulation settings were used. Conclusions The results of this systematic review indicate that SNM has a positive therapeutic effect on lower urinary tract and bowel dysfunction. Using low‐frequency‐SNM, high‐frequency‐SNM, bilateral SNM, and higher pulse widths showed beneficial effects on storage and evacuation dysfunction in animal studies. An increased variability of stimulation parameters may serve as a basis for future improvement of the effect of SNM in patients suffering from urinary tract or bowel dysfunction.

Objective: THBD (thrombomodulin) is part of the anticoagulant protein C-system that acts at the endothelium and is involved in anti-inflammatory and barrier-stabilizing processes. A recombinant soluble form of THBD was shown to have protective effects in different organs, but how the endogenous THBD is regulated during ischemia, particularly in the brain is not known to date. The aim of this study was to investigate the role of THBD, especially in brain endothelial cells, during ischemic stroke. Approach and Results: To induce ischemic brain damage, we occluded the middle cerebral artery of mice. We found an increased endothelial expression of Thbd in the peri-infarct area, whereas in the core of the ischemic tissue Thbd expression was decreased compared with the contralateral side. We generated a novel Cre/loxP-based mouse line that allows for the inducible deletion of Thbd specifically in brain endothelial cells, which worsened stroke outcome 48 hours after middle cerebral artery occlusion. Unexpectedly, we found no signs of increased coagulation, thrombosis, or inflammation in the brain but decreased vessel diameters and impaired angiogenesis in the peri-infarct area that led to a reduced overall vessel length 1 week after stroke induction. Conclusions: Endogenous THBD acts as a protective factor in the brain during ischemic stroke and enhances vessel diameter and proliferation. These previously unknown properties of THBD could offer new opportunities to affect vessel function after ischemia and thereby improve stroke outcome.

Aim There is an ongoing debate as to whether or not the efficacy of sacral neuromodulation (SNM) is optimized by maximizing the total number of active electrode poles (AEPs) during lead placement because there are more programming options. However, this is at the cost of increased operating time. The aims of this study were to establish if a higher number of AEPs improves SNM efficacy during the trial period and after permanent implantable pulse generator (IPG) placement and if there is there a correlation between number of AEPs and battery life of the first placed IPG. Method This was a single centre retrospective cohort study of new patients with faecal incontinence who underwent SNM between 2000 and 2018. Exclusion criteria were sphincter defect > 30%, rectocele/enterocele Grade 3 or higher and incomplete records. Results In all, 288/456 (63%) patients (women 91%; mean age 58.5 ± 11.7 years) were eligible for analysis. The number of AEPs during lead placement was two (n = 42, 14.5%), three (n = 82, 28.5%) and four (n = 164, 57%). There was no association between the number of AEPs during tined lead placement and long‐term efficacy. Neither the success rate of the trial phase nor the battery life after first placed IPG was influenced by the number of AEPs. Conclusion In this study, the number of AEPs does not seem to influence long‐term efficacy of SNM success rate during the trial phase or the battery life of the first placed IPG. However, we also suggest that at the very least there should be two AEPs at lead placement.

Objective Sacral neuromodulation (SNM) has been used to treat patients with lower urinary tract dysfunction and bowel dysfunction for many years. Success rates vary between 50% and 80%, indicating that there is much room for improvement. Altering stimulation parameters may result in improved outcome. This paper reports a systematic review of the clinical efficacy of nonconventional stimulation parameters on urinary tract and bowel dysfunction. Materials and Methods Three databases were used for the literature search: Ovid (Medline, Embase) and PubMed. Papers were screened by two independent reviewers, who also extracted data from these papers. Clinical papers studying SNM stimulation parameters, that is, intermittent stimulation, frequency, pulse width, and amplitude, in urinary tract and bowel dysfunction were included. Quality of included papers was assessed using standardized guidelines. Results Out of 5659 screened papers, 17 papers, studying various stimulation parameters, were included. Overall quality of these papers differed greatly, as some showed no risk of bias, whereas others showed high risk of bias. Stimulation parameters included intermittent stimulation, frequency, pulse width, amplitude, and unilateral vs. bilateral stimulation. Especially high frequency SNM and either a narrow or wide pulse width seem to improve efficacy in patients with bowel dysfunction. Additionally, implementation of short cycling intervals is promising to improve quality of life for patients with urinary tract or bowel dysfunction. Conclusion The results of our systematic review indicate that stimulation parameters may improve efficacy of SNM in treatment of both urinary tract dysfunction and bowel dysfunction.

Biodiversity studies could strongly benefit from three-dimensional data on ecosystem structure derived from contemporary remote sensing technologies, such as light detection and ranging (lidar). Despite the increasing availability of such data at regional and national scales, the average ecologist has been limited in accessing them due to high requirements on computing power and remote sensing knowledge. We processed Denmark's publicly available national airborne laser scanning (ALS) data set acquired in 2014/15, together with the accompanying elevation model, to compute 70 rasterised descriptors of interest for ecological studies. With a grain size of 10 m, these data products provide a snapshot of high-resolution measures including vegetation height, structure and density, as well as topographic descriptors including elevation, aspect, slope and wetness across more than 40 000 km2 covering almost all of Denmark's terrestrial surface. The resulting data set is comparatively small (∼94 GB, compressed 16.8 GB), and the raster data can be readily integrated into analytical workflows in software familiar to many ecologists (GIS software, R, Python). Source code and documentation for the processing workflow are openly available via a code repository, allowing for transfer to other ALS data sets, as well as modification or re-calculation of future instances of Denmark's national ALS data set. We hope that our high-resolution ecological vegetation and terrain descriptors (EcoDes-DK15) will serve as an inspiration for the publication of further such data sets covering other countries and regions and that our rasterised data set will provide a baseline of the ecosystem structure for current and future studies of biodiversity, within Denmark and beyond. The full data set is available on Zenodo: https://doi.org/10.5281/zenodo.4756556 (Assmann et al., 2021); a 5 MB teaser subset is also available: https://doi.org/10.5281/zenodo.6035188 (Assmann et al., 2022a).

