Search

Zusammenfassung Hintergrund Im Rahmen der gesundheitsökonomischen Analyse wurde in einem Piggyback-Ansatz die Kosteneffektivität des am Point of Care Apotheke erbrachten Präventionsprogrammes der GLICEMIA 2.0-Studie evaluiert, das versuchte, die Teilnehmenden in der Interventionsgruppe zu einer verbesserten glykämischen Kontrolle bei Typ-2-Diabetes mit nachhaltiger Incentivierung von gesundheits-bewusstem Verhalten, therapeutischer Compliance und Adhärenz heranzuführen. Die Kontrollgruppe erhielt ein passives Medikationsmanagement und ein Monitoring zum Diabetes-Status. Methode Primärer Endpunkt der GLICEMIA 2.0-Studie war die Stabilisierung des HbA1c-Wertes. Zur gesundheitsökonomischen Auswertung wurden inkrementale Unterschiede in Output-Veränderungen untersucht, definiert als Differenz der Häufigkeitsverteilung der HbA1c-Werte zwischen den Gruppen im zeitlichen Verlauf. Als Kostenparameter wurden direkte Programmkosten und antizipierte indirekte Kosten der Inanspruchnahme ärztlicher Leistungen erfasst. Zur Validierung von Kosteneffektivitätsschwellen wurde über die Bildung von ICER-Werten ein Net-Monetary-Benefit-Ansatz herangezogen. Ergebnis Die Interventionsgruppe erreichte signifikant höhere Verbesserungen der HbA1c-Werte. Durch die vorgenommene Risikostratifizierung über den Anfangsmedian der HbA1c-Werte können Kosteneffektivitätspotenziale bei hohen HbA1c-Ausgangswertengezeigt werden. Aufgrund des Untersuchungszeitraums sind keine langfristigen Unterschiede in Inanspruchnahmen ärztlicher Leistungen ersichtlich. Schlussfolgerung Das GLICEMIA 2.0-Programm indiziert deutliche Effektivitätspotenziale besonders bei höheren Risikograden. Der Wirkeffekt scheint die Adhärenz der Interventions- im Vergleich zur Kontrollgruppe befördert zu haben. Eine Ermittlung der unmittelbaren Wirkungshebel der Gruppenintervention würde aufgrund des Charakters einer komplexen Intervention einen längeren Zeitraum benötigen. Aufgrund eines fehlenden Follow-up können über längerfristige Effekte nur eingeschränkte Aussagen getroffen werden.

Emissions of nitrogen oxides (NOx) from marine propulsion systems have gained public interest resulting in emission limits as defined by the International Maritime Organization (IMO) with IMO Tier III, especially for vessels operating in Emission Control Areas (ECA). The reduction of greenhouse gas emissions is also increasingly important for marine propulsion. Minimizing NOx while reducing climate impact calls for technologies such as the gas engine with aftertreatment systems, preferably with the ability to run on alternative fuels. A proven technology for reducing NOx in marine engines is the Selective Catalytic Reduction (SCR) aftertreatment system. It is also possible to avoid engine raw emissions by shifting the combustion process to lower temperature levels. Hydrogen is an alternative fuel with combustion properties enabling premixed operation at significantly higher air-fuel ratio than natural gas (NG) and thus, reducing raw NOx emissions. The study uses a systematic approach to compare emissions and efficiency of a lean-burn gas engine with a natural gas and a mild conversion hydrogen setup, utilizing two different strategies: combustion of NG with the assumption of an SCR catalyst and high raw NOx emissions and combustion of pure hydrogen using the NOx reduction potential of higher excess air. The scope of the study makes it possible to illustrate engine concepts for future applications in the displacement class of 4.8 L per cylinder. The highest efficiency of 45.3% was achieved with the natural gas engine and SCR. The concept with the lowest Global Warming Potential (GWP) was the hydrogen fueled engine under the prerequisite of using green hydrogen, accompanied by a reduction in efficiency of 0.6% compared to the efficiency optimum of NG with SCR. Assuming the use of gray hydrogen, the GWP was 48% and 52% higher than with NG and NG with SCR, respectively, at the efficiency-optimal operating points.

