Beschrieben wird eine vollständige Definition für zylindrische Evolventenverzahnungen als dreidimensionales Formelement. Grundlage ist ein evolventisches Koordinatensystem. Mit ihm lassen sich innen ...und außen verzahnte Räder mit linkssteigender und rechtssteigender Flankenrichtung sowie Geradverzahnungen darstellen. Besondere Bedeutung gewinnt diese Darstellung im Bereich der Verzahnungs- und Koordinatenmesstechnik. Gewöhnlich liegen die Messpunkte als kartesische Koordinaten in Form von Tastkugelmittelpunkten des Antastelements vor. Diese können außerhalb ihrer Bezugsflächen nahezu beliebig über die Flanke verteilt sein. Der Einsatz von Evolventenkoordinaten ist Grundlage für eine einfache Auswertung der Verzahnungsparameter. Die dargestellten Definitionen und Algorithmen ergänzen bestehende Richtlinien und Normen, in denen die Zusammenhänge bisher nicht beschrieben sind.
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Background: Pts with mCRPC have a poor prognosis with limited treatment options, including minimal response to immunotherapies. REGN5678 is a first-in-class, full-length anti-PSMAxCD28 bispecific ...costimulatory antibody designed to target prostate cancer cells and enhance T-cell activation. We report preliminary results from the dose escalation part of a first-in-human, open-label, Phase 1/2 study (NCT03972657) examining REGN5678 in combination with cemiplimab, a PD-1 blocking antibody. Methods: Pts with mCRPC had received ≥2 lines of systemic therapy in the metastatic and/or castration-resistant setting, including ≥1 second-generation anti-androgen. Pts received REGN5678 weekly at dose levels DL 0.1–300 mg, initially as monotherapy for 3 weeks, followed by combination with cemiplimab (350 mg Q3W) until progression or toxicity. Primary objectives are safety, tolerability, and pharmacokinetics. Preliminary efficacy measurements include decline in prostate-specific antigen (PSA) from the start of combination treatment and radiographic response from baseline. Results: At the data cutoff (DCO; July 27 2022), 35 pts had been treated. Treatment-emergent adverse events (TEAEs) ≥Grade (G)3 occurred in 54% (19/35) of pts. Cytokine release syndrome occurred in 6 pts (all G1) and there were 2 dose-limiting toxicities (both G3): pain (at 1 mg) and Guillain-Barré syndrome (at 300 mg). 4 pts (11%) experienced a ≥G3 immune-mediated adverse event (imAE; at DLs 30–300 mg). REGN5678 exposure was non-linear over the tested DLs (more than dose proportional). There were minimal signs of efficacy at lower DLs (REGN5678 0.1–10 mg), with only 1/16 pts showing a PSA decline (of 21%). More PSA declines occurred at higher DLs: 1/4 pts at 30 mg (a PSA decline of 100%), 3/8 at 100 mg (>99%, 44%, 22%), and 3/4 at 300 mg (>99%, 99%, 82%). Notably, all ≥G3 imAEs occurred in pts with PSA declines. Among pts with measurable disease and ≥1 on-treatment scan, radiographic response per RECIST 1.1 occurred in 1/3 pts at 30 mg (complete response), 1/4 at 100 mg (unconfirmed partial response PR), and 1/1 at 300 mg (PR confirmed after DCO). Conclusions: Preliminary data on REGN5678 plus cemiplimab in pts with mCRPC provide first evidence of clinical activity of a CD28 co-stimulatory bispecific antibody in solid tumors. Clinical activity was observed at DLs 30–300 mg. ≥G3 imAEs occurred in pts with PSA declines, suggesting a possible association. The study is ongoing to determine the maximum tolerated and recommended Phase 2 doses. Clinical trial information: NCT03972657 . Table: see text
Due to the lack of data, the extent, thickness and drift patterns of sea ice and icebergs in the glacial Arctic remains poorly constrained. Earlier studies are contradictory proposing either a ...cessation of the marine cryosphere or an ice drift system operating like present-day. Here we examine the marine Arctic cryosphere during the Last Glacial Maximum (LGM) using a high-resolution, regional ocean-sea ice model. Whereas modern sea ice in the western Arctic Basin can circulate in the Beaufort Gyre for decades, our model studies present an extreme shortcut of glacial ice drift. In more detail, our results show a clockwise sea-ice drift in the western Arctic Basin that merges into a direct trans-Arctic path towards Fram Strait. This is consistent with dated ice plow marks on the seafloor, which show the orientation of iceberg drift in this direction. Also ice-transported iron-oxide grains deposited in Fram Strait, can be matched by their chemical composition to similar grains found in potential sources from the entire circum-Arctic. The model results indicate that the pattern of Arctic sea-ice drift during the LGM is established by wind fields and seems to be a general feature of the glacial ocean. Our model results do not indicate a cessation in ice drift during the LGM.
► First simulation of glacial Arctic Ocean by a regional model. ► Robust pattern of glacial Arctic sea-ice drift consistent with proxy data. ► Sea-ice transport to the northern North Atlantic is dominated by wind forcing. ►We reject earlier hypotheses of ice drift reconstruction.
Background: Here, we describe an integrative method to detect carbapenemase-producing Gram-negative bacteria (gn-Cp) on surfaces/fomites in the patient environment. We examined environmental samples ...from 28 patient rooms occupied with patients who were proven to be colonised with gn-Cp by rectal screening. Methods: We took samples after 24 h, 72 h and one week. For sampling, we divided the patient environment into four parts and took samples from near- and extended patient areas. To obtain a representative bacterial swab from a larger surface, such as the patient cabinet, we used Polywipes. Bacterial DNA was isolated. Carbapenemase was detected with specific qPCR primers. Results: With this culture- and molecular-based approach, we could control the effectiveness of cleaning and disinfection in everyday clinical practice. Therefore, we could track the spread of gn-Cp within the patient room. The number of positive detections fluctuated between 30.5% (mean value positive results after 72 h) and 35.2% (after 24 h and one week). Conclusion: The method used to detect multidrug-resistant bacteria in the environment of patients by using PolywipesTM is reliable and can therefore be used as an effective, new tool in hygiene and infection control.