Supplemental Digital Content is Available in the Text., Aortic valve replacement for severe stenosis is a standard procedure in cardiovascular medicine. However, the use of biological prostheses has limitations especially in young patients because of calcifying degeneration, resulting in implant failure. Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, was shown to decrease the degeneration of native aortic valves. In this study, we aim to examine the impact of pioglitazone on inflammation and calcification of aortic valve conduits (AoC) in a rat model. Cryopreserved AoC (n = 40) were infrarenally implanted into Wistar rats treated with pioglitazone (75 mg/kg chow; n = 20, PIO) or untreated (n = 20, controls). After 4 or 12 weeks, AoC were explanted and analyzed by histology, immunohistology, and polymerase chain reaction. Pioglitazone significantly decreased the expression of inflammatory markers and reduced the macrophage-mediated inflammation in PIO compared with controls after 4 (P = 0.03) and 12 weeks (P = 0.012). Chondrogenic transformation was significantly decreased in PIO after 12 weeks (P = 0.001). Calcification of the intima and media was significantly reduced after 12 weeks in PIO versus controls (intima: P = 0.008; media: P = 0.025). Moreover, echocardiography revealed significantly better functional outcome of the AoC in PIO after 12 weeks compared with control. Interestingly, significantly increased intima hyperplasia could be observed in PIO compared with controls after 12 weeks (P = 0.017). Systemic PPAR-gamma activation prevents inflammation as well as intima and media calcification in AoC and seems to inhibit functional impairment of the implanted aortic valve. To further elucidate the therapeutic role of PPAR-gamma regulation for graft durability, translational studies and long-term follow-up data should be striven for.

ZusammenfassungDer Priapismus als klinische Manifestation einer hämatologischen Erkrankung ist selten. In diesem Fall liegt ein sowohl urologischer als auch internistischer Notfall vor, der einer umgehenden Therapie bedarf. Dieser Artikel beschreibt den klinischen Fall eines Priapismus als Erstmanifestation einer bis dahin nicht diagnostizierten chronisch-myeloischen Leukämie (CML) und erläutert die Resultate einer Literaturrecherche zu dieser Thematik.

Die optimierte Biokompatibilitat ist entscheidend fur die Haltbarkeit von Herz-Kreislauf-Implantaten. Bisher wurde gezeigt, dass eine kombinierte Beschichtung mit Fibronektin (FN) und Stromal cell-derived factor 1α (SDF1α) die In-vivo-Zellularisierung von synthetischen Gefastransplantaten beschleunigt und die Verkalkung von biologischen Pulmonalarterienstammtransplantaten verringert. In dieser Studie wurde die Wirkung einer seitenspezifischen Beschichtung mit SDF1α und FN auf die In-vivo-Rebesiedlung und -degeneration von dezellularisierten Aortenklappen-Conduit-Transplantaten untersucht. Spenderaorten wurden mit einem detergenzienbasierten Verfahren dezellularisiert. Die endoluminale Oberflache wurde mit SDF1α beschichtet, wahrend die Adventitiaoberflache mit FN beschichtet wurde. Mit SDF1α beschichtete und unbeschichtete Transplantate wurden Empfangerratten infrarenal implantiert (n = 20) und bis zu 8 Wochen nachuntersucht. Die Intimazellrepopulation wurde durch eine luminale SDF1α-Beschichtung beschleunigt (92,4 ± 2,95 % gegenuber 61,1 ± 6,51 % bei den Kontrollen, p

The combination of Imatinib (IM) and hydroxyurea (HU) was explored for the treatment of chronic myelogenous leukemia (CML).AfterAdditive specific inhibition of CML cells by IM/HU was detectedIM/HU combination was more potent in selectively inhibiting CML cells

Proton exchange membrane water electrolysis is technically the most suitable technology for the production of green hydrogen on a large scale. Although it is still more expensive than hydrogen produced from fossil sources, it has already been commercialized. Novel components with cost-effective materials and efficient manufacturing processes are being rapidly developed. However, these components must endure durability tests that can guarantee a lifetime of at least 50,000 operation hours. Consequently, there is an urgent need to develop accelerated stress test protocols based on a deep understanding of degradation mechanisms of stack components. Recent reports show that the main degradation mechanisms are associated to anode catalyst dissolution, membrane chemical decomposition, and formation of semiconducting oxides on the metal components. These mechanisms can be accelerated by stressors such as high current density, dynamic operation, and shutdown modes. On the basis of these reports and knowledge of the operational requirements for large-scale proton exchange membrane water electrolysis, we propose an accelerated stress test protocol for the fast evaluation of newly developed cost efficient and durable components.