Large granular lymphocytic leukaemia (LGLL) has been described in a range of species but has been most commonly reported in humans and dogs. In both species, this neoplasia exhibits diversity in both phenotype and biological behaviour with phenotype only partially predicting behaviour. There is currently little knowledge of concurrent haematological and serum biochemistry features or concurrent occurrence of distinct neoplasia in canine LGLL cases. This study presents a canine case series and defines haematological parameters, novel serum biochemistry findings and phenotype of the large granular lymphocytes in an Australian case series. Neutrophilia was the most common haematological abnormality, identified in 43% of dogs, and 84% of dogs with biochemistry data available had elevated serum gamma-glutamyl transferase. Five of the 40 dogs in this study exhibited concurrent neoplasia during the period of the study, demonstrating this is a relatively common clinical outcome in canine LGLL cases. In agreement with previous canine and human studies, the most common LGLL phenotype in dogs is CD3+, CD4- and CD8+. Further work is needed to define the variables predictive of the biological behaviour of LGLL in dogs.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Bundesministerium für Bildung und Forschung. Background and introduction Cardiovascular diseases (CVD) remain the most common cause of death, although mortality due to CVD in Germany has decreased continuously over the past 20 years. The reasons for this decline are manifold. Besides the identification of risk factors, the application of algorithms for risk stratification, and the promotion of preventive means, the improvement in treatment strategies was of crucial importance [1, 2]. The ABC-CHD risk model combines novel biomarkers such as N-terminal pro-B-natriuretic peptide (NT-proBNP) and cardiac troponin T (hs-cTnT) with conventional factors in a unifying risk score which has been shown to reliably assess risk for CV mortality in patients with chronic coronary syndrome (CCS) [3]. However, data from the tertiary prevention setting, comparing its performance during different time periods, are scarce. Aims This study aimed to describe the characteristics and mortality of two cohorts of patients with CCS with identical study designs recruited in the same rehabilitation clinics approximately 10 years apart. Methods The KAROLA cohorts included patients with CCS participating in an inpatient cardiac rehabilitation programme in Germany (KAROLA-I: 1999/2000, KAROLA-II: 2009-2011) [details in 4]. Blood samples and information on sociodemographic factors, lifestyle, and medical treatment were collected at baseline, at the end of rehabilitation, and after 1-year follow-up. A biomarker-based risk model (ABC-CHD model) [3] and Cox regression analysis were used to predict cardiovascular (CV) and non-CV mortality risk during 10 years of follow-up. Results We included 1130 patients from KAROLA-I (mean age 58.7 years, 84.4% men) and 860 from KAROLA-II (mean age 60.4 years, 83.4% men). Patients in the KAROLA-I cohort had significantly higher concentrations of CV biomarkers and fewer patients were taking CV medications, except for statins. The ABC-CHD model which also included age, current smoking, history of diabetes, peripheral arterial disease, as well as hs-cTNT, NT-proBNP, and LDL-cholesterol provided a higher estimate of CV death risk for patients in the KAROLA-I cohort (mean 3-year risk, 3.8%) than for patients in the KAROLA-II cohort (mean 3-year risk, 2.7%, p for difference Conclusions Advances in disease management including pharmacological treatment over the past 20 years may have led to modest improvement of long-term prognosis of patients with CCS.

