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Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed). From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 [67%] of 33), upper respiratory infection (11 [33%]), and increased alanine aminotransferase (nine [27%]). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study. STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Novartis Gene Therapies.

This article reports world averages of measurements of b -hadron, c -hadron, and τ -lepton properties obtained by the Heavy Flavor Averaging Group using results available through summer 2016. For the averaging, common input parameters used in the various analyses are adjusted (rescaled) to common values, and known correlations are taken into account. The averages include branching fractions, lifetimes, neutral meson mixing parameters, C P  violation parameters, parameters of semileptonic decays, and Cabbibo–Kobayashi–Maskawa matrix elements.

The former industrial site of uptownBasel in Arlesheim, Switzerland, has great potential for local reuse of steel profiles, as disassembly, processing, and storage can be handled within the same site. The direct reuse of steel is significant because it contributes to a reduction in greenhouse gas emissions, especially when transportation and processing are minimized. This study addresses how the dismantled steel profiles in uptownBasel can be made accessible for future use, considering both physical and digital accessibility. Based on stakeholder consultations and literature research, this study examines which technologies and processes are suitable for the reuse of dismantled steel profiles in uptownBasel. It analyzes and compares existing Track-and-Trace as well as data storage technologies. Data requirements for the reuse of steel are examined by regarding constant and variable information and structuring it according to its data type (numeric, alphanumeric, vector, or image-based) specific to the uptownBasel use case. Furthermore, an analysis of storage types reveals important distinctions: Whether single or multiple storage units are needed, whether the storage is intended to be long-term or short-term, and whether materials should be stored sorted or unsorted. Finally, this study provides an outlook on how the process and the tasks of those involved in the project change when steel profiles are labelled and their information is made digitally accessible.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3β. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17–29) were prepared and evaluated for the inhibition of GSK-3β at 25 μM. The IC50 values of five of these compounds was determined; the two best inhibitors are 5-[(4′-chloro-2-pyridinyl)methylene]hydantoin (IC50 = 2.14 ± 0.18 μM) and 5-[(6′-bromo-2-pyridinyl)methylene]hydantoin (IC50 = 3.39 ± 0.16 μM). The computational docking of the compounds with GSK-3β (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 μM and against human carbonic anhydrase at 200 μM, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 μM.

Background and Objectives: The aim of this study was to investigate the prediction of adverse perinatal outcomes using the cerebroplacental (CPR) and umbilicocerebral (UCR) ratios in different cohorts of singleton pregnancies. Materials and Methods: In this retrospective cohort study, we established our own Multiple of Median (MoM) for CPR and UCR. The predictive value for both ratios was studied in the following outcome parameters: emergency cesarean delivery, operative intervention (OI), OI due to fetal distress, 5-min Apgar < 7, admission to neonatal intensive care unit, and composite adverse perinatal outcome. The performance of the ratios was assessed in the following cohorts: total cohort (delivery ≥ 37 + 0 weeks gestation, all birth weight centiles), low-risk cohort (delivery ≥ 37 + 0 weeks gestation, birth weight ≥ 10. centile), prolonged pregnancy cohort (delivery ≥ 41 + 0 weeks gestation, birth weight ≥ 10. centile) and small-for-gestational-age fetuses (delivery ≥ 37 + 0 weeks gestation, birth weight < 10. centile). The underlying reference values for MoM were estimated using quantile regression depending on gestational age. Prediction performance was evaluated using logistic regression models assessing the corresponding Brier score, combining discriminatory power and calibration. Results: Overall, 3326 cases were included. Across all cohorts, in the case of a significant association between a studied outcome parameter and CPR, there was an association with UCR, respectively. The Brier score showed only minimal differences for both ratios. Conclusions: Our study provides further evidence regarding predictive values of CPR and UCR. The results of our study suggest that reversal of CPR to UCR does not improve the prediction of adverse perinatal outcomes.

Background High mammographic density (MD) is a risk factor for the development of breast cancer (BC). Changes in MD are influenced by multiple factors such as age, BMI, number of full-term pregnancies and lactating periods. To learn more about MD, it is important to establish non-radiation-based, alternative examination methods to mammography such as ultrasound assessments. Methods We analyzed data from 168 patients who underwent standard-of-care mammography and performed additional ultrasound assessment of the breast using a high-frequency (12 MHz) linear probe of the VOLUSON ® 730 Expert system (GE Medical Systems Kretztechnik GmbH & Co OHG, Austria). Gray level bins were calculated from ultrasound images to characterize mammographic density. Percentage mammographic density (PMD) was predicted by gray level bins using various regression models. Results Gray level bins and PMD correlated to a certain extent. Spearman’s ρ ranged from − 0.18 to 0.32. The random forest model turned out to be the most accurate prediction model (cross-validated R 2 , 0.255). Overall, ultrasound images from the VOLUSON ® 730 Expert device in this study showed limited predictive power for PMD when correlated with the corresponding mammograms. Conclusions In our present work, no reliable prediction of PMD using ultrasound imaging could be observed. As previous studies showed a reasonable correlation, predictive power seems to be highly dependent on the device used. Identifying feasible non-radiation imaging methods of the breast and their predictive power remains an important topic and warrants further evaluation. Trial registration 325-19 B (Ethics Committee of the medical faculty at Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany).

A method is proposed to measure the photon polarisation parameter \\[\\lambda _{\\gamma }\\] in \\[{{b}} \\!\\rightarrow {s} {\\gamma } \\] transitions using an amplitude analysis of \\[B\\!\\rightarrow K\\pi \\pi {\\gamma } \\] decays. Simplified models of the \\[{K} {\\pi } {\\pi } \\] system are used to simulate \\[{{{B} ^+}} \\!\\rightarrow {{K} ^+} {{\\pi } ^-} {{\\pi } ^+} {\\gamma } \\] and \\[{{B} ^0} \\!\\rightarrow {{K} ^+} {{\\pi } ^-} {{\\pi } ^0} {\\gamma } \\] decays, validate the amplitude analysis method, and demonstrate the feasibility of a measurement of the \\[\\lambda _{\\gamma }\\] parameter irrespective of the model parameters. Similar sensitivities to \\[\\lambda _{\\gamma }\\] are obtained with both the charged and neutral hadronic systems. In the absence of any background and distortion due to experimental effects, the statistical uncertainty expected from an analysis of \\[{{{B} ^+}} \\!\\rightarrow {{K} ^+} {{\\pi } ^-} {{\\pi } ^+} {\\gamma } \\] decays in an LHCb data set corresponding to an integrated luminosity of 9 \\[\\,\\hbox {fb}^{-1}\\] is estimated to be 0.009. A similar measurement using \\[{{B} ^0} \\!\\rightarrow {{K} ^+} {{\\pi } ^-} {{\\pi } ^0} {\\gamma } \\] decays in a Belle II data sample corresponding to an integrated luminosity of 5 \\[\\hbox {\\,ab}^{-1}\\] would lead to a statistical uncertainty of 0.018.