BackgroundExcessive tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP) are all potential causes of ventilator-induced lung injury, and all contribute to a single variable: the mechanical power. The authors aimed to determine whether high tidal volume or high respiratory rate or high PEEP at iso-mechanical power produce similar or different ventilator-induced lung injury.MethodsThree ventilatory strategies—high tidal volume (twice baseline functional residual capacity), high respiratory rate (40 bpm), and high PEEP (25 cm H2O)—were each applied at two levels of mechanical power (15 and 30 J/min) for 48 h in six groups of seven healthy female piglets (weight: 24.2 ± 2.0 kg, mean ± SD).ResultsAt iso-mechanical power, the high tidal volume groups immediately and sharply increased plateau, driving pressure, stress, and strain, which all further deteriorated with time. In high respiratory rate groups, they changed minimally at the beginning, but steadily increased during the 48 h. In contrast, after a sudden huge increase, they decreased with time in the high PEEP groups. End-experiment specific lung elastance was 6.5 ± 1.7 cm H2O in high tidal volume groups, 10.1 ± 3.9 cm H2O in high respiratory rate groups, and 4.5 ± 0.9 cm H2O in high PEEP groups. Functional residual capacity decreased and extravascular lung water increased similarly in these three categories. Lung weight, wet-to-dry ratio, and histologic scores were similar, regardless of ventilatory strategies and power levels. However, the alveolar edema score was higher in the low power groups. High PEEP had the greatest impact on hemodynamics, leading to increased need for fluids. Adverse events (early mortality and pneumothorax) also occurred more frequently in the high PEEP groups.ConclusionsDifferent ventilatory strategies, delivered at iso-power, led to similar anatomical lung injury. The different systemic consequences of high PEEP underline that ventilator-induced lung injury must be evaluated in the context of the whole body.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

Das hepatozellulare Karzinom (HCC) wird zu einer immer groser werdenden soziookonomischen Herausforderung. Internationale Leitlinien sprechen sich vorwiegend gegen die pratherapeutische Bestimmung der α‑Feto-Protein(AFP)-Konzentration aus. Bezuglich der prognostischen Aussagekraft des AFP ist die europaische Studienlage nicht aussagekraftig genug. Diese Arbeit soll mogliche Aspekte des AFP-Spiegels aufzeigen und die prognostische Vorhersagekraft des AFP-Spiegels untersuchen sowie Anregungen fur zukunftige prospektive Studien geben. Eine prospektive Leberdatenbank (n = 1382) wurde im Hinblick auf HCC-Patienten, die einen histologisch gesicherten Tumor aufweisen (n = 92), ausgewertet. Es lagen Informationen zu T‑, N‑, M‑, G‑Stadium und R‑Status bzw. zu Geschlecht, Alter, Genese vor. Fur die Analyse teilten wir das Patientengut anhand von 3 Cut-off-Werten in 6 Gruppen ein. Des Weiteren fuhrten wir eine Uberlebensanalyse mittels Kaplan-Meier und eine multifaktorielle Analyse der Einflussfaktoren auf das Outcome durch. Es gibt einen statistisch signifikanten Zusammenhang zwischen dem AFP-Spiegel, dem Tumordurchmesser (T1/2 vs. T3/4) und dem Grading (G1/G2 vs. G3/G4). In allen Gruppen fiel die Uberlebensprognose in der jeweiligen Gruppe mit dem hoheren AFP-Spiegel signifikant schlechter aus (p 8 μg/l betrug 35 Monate; bei Patienten mit AFP-Spiegeln von >200 μg/l bzw. >400 μg/l betrug das mediane Uberleben 15 Monate bzw. 11 Monate. Hohe AFP-Spiegel sind unabhangig vom T‑Stadium, Alter und R‑Status des Patienten im Vergleich zu niedrigen AFP-Spiegeln ein signifikanter Einflussfaktor fur das Outcome. Unter Berucksichtigung der vorliegenden Ergebnisse kann dem AFP-Spiegel eine therapeutische Nutzlichkeit zugeschrieben werden. Es konnten sich aus der Hohe der gemessenen AFP-Konzentration therapeutische Konsequenzen im Hinblick auf die Therapiestrategie ergeben. Demnach empfehlen wir bei allen HCC-Patienten die pra- und postoperative Bestimmung des AFP-Spiegels.

Background Although randomized controlled trials (RCTs) provide the most reliable form of scientific evidence, they are challenging to complete because of a variety of enrollment obstacles. We evaluated obstacles in a large RCT by comparing survey results at high-performing sites (HPS) and low-performing sites (LPS). Methods The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) trial is a prospective, pragmatic, multicenter, and multispecialty RCT that will compare clinical outcomes, quality of life, and cost in patients with CLI randomized to surgical bypass or endovascular therapy. BEST-CLI aims to enroll 2100 patients at 160 sites in North America, Europe, and New Zealand. We surveyed the 30 HPS and 30 LPS to assess perceptions of enrollment obstacles. HPS were defined by enrollment of 0.5 subjects or more per month or more than 8 total subjects enrolled. LPS were defined by enrollment of 0.1 subjects per month or only 1 subject total. Responses were compared by site performance status. Results There were 22 of 30 (73%) HPS and 14 of 30 (47%) LPS that answered the survey (P = 0.06), including 17 investigators and 31 coordinators. The mean total enrollment and rate of enrollment at HPS and LPS were 12.5 subjects at 1.5 subjects/month and 1.0 subject at 0.1 subjects/month, respectively. The most common barrier to enrollment at HPS was difficulty convincing patients and their families to participate (36%), whereas at LPS both difficulty convincing patients and difficulty motivating investigators to enroll (29% each) were most frequently cited. At HPS, the most common obstacle to consenting patients for the trial was patient/family having strong preference toward revascularization strategy (32%) and at LPS it was patient/family not wanting to have treatment chosen at random (36%). At 55% of HPS and 43% of LPS, the trial team was reported as extremely collaborative (P = 0.73), whereas 68% of HPS and 64% of LPS reported having identified a trial champion on their team (P = 1). The most restrictive perceived enrollment criterion at HPS was prior index limb stenting with significant restenosis (32%), whereas at LPS it was excessive risk for surgical bypass (43%). Materials to aid enrollment were used equally at HPS and LPS: patient brochures at 59% HPS and 64% LPS (P = 1); investigator talking points at 45% of HPS and 36% of LPS (P = 0.73). Conclusions Patient perceptions and investigator biases are significant challenges to enrollment in large RCTs. In the BEST-CLI trial, difficulty convincing patients and families to allow treatment randomization and difficulty in motivating investigators were major enrollment obstacles.