This paper provides an overview of possible engine design optimizations by utilizing highly knock-resistant potential greenhouse gas (GHG) neutral synthetic fuels. Historically the internal combustion engine was tailored to and highly optimized for fossil fuels. For future engine generations one of the main objectives is to achieve GHG neutrality. This means that either carbon-free fuels such as hydrogen or potential greenhouse gas neutral fuels are utilized. The properties of hydrogen make its use challenging for mobile application as it is very diffusive, not liquid under standard temperature/pressure and has a low volumetric energy density. C1-based oxygenated fuels such as methanol (MeOH), dimethyl carbonate (DMC) and methyl formate (MeFo) have properties like conventional gasoline but offer various advantages. Firstly, these fuels can be produced with renewable energy and carbon capture technologies to be GHG neutral. Secondly, the C1-based fuels burn with significantly less pollutant emissions. A third advantage is the high knock resistance of those fuels. This inherits a drastic efficiency potential for spark ignition engines as the compression ratio and therefore the potential thermal efficiency can be directly increased. In the single cylinder engine, a compression ratio (CR) of ~20:1 is investigated proving the high knock resistance as well as the efficiency potential of MeOH and a mixture containing 65 vol% DMC and 35 vol% MeFo (C65F35). Special attention is paid to the direct injection strategy, which utilizes up to quadruple injections and 35MPa fuel pressure. Later on, a more moderate CR increase to 15:1 with a CFD optimized piston design is investigated at a state of the art four-cylinder engine (4CE) utilizing C65F35. The whole engine map is presented proving the real-world usability and efficiency potential of this fuel type in combination with the optimized piston. WLTC and RDE tests were performed, underling both the practicality and the efficiency potential in dynamic conditions. The 4CE tests are rounded off by showcasing the potential of lean operation with two different high-energy ignition systems (Corona and passive pre-chamber ignition). The performance investigation on both engines is accompanied by emission measurements utilizing standard exhaust analyzers, an FTIR-device and particle number counting systems.

This study provides an overview of injector design adaptations and fuel pressure variations for oxygenated synthetic fuels, benchmarked against gasoline. The promising oxygenated fuels exhibited reduced emissions, especially with respect to particles. In gasoline engines, high fuel pressures are needed to keep the particle emissions below the permitted level. In oxygenated fuels, high fuel pressures are required to compensate for the lower volumetric energy density when used with non-adapted injectors. This study demonstrates that an adapted injector design enables engine operation with a fuel pressure reduction from 35 MPa to 10 MPa, without emission drawbacks.The fuel investigated contained dimethyl carbonate (DMC) and methyl formate (MeFo). The fuel mass contained around 50% oxygen. A relatively high percentage of 35 vol.% MeFo was chosen because of its high vapor pressure, thus providing fast mixture formation and enabling very late compression stroke injections. The basic design adaptations are expected to be transferable to other oxygenated synthetic fuels, e.g., containing methanol (MeOH) and MeFo.The main tests were conducted on a single cylinder research engine, based on a four-cylinder automotive engine. The exhaust gas composition was measured using an FTIR equipped with a fuel-tailored evaluation method, several standard exhaust gas analyzers, and a solid particle counting system with 10 and 23 nm cut-off sizes. The spray from both the two synthetic fuel injectors and the standard injector was further investigated at a spray chamber by means of a high-speed camera. Given a standard injector the spray pattern of 65vol% DMC+ 35vol%MeFo, and 85vol%MeOH+15 vol% MeFo were compared to the pattern of G100. All of the injectors were further investigated at an injection rate analyzer in order to provide necessary information about the injected fuel mass.

Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.

Enzalutamide activates AR signaling in the absence of androgen in HepG2 transiently transfected with AR F877L and AR F877L/T878A constructs but not AR T878A only

Kinase panel (KINOMEscan)

93-cell line proliferation assay was performed and data analyzed by OncoLead

JNJ-63576253 and enzalutamide inhibit KLK3 and FKBP5 mRNA expression in LNCaP AR/cs.

The synthetic androgen R1881 induces maximum proliferation in LNCaP AR/cs and LNCaP F877L cell lines at 0.1nM concentrations

Plasmid maps sequences

JNJ-63576253 inhibits AR nuclear localization

Body weights for LNCaP F877L xenograft model in castrated male SHO mice

Image-based profiling has emerged as a powerful technology for various steps in basic biological and pharmaceutical discovery, but the community has lacked a large, public reference set of data from chemical and genetic perturbations. Here we present data generated by the Joint Undertaking for Morphological Profiling (JUMP)-Cell Painting Consortium, a collaboration between 10 pharmaceutical companies, six supporting technology companies, and two non-profit partners. When completed, the dataset will contain images and profiles from the Cell Painting assay for over 116,750 unique compounds, over-expression of 12,602 genes, and knockout of 7,975 genes using CRISPR-Cas9, all in human osteosarcoma cells (U2OS). The dataset is estimated to be 115 TB in size and capturing 1.6 billion cells and their single-cell profiles. File quality control and upload is underway and will be completed over the coming months at the Cell Painting Gallery:https://registry.opendata.aws/cellpainting-gallery. A portal to visualize a subset of the data is available athttps://phenaid.ardigen.com/jumpcpexplorer/.