Background and Aims Glycogen storage disease type 1a (GSD1a) is an inherited disease caused by a deficiency in the catalytic subunit of the glucose-6 phosphatase enzyme (G6Pase). GSD1a is ...characterized by hypoglycaemia, hyperlipidemia, and lactic acidosis with associated hepatic (including hepatocellular adenomas), renal, and intestinal disorders. A total G6pc (catalytic subunit of G6Pase) knock-out mouse model has been generated that mimics the human pathology. However, these mice rarely live longer than 3 months and long-term liver pathogenesis cannot be evaluated. Herein, we report the long-term characterization of a liver-specific G6pc knock-out mouse model (L- G6pc−/− ). Methods We generated L- G6pc−/− mice using an inducible CRE-lox strategy and followed up the development of hepatic tumours using magnetic resonance imaging. Results L- G6pc−/− mice are viable and exhibit normoglycemia in the fed state. They develop hyperlipidemia, lactic acidosis, and uricemia during the first month after gene deletion. However, these plasmatic parameters improved after 6 months. L- G6pc−/− mice develop hepatomegaly with glycogen accumulation and hepatic steatosis. Using an MRI approach, we could detect hepatic nodules with diameters of less than 1 mm, 9 months after induction of deficiency. Hepatic nodules (1 mm) were detected in 30–40% of L- G6pc−/− mice at 12 months. After 18 months, all L- G6pc−/− mice developed multiple hepatocellular adenomas of 1–10 mm diameter. Conclusions This is the first report of a viable animal model of the hepatic pathology of GSD1a, including the late development of hepatocellular adenomas.
This paper presents a comparison of experimental and numerical results for a series of turbulent reacting jets where silica nanoparticles are formed and grow due to surface growth and agglomeration. ...We use large-eddy simulation coupled with a multiple mapping conditioning approach for the solution of the transport equation for the joint probability density function of scalar composition and particulate size distribution. The model considers inception based on finite-rate chemistry, volumetric surface growth and agglomeration. The sub-models adopted for these particulate processes are the standard ones used by the community. Validation follows the “paradigm shift” approach where elastic light scattering signals (that depend on particulate number and size), OH- and SiO-LIF signals are computed from the simulation results and compared with “raw signals” from laser diagnostics. The sensitivity towards variable boundary conditions such as co-flow temperature, Reynolds number and precursor doping of the jet is investigated. Agreement between simulation and experiments is very good for a reference case which is used to calibrate the signals. While keeping the model parameters constant, the sensitivity of the particulate size distribution on co-flow temperature is predicted satisfactorily upstream although quantitative differences with the data exist downstream for the lowest coflow temperature case that is considered. When the precursor concentration is varied, the model predicts the correct direction of the change in signal but notable qualitative and quantitative differences with the data are observed. In particular, the measured signals show a highly non-linear variation while the predictions exhibit a square dependence on precursor doping at best. So, while the results for the reference case appear to be very good, shortcomings in the standard submodels are revealed through variation of the boundary conditions. This demonstrates the importance of testing complex nanoparticle synthesis models on a flame series to ensure that the physical trends are correctly accounted for.
Epidemiological studies have widely proven the impact of ozone (O
) on respiratory mortality, while only a few studies compared the association between different O
indicators and health.
This study ...explores the relationship between daily respiratory hospitalization and multiple ozone indicators in Guangzhou, China, from 2014 to 2018. It uses a time-stratified case-crossover design. Sensitivities of different age and gender groups were analyzed for the whole year, the warm and the cold periods. We compared the results from the single-day lag model and the moving average lag model.
The results showed that the maximum daily 8 h average ozone concentration (MDA8 O
) had a significant effect on the daily respiratory hospitalization. This effect was stronger than for the maximum daily 1 h average ozone concentration (MDA1 O
). The results further showed that O
was positively associated with daily respiratory hospitalization in the warm season, while there was a significantly negative association in the cold season. Specifically, in the warm season, O
has the most significant effect at lag 4 day, with the odds ratio (OR) equal to 1.0096 95% confidence intervals (CI): 1.0032, 1.0161. Moreover, at the lag 5 day, the effect of O
on the 15-60 age group was less than that on people older than 60 years, with the OR value of 1.0135 (95% CI: 1.0041, 1.0231) for the 60+ age group; women were more sensitive than men to O
exposure, with an OR value equal to 1.0094 (95% CI: 0.9992, 1.0196) for the female group.
These results show that different O
indicators measure different impacts on respiratory hospitalization admission. Their comparative analysis provided a more comprehensive insight into exploring associations between O
exposure and respiratory health.
Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated but it is unclear if this is a causal relationship or confounding. We used genetic ...analyses and sibling comparisons to clarify the direction this relationship.
Methods: Linkage Disequilibrium Score Regression and two-sample Mendelian randomization (MR) were used to test for genetic correlation (r g ) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and six PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N=2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons).
Results: ADHD and PTSD had consistent r g (r g range, 0.43-0.52; P < .001). ADHD genetic liability was causally linked with increased risk for PTSD (Beta=0.367, 95% confidence interval (CI), 0.186-0.552, P=7.68x10 -5 ). This result was not affected by heterogeneity, horizontal pleiotropy (MR Egger intercept=4.34x10 -4 , P=0.961), or other phenotypes, and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio=2.37, 95% CI 1.98-3.53).
Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.
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