Introduction: Approximately 1 out of 4 stroke patients suffers ischemic stroke secondary to atrial fibrillation (AF). Although indicated, withholding of anticoagulants for secondary prevention is a widespread phenomenon. Objective: We examined the longitudinal change of recommendation and prescription of secondary preventive anticoagulation in AF patients in an acute stroke center setting focusing on the impact of the introduction of direct oral anticoagulants (DOACs) and the change of national stroke prevention guidelines. Methods: Consecutive patients admitted with an acute cerebrovascular ischemic event underwent regular diagnostic work-up. Pseudonymized clinical data were entered into the institution’s stroke registry. In those patients with AF, discharge letters were collected and evaluated for temporal trends and affecting factors of recommended and prescribed antithrombotic secondary medication at the time of discharge from hospital. Results: Of 7,175 patients admitted between January 2009 and December 2018, 1,812 (25.3%) suffered stroke caused by AF. Frequency of patients with recommended anticoagulation increased within the observation period from 66.7 to 95.8% (per year; adjusted odds ratio [OR], 1.309; confidence interval [CI], 1.153–1.486). Independently from this time trend, DOAC approval (adjusted OR, 4.026; CI 1.962–8.265) and guideline change (adjusted OR, 2.184; CI, 1.006–4.743) were associated with an increasing frequency of recommendation for anticoagulation. The rate of patients already receiving recommended anticoagulation for secondary prevention at discharge increased from 42.1 to 62.5%. Introduction of DOACs was not associated with this trend, and guideline change was even associated with decreasing frequency of anticoagulated patients at hospital discharge (adjusted OR, 0.641; CI, 0.414–0.991). Fear of early intracerebral bleeding was the most common reason for withholding anticoagulation (37%) at hospital discharge and stayed stable during the observation period. Conclusions: Changing national guidelines with discard of contraindications for anticoagulation and the introduction of DOACs led to a broader recommendation of oral anticoagulation. However, both, new guidelines and DOACs, were not found to be associated with an increasing percentage of patients discharged from our hospital already on recommended anticoagulant prevention. This might be explained by the decreasing length of hospital stay during the study period and a missing evidence of early bleeding risk of DOACs in patients with acute brain infarction. Evidence-based data to close this therapeutic gap are needed.

Purpose Faecal incontinence (FI) is estimated to affect around 7.7% of people. There is a lack of uniformity in outcome definitions, measurement and reporting in FI studies. Until now, there is no general consensus on which outcomes should be assessed and reported in FI research. This complicates comparison between studies and evidence synthesis, potentially leading to recommendations not evidence-based enough to guide physicians in selecting an FI therapy. A solution for this lack of uniformity in reporting of outcomes is the development of a Core Outcome Set (COS) for FI. This paper describes the protocol for the development of a European COS for FI. Methods Patient interviews and a systematic review of the literature will be performed to identify patient-, physician- and researcher-oriented outcomes. The outcomes will be categorised using the COMET taxonomy and put forward to a group of patients, physicians (i.e. colorectal surgeons, gastroenterologists and general practitioners) and researchers in a Delphi consensus exercise. This exercise will consist of up to three web-based rounds in which participants will prioritise and condense the list of outcomes, which is expected to result in consensus. A consensus meeting with participants from all stakeholder groups will take place to reach a final agreement on the COS. Discussion This study protocol describes the development of a European COS to improve reliability and consistency of outcome reporting in FI studies, thereby improving evidence synthesis and patient care. Trial registration This project has been registered in the COMET database on the 1st of April 2020, available at http://www.comet-initiative.org/Studies/Details/1554. The systematic review has been registered on the PROSPERO database on the 31st of August 2020, available at https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=202020&VersionID=1381336.