ZusammenfassungDie mechanischen Verluste von Verbrennungsmotoren hängen maßgeblich von den auftretenden Reibkräften innerhalb der Kolbengruppe ab. Da die Kolbengruppe das komplexeste tribologische System im Motor darstellt, ist ein hohes Systemverständnis notwendig, um die Bauteile gezielt zu optimieren. Um dieses Maß an Systemverständnis zu generieren, müssen die auftretenden Reibungsverluste direkt und kurbelwinkelaufgelöst gemessen werden. Eine Möglichkeit dazu bietet die Floating-Liner Methode, bei der in Einzylinder Forschungsmotoren die Laufbuchse axial schwimmend auf Kraftmessdosen gelagert wird. Eine Einschränkung dieser Messmethode ist die hohe Anfälligkeit für Störungen, vor allem aus Schwingungen des Motorbetriebs. Ein Teil dieser Schwingungen stammt aus dem Nockenwellen-Antrieb und dem bei Einzylindermotoren typischerweise verbauten Massenausgleich. Riementriebe mit kontinuierlichem Zahneingriff wie beispielsweise doppelschrägverzahnte Riemen können in der Theorie den Schwingungseinfluss dieser Antriebe reduzieren. Aus diesem Grund wurden im Rahmen dieser Arbeit zwei Riementriebe eines Einzylinder Forschungsmotors zur Reibkraftmessung nach dem Floating-Liner Prinzip mit solch doppelschrägverzahnten Riemen ausgestattet. Der kontinuierliche Zahneingriff reduziert die mittlere Schwingungsbreite der auftretenden Schwingungsanregung des Kraftsignals in Abhängigkeit der Motordrehzahl um bis zu 22 %. Eine genaue Schwingungsanalyse zeigt zudem, dass, im Gegensatz zum geradverzahnten Riemensystem, keine Anregungen durch die verbauten Riemenscheiben mehr auftreten. Zusätzlich wird die Amplitude der Schwingungsanregung der Kraftmessung reduziert. Insgesamt bieten somit doppelschrägverzahnte Riementriebe eine einfache Möglichkeit, die Störgrößen in für Schwingungen anfälligen Systemen, wie den Forschungsmotoren zur Reibkraftmessung, deutlich zu reduzieren.

Dieser Beitrag präsentiert ein Konzept für den simulationsgestützten Betrieb von Flugrobotern im dynamischen Produktionsumfeld einer wandlungsfähigen Fabrik. Zentrale Bedeutung wird dabei dem digitalen Zwilling beigemessen, der ein Umgebungsmodell inklusive Realdatenanbindung bereitstellt. Darauf basierend können Dienste implementiert werden, die den Betrieb eines Flugroboters unterstützen, beispielsweise zur Lokalisierung, Bahnplanung oder Mensch-Flugroboter-Interaktion. This paper presents an approach for the simulation-based operation of flight robots in the dynamic production environment of a flexible factory. An important role is assigned to the digital twin, which provides an environment model including real data connection. Based on this, services can be implemented supporting the operation of a flight robot, e.g. for localization, path planning or human-robot interaction.

Cold-start emissions of the sustainable alternative diesel fuel OME are predominantly NOx, formaldehyde, formic acid and unburned OME. Electrical heating in combination with fuel dosing is an effective method for after-treatment system heating.

OME as sustainable alternative diesel fuel burns without the agglomeration of soot particles which is the case for fossil and paraffinic diesel fuels. Nuclei mode particles are mainly of a volatile nature and do not survive exhaust aftertreatment.