The development of crowdsourcing software is commonly organized around platforms that allow a requester to submit a task and connect it with a crowd of individuals, who will provide likely solutions to the task. However, these platforms often ignore factors that provide a satisfactory user experience, reflecting, among others, the abandonment of tasks. To this end, it is essential to identify and understand User Experiences (UX) on platforms, assist in the improvement/development of these environments, and minimize barriers imposed by unsatisfactory experiences problems. This paper aimed to investigate long-term UX on a crowdsourcing platform. It is a qualitative exploratory study, carried out from a quasi-experiment, in which 10 undergraduate students selected for convenience participated. Participants performed tasks on the TopCoder platform over 3 months and answered the online questionnaire. Throughout the period, participants reported their experiences with the platform, describing their impressions about the use. The results showed the most satisfactory experiences occurred mainly in the last weeks of study and were mainly associated with the completion and task submission. For less satisfactory experiences, the main reasons identified were mainly associated with the difficulty of use and low usability. All participants informed that they would recommend the platform to others. It is concluded that, even with usability problems, the user's experience when using the platform was satisfactory. The results can be used to suggest mechanisms that reduce the barriers imposed by problems of less satisfactory experiences, spreading the crowdsourcing software and, consequently, expanding its adoption in the software development industry.

In this chapter, different strategies to be considered for the decision on personalized approaches to coronary artery bypass grafting are discussed. Particularly, aspects regarding the bypass material, the bypass architecture, the revascularization strategy, the operative risk reduction and the trauma minimization are described, analyzed, and a short literature review is provided.

Hintergrund Der autosomal-rezessiv vererbte Defekt der aromatischen L‑Aminosäure-Decarboxylase (AADC) führt zu einem ausgeprägten, kombinierten Mangel an Dopamin, Serotonin und Katecholaminen. Das klinische Bild ist charakterisiert durch eine rumpfbetonte, muskuläre Hypotonie, verzögertes oder fehlendes Erreichen der motorischen Meilensteine und okulogyre Krisen ab dem Säuglingsalter. Der Erfolg der konventionellen, medikamentösen Behandlung ist besonders bei schweren Verläufen sehr limitiert. Mit der intrazerebralen Applikation von Eladocagene exuparvovec (Upstaza®), einer AAV2-basierten Gentherapie, deren Zulassung für Mitte 2021 erwartet wird, steht erstmals ein kausaler Therapieansatz zur Verfügung. Ziel In Zusammenarbeit mit der Gesellschaft für Neuropädiatrie (GNP), der Arbeitsgemeinschaft pädiatrischer Stoffwechselstörungen (APS), der Gesellschaft für Neurochirurgie (DGNC) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ) wurden die Strukturvoraussetzungen und die praktischen Aspekte in der Vorbereitung, Durchführung und Nachsorge der Therapie mit Eladocagene exuparvovec erarbeitet. Diskussion Die vorliegende Stellungnahme stellt die notwendigen Rahmenbedingungen für eine qualitätsgesicherte Anwendung von Eladocagene exuparvovec zusammen. Die Behandlung erfordert eine prästationäre, stationäre und poststationäre Betreuung durch ein multiprofessionelles Team in einem spezialisierten und qualifizierten Therapiezentrum. Die Nachsorge der Patienten soll zu einer wissensgenerierenden Versorgung beitragen. Aufgrund von fehlenden Daten zur therapeutischen (Langzeit‑)Wirkung sowie zu Vor- und Nachteilen der verschiedenen stereotaktischen Prozeduren sind ein strukturierter Nachsorgeplan und die Erfassung in einem geeigneten, industrieunabhängigen Register notwendig. Background The autosomal recessive defect of aromatic L‑amino acid decarboxylase (AADC) causes a severe combined deficiency of dopamine, serotonin and catecholamines. The clinical picture is characterized by truncal hypotonia, delayed or absent achievement of motor milestones, and oculogyric crises from infancy onwards. The response to conventional drug treatment is very limited, especially in severe cases. The intracerebral application of eladocagene exuparvovec, an AAV2-based gene therapy, which is expected to be approved in mid-2021, is the first available causal therapeutic approach. Aim In collaboration with the German Society of Neuropediatrics (GNP), the Working Group of Pediatric Metabolic Disorders (APS), the German Society of Neurosurgery (DGNC) and the German Society of Pediatrics and Adolescent Medicine (DGKJ), the structural requirements and practical aspects in the preparation, implementation and follow-up of the treatment with eladocagene exuparvovec were elaborated. Discussion The present statement compiles the necessary framework conditions for a quality-assured administration of eladocagene exuparvovec. The treatment requires prehospital, inpatient and posthospital care by a multiprofessional team in a specialized and qualified treatment center. Patient follow-up is intended to contribute to knowledge-generating care. Due to lack of data on the therapeutic (long-term) effect as well as on advantages and disadvantages of the different stereotactic approaches, a structured follow-up plan and documentation in an appropriate, industry-independent registry are necessary.

Optically inactive or dark excitons play an important role in exciton and polariton devices. On one hand, they supply excitons to the light cone and feed the photoluminescence signal. On the other hand, they repel radiatively active excitons due to the exchange interaction and contribute to the formation of lateral potentials for exciton and polariton condensates. On top of this, they play an important role in scattering and energy relaxation dynamics of quasiparticles in semiconductors. So far, because of optical inaccessibility, studies were focused typically on one experimental technique, giving information about one quantity of dark excitons. Here we present a comprehensive study of the dark exciton reservoir in a high-quality 14-nm GaAs/AlGaAs quantum well using several experimental techniques. We develop a new method of nonradiative broadening spectroscopy of exciton resonances and combine it with nondegenerate pump-probe spectroscopy. The exciton and carrier dynamics in the reservoir is monitored via dynamic broadening of exciton resonances induced by exciton-exciton and exciton-carrier scattering. The dynamics is found to be strongly dependent on the optical excitation conditions. Based on the experimental results, we develop a model of dynamics in a reservoir of excitons and free carriers. The model allows us to describe the experimentally measured photoluminescence kinetics with no fitting parameters. We also demonstrate the optical control of the dark exciton density by means of an additional excitation that creates imbalance of free carriers depleting the reservoir. These results shed light onto the dynamics of the excitonic ``dark matter'' and pave the way to the high-precision engineering of optically induced potentials in exciton-polariton and integrated photonic devices. We expect that the observed results can be transferred also to other semiconductors so that the current quantum well serves as a high-quality model system.

Publisher's version (útgefin grein), Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need., The work of the co-ordinating centre was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/ 002), British Heart Foundation Cambridge Cardiovascular Centre of Excellence, UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The Emerging Risk Factor Collaboration’s website https://www.phpc.cam.ac.uk/ceu/erfc/list-of-studies/ has compiled a list provided by investigators of some of the funders of the component studies in this analysis. I.W. was supported by the Medical Research Council Unit Programme MC_UU_12023/21. M.K. is supported by the Netherlands Organization for Scientific Research (NWO) Veni grant (Veni, 91616079). J.P. is supported by Erasmus Mundus Western Balkans (ERAWEB), a project funded by the European Commission.

portuguesO objetivo deste trabalho foi identificar alturas de manejo para pastos de papua sob lotacao continua em sistemas de integracao lavoura-pecuaria (ILP). Para tanto, doze pastos foram cultivados em uma area de ILP e mantidos em 10, 20, 30 ou 40 cm por meio de lotacao continua com caprinos. As seguintes variaveis foram analisadas: massa; taxa de acumulo e oferta de forragem e de folhas; relacao lâmina:colmo; composicao quimica de amostras de simulacao de pastejo; carga animal; ganho medio diario e producao animal por area. Os dados foram submetidos a analises de regressao e correlacao. A significância adotada foi de 5% (P≤0,05). Os principais resultados foram: i) houve um aumento linear na massa de forragem e folhas com o aumento da altura de manejo e pastos com mais de 20 cm ja apresentavam a quantidade minima recomendada para cobertura de solo em ILP ii) o desempenho animal atingiu um plato assintotico nos pastos manejados entre 30-40 cm e foi altamente correlacionado com a altura de manejo e a disponibilidade de forragem (massa e oferta). Pastos de Papua manejados sob lotacao continua em ILP devem ser mantidos entre 30-40 cm para favorecer a producao de biomassa de cobertura e o desempenho animal. EnglishThe aim of this experiment was to identify grazing height targets for Alexandergrass pastures under continuous stocking in integrated crop-livestock system (ICLS). For this purpose, twelve pastures were cultivated into an ICLS area, and maintained at 10, 20, 30, or 40 cm using grazing goats. The following variables were analyzed: leaf and herbage mass, accumulation rate, and allowance; leaf:stem ratio; chemical composition of hand-plucked samples; stocking rate; average daily gain and gain per area. The data were submitted to regression and correlation analysis. Significance was set at 5% (P≤0.05). The main results were: i) herbage and leaf lamina mass increased linearly with grazing height, and pastures maintained at 20 cm already presented the minimum amount recommended for soil cover in ICLS; ii) animal performance achieved an upper asymptotic plateau in pastures maintained around 30-40 cm and it was highly correlated with both grazing height and forage availability (mass and allowance). Alexandergrass pastures under continuous stocking in ICLS should be maintained between 30-40 cm to improve both cover crop biomass and animal performance

Optimized biocompatibility is crucial for the durability of cardiovascular implants. Previously, a combined coating with fibronectin (FN) and stromal cell-derived factor 1α (SDF1α) has been shown to accelerate the in vivo cellularization of synthetic vascular grafts and to reduce the calcification of biological pulmonary root grafts. In this study, we evaluate the effect of side-specific luminal SDF1α coating and adventitial FN coating on the in vivo cellularization and degeneration of decellularized rat aortic implants. Aortic arch vascular donor grafts were detergent-decellularized. The luminal graft surface was coated with SDF1α, while the adventitial surface was coated with FN. SDF1α-coated and uncoated grafts were infrarenally implanted (n = 20) in rats and followed up for up to eight weeks. Cellular intima population was accelerated by luminal SDF1α coating at two weeks (92.4 ± 2.95% versus 61.1 ± 6.51% in controls, p α coating inhibited neo-intimal hyperplasia, resulting in a significantly decreased intima-to-media ratio after eight weeks (0.62 ± 0.15 versus 1.35 ± 0.26 in controls, p α group as compared to the control group (area of calcification in proximal arch region 1092 ± 517 μm2 versus 11 814 ± 1883 μm2, p α promotes early autologous intima recellularization in vivo and attenuates neo-intima hyperplasia as well as calcification of decellularized vascular grafts.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

The carabids of the tribe Platynini from the southern Levant (Egypt: Sinai Peninsula, Israel, Jordan) and adjacent regions of Egypt, Lebanon, Syria, Iraq, and Saudi Arabia are reviewed in terms of species taxonomy, ecological, distributional traits, and conservation biology. In addition to a classical dichotomous identification key to the 14 species of the region, identification tools are made freely available via the Xper3 knowledge database “Platynini, southern Levant”. Besides an interactive identification key, a matrix with character states for the species and single access identification keys are available. A database including all available records from the southern Levant is also provided. First faunistic records are recorded for Anchomenus dorsalis infuscatus from Sinai (Egypt), Olisthopus fuscatus from Lebanon and Iraq, and for O. glabricollis from Iraq. Threatened species are discussed, also with regard to the reasons of their decline. The majority of species lives in wetlands, especially on the shore of winter ponds and streams, which have been extremely degraded in the last decades.