Archaeology Program, La Trobe University

BackgroundAngiostrongylus cantonensis(rat lungworm) is recognised as the leading cause of human eosinophilic meningitis, a serious condition observed when nematode larvae migrate through the CNS. Canine Neural Angiostrongyliasis (CNA) is the analogous disease in dogs. Both humans and dogs are accidental hosts, and rapid diagnosis is warranted. A highly sensitive PCR based assay is available but often not readily accessible in many jurisdictions. An alternative DNA amplification assay that would further improve the accessibility is needed. This study aimed to assess the diagnostic utility of a newly designed LAMP assay to detect DNA of globally distributed and invasiveA. cantonensisandAngiostrongylus mackerrasae, the only other neurotropicAngiostrongylusspecies, which is native to Australia.Methodology/Principal FindingsCerebrospinal fluid (CSF) from dogs (2020-2022) with a presumptive diagnosis ofA. cantonensisinfection were received for confirmatory laboratory testing and processed for DNA isolation and ultrasensitiveAngiostrongylusqPCR. A newly designed LAMP assay targeting AcanR3390 in a diagnostic laboratory setting was directly compared to the reference ultrasensitive qPCR for determination of presence ofA. cantonensisDNA to aid the diagnosis of CNA. The LAMP assay (Angie-LAMP) allowed the sensitive detection ofA. cantonensisDNA from archived DNA specimens (Kappa=0.81, 95%CI 0.69-0.92;n=93) and rapid single-step lysis of archived CSF samples (Kappa=0.77, 95%CI 0.59-0.94;n=52). OnlyA. cantonensisDNA was detected in canine CSF samples, and co-infection withA. mackerrasaeusing amplicon deep sequencing (ITS-2 rDNA) was not demonstrated. Both SYD.1 and AC13 haplotypes were detected using sequencing of partialcox1.Conclusions/SignificanceThe Angie-LAMP assay is a useful molecular tool for detectingAngiostrongylusDNA in CSF of dogs and performs comparably to laboratoryAngiostrongylusqPCR. Adaptation of single-step sample lysis improved potential applicability for effective diagnosis of angiostrongyliasis in a clinical setting for dogs and by extension for humans.Authors summaryA potentially fatal disease, neural angiostrongyliasis, is caused by the rat lungworm (Angiostrongylus cantonensis). The parasite migrates into the spinal cord and brain of accidental hosts, such as humans and dogs, after ingestion of infective larvae. Recently, an ultrasensitive molecular assay which can detect tiny fragments of the parasite’s DNA was developed and has been used for confirmatory diagnosis. Although this assay outperforms previously developed assays, it requires clean DNA with specialised equipment in a laboratory setting. There is an urgent need for an alternative diagnostic method which is sensitive and portable, for deployment in the field and in the hospitals in remote areas or in low-income countries. The authors developed a fast and portable loop-mediated isothermal amplification (LAMP) assay that compares favourably to the ultra-sensitive PCR assay when tested using cerebrospinal fluid from dogs on the Australian east coast with presumptive neural angiostrongyliasis. Considering a ‘One Health’ approach to diagnostics, this assay enables portable emergency diagnostics equally suitable to humans, dogs and wildlife. The newly developed assay will also enable water supplies to be screened, as well as crustaceans and molluscs used as potential food sources, for presence of the parasite.

Against the backdrop of the plurality of agents and contexts, Africa’s peace and security norms have remained contested and open to interpretation in political practice. This article argues that African agents manifest their agencies precisely through their distinct interpretation and implementation of security norms. Based on Tanzania’s rejection to join the African Union Mission in Somalia (AMISOM) in 2007, this article zooms into the underlying domestic complexities by focusing in particular on the crucial influence of national identities for the ongoing construction of normative meaning in Africa’s peace and security landscape.