Graphical abstract, Highlights • The coexistence of diabetes and hypertension represents a major risk factor for the onset of cardiovascular problems. • The purinergic signaling pathway constitutes a ubiquitous system of cell–cell communication. • Purinergic system plays a pivotal role in physiopathological conditions. • Several alterations in purine metabolism have been demonstrated in diabetes and hypertension. • Purinergic system can be an important target related to therapeutic approaches in diabetes and hypertension., Diabetes mellitus (DM) and hypertension are highly prevalent worldwide health problems and frequently associated with severe clinical complications, such as diabetic cardiomyopathy, nephropathy, retinopathy, neuropathy, stroke, and cardiac arrhythmia, among others. Despite all existing research results and reasonable speculations, knowledge about the role of purinergic system in individuals with DM and hypertension remains restricted. Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the recognition and degradation of extracellular nucleotides and adenosine. The main components of this system that will be presented in this review are: P1 and P2 receptors and the enzymatic cascade composed by CD39 (NTPDase; with ATP and ADP as a substrate), CD73 (5′-nucleotidase; with AMP as a substrate), and adenosine deaminase (ADA; with adenosine as a substrate). The purinergic system has recently emerged as a central player in several physiopathological conditions, particularly those linked to inflammatory responses such as diabetes and hypertension. Therefore, the present review focuses on changes in both purinergic P1 and P2 receptor expression as well as the activities of CD39, CD73, and ADA in diabetes and hypertension conditions. It can be postulated that the manipulation of the purinergic axis at different levels can prevent or exacerbate the insurgency and evolution of diabetes and hypertension working as a compensatory mechanism.

Inequality and discrimination according to gender have been debated for decades, gender equality is among the Millennium Development Goals, proposed by the UN. Numerous barriers are still faced in the academic and work world, with regard to the participation of women in science and technology. The Girls High-Tech project was created in line with the “Digital Girls” program, proposed by the Brazilian Computer Society, working within the scope of the IFRS Happy Campus and schools located in the region. The main objective of the project is to promote reflections and actions on female participation in the area of Information Technology (IT), seeking to encourage the performance of girls in this area and problematizing gender inequalities.

The impact of different extracorporeal circulation (ECC) scenarios on arterial blood flow profiles has not yet been revealed. To allow for exact measurements, magnetic resonance imaging (MRI) during ECC is required. Therefore, the present study addressed the feasibility of a high-resolution MRI-compatible animal model of ECC. For usage in New Zealand White rabbits, we developed an ECC device, the tubes of which were long enough to eliminate impacts of the magnetic field on the blood pump and heart–lung control machine. The miniaturized ECC system via thoracic access comprised an infant oxygenator, a pulsatile centrifugal pump, 1/8″ tubes, a 10-Fr aortic cannula and a 12-Fr venous cannula for vacuum-assisted drainage. This miniaturized ECC system has very low priming volume (230–255 ml) to reduce the system-inherent haemodilution to 50%. Consequently, haemoglobin rates remained high enough to guarantee adequate oxygenation (arterial pressure of oxygen >200 mmHg). Optimized venous drainage by an additionally inserted pulmonary artery vent catheter resulted in sufficient blood flow (31.6–65.8 ml/min/kg) that was maintained for 60 min with pulsatility. The current study demonstrates the feasibility of MRI-compatible ECC in rabbits, and this model allows for real-time blood flow profile measurements during different ECC scenarios in future projects.

Globalization has advanced at an accelerated pace during the 20th century. This is also true for the expansion of East Asian cuisines in Germany, which is the major theme discussed in the yearbook ...

In order to reduce the prognostically relevant time interval between the initial manifestation of a rheumatic and musculoskeletal disease and diagnosis as well as the consecutive initiation of an appropriate treatment, several rheumatological centers in Germany have improved the access to initial rheumatologic evaluation by establishing early recognition/screening clinics at their respective sites. Corresponding models located at Altoetting·Burghausen, Bad Pyrmont, Berlin Buch, Duesseldorf, Heidelberg, Herne, Mannheim as well as supraregional/multicenter initiatives Rheuma Rapid, RhePort and Rheuma-VOR are presented in this overview along with the respective characteristics, potential advantages and disadvantages, but also first evaluation results of several models. The aim of this publication is to promote early detection of rheumatic and musculoskeletal diseases as one of the most important challenges in current rheumatology by encouraging further rheumatologic centers and practices to launch their own early recognition/screening consultation model on the basis of aspects presented herein.

Die rheumatoide Arthritis, die Psoriasisarthritis und die axiale Spondyloarthritis zahlen zu den haufigsten rheumatischen Erkrankungen. Bei allen 3 Erkrankungsbildern kristallisiert sich eine moglichst fruhe Diagnose und Therapieeinleitung als entscheidend heraus. Die aus ADAPTHERA weiterentwickelte und auf mehrere Bundeslander erweiterte prospektive Proof-of-Concept-Netzwerkstudie „Rheuma-VOR“ verfolgt das Ziel, diese 3 entzundlich-rheumatischen Erkrankungen so fruh wie moglich zu erkennen und die Versorgungsqualitat mithilfe von multidisziplinaren Koordinationsstellen zu verbessern. Bis dato wurden 3710 Screeningbogen mit einer moglichen Verdachtsdiagnose von rheumatoider Arthritis, Psoriasisarthritis oder axialer Spondyloarthritis von 1298 verschiedenen Primarversorgern bei den bundeslandspezifischen Koordinationsstellen gemeldet. Insgesamt wurden 1958 Termine bei 53 teilnehmenden rheumatologischen Spezialisten vergeben. Bei 876 Patienten wurde eine der 3 rheumatischen Erkrankungen im Fruhstadium diagnostiziert. Die Wartezeit liegt in Abhangigkeit des Bundeslandes bei durchschnittlich 42,5 Tagen und somit deutlich unter dem Bundesdurchschnitt. Ebenso ist festzuhalten, dass die Kapazitat der rheumatologischen Spezialisten durch die koordinierte Kooperation und die Risikostratifizierung der Rheuma-VOR-Koordinationsstellen um 1281 Termine (34,5 %) entlastet werden konnte. Daruber hinaus zeigen die 2‑wochige Rheuma-Bus-Tour und die in Rheinland-Pfalz begleitend durchgefuhrten Initiativen (Rheuma-VOR-Screening-App, Sichtungssprechstunde) erste vielversprechende positive Ergebnisse.

Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations.The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients.We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463 A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3602dupC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense mediated decay.Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Objective: To identify health-related quality of life in adolescents with excess weight and associated factors, such as gender, age, and weight categories. Method: A cross-sectional study with collected and secondary data from 276 adolescents aged between 10 and 19 years with overweight and obesity, and whose parents or guardians authorized their participation. Anthropometric data, pubertal development, and the PedsQL 4.0 questionnaire were collected for the health-related quality of life assessment. Categorical data were described as numbers and percentages. For the description of health-related quality of life subscales, medians and the 25th and 75th percentiles were used, as well as the Mann–Whitney test for comparisons between age group, gender, and weight categories. Results: The median health-related quality of life total score was 78.3 (68.5–87.4). The lowest scale was the “emotional score”, 65 (50–80). Higher health-related quality of life was found in boys in most of the scores (p

Background: Low-grade chronic inflammation has been suggested to play a substantial role in the etiology of depression; however, studies on the prospective association between the inflammatory potential of the diet and depression are limited.Objective: The aim of this study was to investigate the association between the inflammatory potential of the diet (measured using the Alternate Dietary Inflammatory Index, ADII) and incident depressive symptoms. We also tested the potential modulating effect of sex, age, BMI, and lifestyle indicators.Methods: The study sample consisted of 26,730 participants (aged 18-86 y) from the NutriNet-Sante study. Baseline ADII was computed using repeated 24-h dietary records collected during the first 2 y of the follow-up. Incident cases of depressive symptoms were defined by a Center for Epidemiologic Studies Depression scale >= 17 for men and >= 23 for women at least once during follow-up. HR and 95% CI were estimated using multivariable Cox proportional hazards models.Results: A total of 2221 incident cases of depressive symptoms were identified over a mean follow-up of 5.4 y. After accounting for a wide range of potential confounders, the highest quartile of the ADII was associated with a 15% (95% CI: 2, 31) increase in the risk of depressive symptoms compared with the lowest quartile. In the stratified analyses, associations were statistically significant only among women (HRquartile4 (vs. quartile1): 1.19; 95% CI: 1.02, 1.37), middle-age adults (HRquartile4 vs. quartile1: 1.16; 95% CI: 1.00, 1.35), and participants with a BMI >= 25 (HRquartile4 vs. quartile1: 1.29; 95% CI: 1.04, 1.60).Conclusions: Overall, a proinflammatory diet was associated with a higher risk of depressive symptoms, especially among women, middle-age adults, and participants with overweight or obesity. These findings contribute to the increasing scientific evidence showing a detrimental role of the proinflammatory diet. The NutriNet-Sante study is registered at clinicaltrials.gov as NCT03335644.

Pesticides are used in the control and prevention of pests, improving the productivity and the quality of agricultural production. The adoption of the Brazilian agricultural model, which uses pesticides on a large scale and indiscriminately, has been worrying public authorities about their impacts on human health and environmental sustainability. Thus, studies that contribute to a better understanding of agrochemicals and their effects on ecosystems and human health are timely. The aim was to investigate the history of the production and use of pesticides, their classifications, sources of exposure and their risks to human health. The research was carried out through literature review in databases to verify scientific information about the history of pesticides, structural and toxicological classifications, sources of exposure and their risks to human health. The use of pesticides dates back many years. During the nineteenth century until the mid-twentieth century, some chemicals nowadays used was pesticides were used for public health or for war purposes. About the classification of pesticides, due to the different biological targets, the agrochemicals market is segmented into different action targets (herbicides, fungicides and insecticides). Pesticides can be classified as contact, ingestion or systemic according to the mode of action. As for the chemical structure, the main classes of pesticides are organochlorines, organophosphates, pyrethroids and carbamates. The toxicity of pesticides ranges from low toxic to extremely toxic. Exposure to pesticides can occur directly through occupational exposure, or indirectly, through environmental exposure and food. The impacts on human health are divided into acute and chronic form. The prolonged human exposure to pesticides may result in neurological, reproductive, teratogenic and immunological disorders. The results presented in this literature review contribute to a better understanding of agrochemicals and their effects on human health.