Objective and aims The primary aim of this study was to evaluate the correlation between incidental focal colorectal foci on fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) with colonoscopic and histopathological results. The secondary aim was to determine to what extent these findings led to a change in patient management. Materials and methods A retrospective study was performed among 5850 patients who had an FDG-PT/CT scan from July 2015 to July 2018. Among these patients, we identified patients with a PET/CT description of incidental colorectal FDG uptake, and a colonoscopy within 90 days from the PET/CT scan. PET/CT findings were compared with colonoscopy-detected lesions and eventually histopathology on a per-lesion analysis and a per-person analysis. Results A total of 145 patients were included in the study. A total of 180 foci of colorectal FDG uptake were detected on FDG-PET/CT. Of these, 86 foci corresponded to advanced colorectal neoplasia (ACRN), positive predictive value (PPV) 47.8%; 95% CI: 40.5-55.1%). On a per-patient analysis 81 patients had a least one ACRN at colonoscopy (PPV 55.9%; 95% CI: 47.6-63.8), this group included 20 patients (13.8%) diagnosed with cancer. There was a small positive correlation between focal FDG-uptake and the finding of ACRN at the same colonic segment at colonoscopy, which was statistically significant, rho = 0.2565, p = .002. The findings changed patient management in 67 (46.2%) cases. Conclusions Incidental focal colorectal FDG uptake on PET/CT is associated with a high risk of ACRN and is affecting subsequent patient management. Further evaluation with colonoscopy is recommended when the patient is considered suitable for further treatment.

We consider a structured estimation problem where an observed matrix is assumed to be generated as an $s$-sparse linear combination of $N$ given $n\times n$ positive-semi-definite matrices. Recovering the unknown $N$-dimensional and $s$-sparse weights from noisy observations is an important problem in various fields of signal processing and also a relevant preprocessing step in covariance estimation. We will present related recovery guarantees and focus on the case of non-negative weights. The problem is formulated as a convex program and can be solved without further tuning. Such robust, non-Bayesian and parameter-free approaches are important for applications where prior distributions and further model parameters are unknown. Motivated by explicit applications in wireless communication, we will consider the particular rank-one case, where the known matrices are outer products of iid. zero-mean sub-Gaussian $n$-dimensional complex vectors. We show that, for given $n$ and $N$, one can recover non-negative $s$-sparse weights with a parameter-free convex program once $s\leq O(n^2 / \log ^2(N/n^2)$. Our error estimate scales linearly in the instantaneous noise power whereby the convex algorithm does not need prior bounds on the noise. Such estimates are important if the magnitude of the additive distortion depends on the unknown itself.

Rising engine efficiency, increasingly stringent exhaust limits, and the use of synthetic and renewable fuels are all factors that demand a deeper knowledge of the combustion process. State-of-the-art investigations employ optical and laser-optical measurement techniques that rely on having optical access to the engine. In this paper, a new endoscopic system that provides full optical access to a high-speed large-bore engine is compared by thermodynamic experimentation to the equivalent all-metal engine. This comparison provides an insight into the altered combustion behavior resulting from modifying the engine to accommodate the optical elements. The successfully realized concept consists of two individually usable access points integrated in an engine with a bore of 170 mm and a stroke of 210 mm. The lateral endoscopic access is designed for full-load operating conditions and provides the best comparability to an all-metal engine. It is compared directly to the all-metal engine in the present investigations. Despite the changes in engine-out emissions from the optical engine, the experimental results display relatively equal combustion behavior in both setups. The lateral endoscopic access is then extended by adding a fisheye endoscope in place of one exhaust valve. This setup is compared to findings obtained with the endoscopic lateral access. The investigations reveal further deviations of the combustion process due to the more extensive modifications needed to fit the fisheye endoscope to the cylinder head. Nevertheless, the results display an overall good level of comparability of the combustion behaviors in these setups and, in turn, of the validity of further fundamental experiments based on the optical engine.

Background High-density lipoprotein (HDL) function rather than concentration plays an important role in the pathogenesis of cardiovascular diseases associated with oxidative stress and inflammation such as coronary artery disease (CAD). In the last years, inflammation has been identified to have a pivotal role in the pathogenesis of acute coronary syndrome (ACS). Purpose The aim of the present study is to determine whether reduced antioxidant function of HDL is associated with ACS. Methods 197 patients with ACS were prospectively recruited and blood samples were taken in the first 48h after enrollment. Patients with chronic coronary syndrome CCS (n=727) and with invasively excluded CAD (no CAD, n=498) from another cohort from our group served as control patients. A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function as assessed by increased HDL-lipid peroxide content (HDLox) normalized by HDL-C levels and the mean value of a pooled serum control from healthy participants (nHDLox; no units). Results Patients with ACS had significantly increased HDLox blood levels compared to patients with CCS and to patients without CAD (p Conclusions HDL peroxidation is associated with the presence of ACS independent of the presence of other traditional risk factors. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): BIOX

High-power silicon field-effect transistors as well as insulated gate bipolar transistors and particularly wide-bandgap semiconductor transistors typically need negative turn- off voltage for a secure off -state, resilience to spurious turn on , and rapid transition through the saturation mode. We present a gate driver configuration with compact and very efficient supply of the high and low sides of power transistor bridges with asymmetric bipolar control voltages without the need for costly and lossy isolated dc–dc converter and only low-voltage active components. The underlying negative voltage gate driver supply circuit consists of only a few cost-efficient components, its electrical potential is referenced to the source of the controlled semiconductor power switch, and its operation is synchronized with the gate driver output. It outcompetes the established use of isolated dc–dc converters in gate circuits with negative voltage needs with respect to cost, size, reliability, and efficiency. Importantly, the proposed negative voltage supply allows bootstrapping without the need for controllable high-voltage semiconductors for the sake of further cost reduction. We present detailed design rules of the circuit and experimentally validate circuit and control. In the automotive prototype implementation, size of the gate driver supply was reduced by 61%, cost by 57%, and loss by more than 16%.

Zusammenfassung Hintergrund und Ziel Um bei kieferorthopädischen Behandlungen die Therapietreue von Kindern zu unterstützen, werden bei herausnehmbaren Apparaturen häufig Glitzerpartikel in den Kunststoff eingebettet, die Aluminium (Al) enthalten. Bei einer Tragedauer von bis zu 16 h täglich über 2–3 Jahre kann angenommen werden, dass über die Zeit Al-Ionen in den Speichel diffundieren. Ziel der Studie war es, die Freisetzung von Al-Ionen aus dem Kunststoff unter Verwendung verschiedener kieferorthopädischer Drähte zu untersuchen. Materialien und Methode Es wurden Prüfkörper (Oberfläche 5,65 cm2) aus kieferorthopädischem Kunststoff und verschiedenen Drähten angefertigt; die Hälfte enthielt Glitzerpartikel aus Aluminium. Die Prüfkörper wurden 7 Tage lang in Petrischalen mit 50 ml Korrosionsmedium (pH 2,3) gem. DIN EN ISO 10271 bei 37 °C eingelegt. Zur Quantifizierung der spezifischen Ionen in der Korrosionslösung wurde die induktiv gekoppelte Plasmamassenspektrometrie (inductively coupled plasma - mass spectrometry, ICP-MS) verwendet. Ergebnisse Die statistische Analyse zeigte einen signifikanten Unterschied in der Konzentration der Al-Ionen zwischen Proben mit und ohne Glitzerpartikel. Die Konzentrationen aus Proben mit Glitzer erreichten bis zu 14.474 μg/l Al-Ionen, Proben ohne Glitzer enthielten im Durchschnitt 1260 μg/l. Ein geringer Anteil der Al-Ionen kann aus den Legierungen der Drähte stammen. Schlussfolgerungen Es sollte untersucht werden, ob die Aluminiumkonzentration zu Gesundheitsrisiken für den Menschen führen kann. Angesichts der Befunde sollten Kieferorthopäden keine glitzerhaltigen Apparaturen anbieten, um die Aluminiumaufnahme mit dem Speichel zu minimieren. Es muss geklärt werden, ob die in der Mundhöhle vorgefundenen Bedingungen zu gleichen Ergebnissen führen wie unter den oben genannten. Gesetzliche Regelungen sollten entwickelt werden, um die Freisetzung von Aluminium aus kieferorthopädischen Produkten zu begrenzen.

Background Angiostrongylus cantonensis (rat lungworm) is recognised as the leading cause of human eosinophilic meningitis, a serious condition observed when nematode larvae migrate through the CNS. Canine Neural Angiostrongyliasis (CNA) is the analogous disease in dogs. Both humans and dogs are accidental hosts, and a rapid diagnosis is warranted. A highly sensitive PCR based assay is available but often not readily accessible in many jurisdictions. An alternative DNA amplification assay that would further improve accessibility is needed. This study aimed to assess the diagnostic utility of a newly designed LAMP assay to detect DNA of globally distributed and invasive A. cantonensis and Angiostrongylus mackerrasae, the other neurotropic Angiostrongylus species, which is native to Australia. Methodology/Principal findings Cerebrospinal fluid (CSF) from dogs with a presumptive diagnosis of A. cantonensis infection (2020–2022) were received for confirmatory laboratory testing and processed for DNA isolation and ultrasensitive Angiostrongylus qPCR targeting AcanR3390. A newly designed LAMP assay targeting the same gene target was directly compared to the reference ultrasensitive qPCR in a diagnostic laboratory setting to determine the presence of A. cantonensis DNA to diagnose CNA. The LAMP assay (Angie-LAMP) allowed the sensitive detection of A. cantonensis DNA from archived DNA specimens (Kappa = 0.81, 95%CI 0.69–0.92; n = 93) and rapid single-step lysis of archived CSF samples (Kappa = 0.77, 95%CI 0.59–0.94; n = 52). Only A. cantonensis DNA was detected in canine CSF samples, and co-infection with A. mackerrasae using amplicon deep sequencing (ITS-2 rDNA) was not demonstrated. Both SYD.1 and AC13 haplotypes were detected using sequencing of partial cox1. Conclusions/Significance The Angie-LAMP assay is a useful molecular tool for detecting Angiostrongylus DNA in canine CSF and performs comparably to a laboratory Angiostrongylus qPCR. Adaptation of single-step sample lysis improved potential applicability for diagnosis of angiostrongyliasis in a clinical setting for dogs and by extension, to humans.

Genetic and epigenetic alterations in the Wnt signaling pathway leading to constitutive activation of the driver oncogene Β-catenin occur in at least 20% of all human cancers. We have developed conformationally hyperstabilized α-helical peptides (Helicons) that bind directly to Β-catenin with picomolar affinity and block its interaction with TCF transcription factors. We describe here the characterization of anti-tumor efficacy, pharmacodynamic biomarkers and mechanism of action using multiple in vivo patient-derived xenograft (PDX) models treated with Helicons. Helicon treatment leads to dose-dependent anti-tumor effects and durable regressions in PDX models from multiple indications with Wnt pathway activating mutations. Anti-tumor responses are seen in the presence of additional driver mutations, including KRAS and PIK3CA. RNA-sequencing and Gene Set Enrichment Analysis confirm Helicon treatment inhibits both Wnt/Β-catenin and MYC-regulated gene sets. Inhibiting Β-catenin-TCF interaction with Helicons represents a first-in-class therapeutic approach for the treatment of cancers resulting from aberrant transcriptional signaling via Β-catenin. Citation Format: YaGuang Si, Minjung Choi, Xinwei Han, Brian White, Ziyang Wu, Erica Visness, Pieter Beerepoot, Elizabeth Jaensch, Jessica Ramirez, Charles Ponthier, Xiaogang Han, Paula Ortet, Peicheng Du, Sorabh Agarwal, Mirek Lech, Aaron Fulgham, Sarah Cappucci, Zhi Li, John McGee, Lihua Yu, Martin Tremblay, Keith Orford, Gregory Verdine, Jonathan Hurov. Anti-tumor activity of Helicon inhibitors of Β-catenin-TCF interaction in patient-derived xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4972.