K+S (Germany)

Background:Sustainable utilization of neurology and allied health professions’ services is pivotal for effective management of Parkinson disease (PD) and is correlated with positive health-related outcomes.Objectives:(1) To describe the utilization of neurology and allied health services by people with PD (PwP); (2) to explore the associations between demographic and structural variables and utilization; and (3) to test associations between utilization and unplanned hospitalizations.Methods:A retrospective observational cohort study of 1761 PwP in the years 2014-2019 was conducted. Utilization of neurology and allied health services was mapped. Regression models were examined to test associations between demographic and structural variables, utilization of neurology and physical therapy (PT), and unplanned hospitalizations.Results:Approximately 50% of the study population utilized neurology services. Utilization rate of allied health services ranged between 0% and 19%. The likelihood of utilizing neurology services increased for people with extended health insurance and people with more years since diagnosis and decreased for women and for people living at a great distance from a neurology service. The likelihood of utilizing PT increased for Jews and people with extended health insurance and decreased for people with more years since diagnosis and for people living at a great distance from a PT service. Among patients with fewer years since diagnosis (<5 years), those who utilized PT had a higher likelihood of unplanned hospitalization.Conclusions:Neurology and allied health services are underutilized by PwP, particularly by minorities and women. Policymakers should take proactive steps to increase utilization.Video availablefor more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A496)

With an increasing focus on sustainable technologies in the pharmaceutical industry, milling provides a solvent-free approach to improve drug dissolution. Milling of drugs with an excipient offers additional opportunities to achieve supersaturation kinetics. Therefore, this work aims to present insights of co-milling fenofibrate and apremilast, two good glass formers with low and high glass transition temperatures (Tgs) respectively. Drugs were co-milled with croscarmellose sodium for various process durations followed by thermal analysis, investigation of crystallinity, surface area and dissolution. The dissolution enhancement of the low-Tg glass former fenofibrate highly correlated with the process-induced increase in surface area of co-milled systems (R2 = 0.96). In contrast, the high-Tg glass former apremilast lost its crystalline order gradually after ≥ 10 min of co-milling, and favourable supersaturation kinetics during biorelevant dissolution testing were observed. Interestingly, the melting point of co-milled apremilast decreased and linearly correlated with the highest measured drug concentration (cmax) during in vitro dissolution (onset temperature R2 = 0.98; peak temperature R2 = 0.96). The melting point depression remained stable after 90 days for apremilast, whereas fenofibrate co-milled for 20 min or more showed an increase in melting point upon storage. This study demonstrated that co-milling with croscarmellose sodium is ideally suited to good glass formers with a high Tg. The melting point depression is thereby proposed as an easily accessible critical quality attribute to estimate likely dissolution performance of drugs in dry co-milled formulations.

Objectives:The aims of the study were to evaluate the safety, tolerability and pharmacokinetics of gadoquatrane in men and women with mild to moderate renal impairment and in matching participants with normal renal function, to predict the pharmacokinetics of gadoquatrane in patients with severe renal impairment, and to assess the dialyzability of gadoquatrane. Gadoquatrane is a new gadolinium-based contrast agent (GBCA) currently in clinical development.Materials and Methods:This evaluation used data from an open-label, nonrandomized, single-dose study in the following 3 parallel cohorts: (i) participants with mild renal impairment, (ii) participants with moderate renal impairment, and (iii) matching controls with normal renal function (3 × 8 = 24 participants between 51 and 79 years of age; 14 women). Each participant received a single IV bolus injection of gadoquatrane (0.025 mmol/kg body weight, corresponding to 0.1 mmol Gd/kg). Study procedures included safety assessments and collection of plasma and urine samples over 6 months. Gadolinium concentrations in plasma and urine were determined by inductively coupled plasma mass spectrometry. Modeling and simulation were used to predict the exposure in patients with severe renal impairment. In vitro experiments were used to assess the dialyzability of gadoquatrane.Results:Following IV injection, gadolinium plasma concentrations rapidly declined in all cohorts, albeit at different rates depending on renal function. With increasing degree of renal impairment, the exposure increased and the total as well as the renal clearance decreased. The total body weight-normalized clearance was lower by 21% in participants with mild renal impairment (90% confidence interval: 4; 35%) and by 42% in participants with moderate renal impairment (90% confidence interval: 30; 53%) than in participants with normal renal function. Maximum plasma concentration and volume of distribution were similar in all cohorts. The mean effective plasma half-life, which reflects the overall elimination of gadoquatrane, was short, even in participants with moderate renal impairment (4.1 hours; coefficient of variation: 31.2%). In all cohorts, approximately 90% of the injected dose was recovered in urine within the first 24 hours; after 7 days, recovery was practically complete (92%–97% of the dose administered, on average). Only trace amounts of gadolinium continued to be excreted (median recovery in 24-hour urine in all cohorts at 6 months after the injection: <0.0001% of the dose administered). For patients with severe renal impairment, simulations indicated a continuous decrease in gadoquatrane clearance and increase in exposure with increasing severity of renal impairment. Dialyzability experiments showed that the in vitro kinetic dialysis profile of gadoquatrane is essentially the same as that of gadobutrol.Conclusions:Gadoquatrane showed the typical, known pharmacokinetic profile of macrocyclic GBCAs. The clearance of gadoquatrane from plasma decreased with increasing degree of renal impairment, but effective elimination of gadoquatrane was also seen in participants with markedly impaired renal function. Trace amounts of gadolinium continued to be excreted until the last observation time point 6 months after the injection, independent of renal function. No relevant safety findings were observed in this study. Because of the safety profile and the pharmacokinetic profile of gadoquatrane correspond to those of the established GBCAs, no dose adjustment is warranted for patients with any degree of renal impairment. The use of modeling and simulation analysis together with in vitro testing for dialyzability made it possible to predict the pharmacokinetics in patients with severe renal impairment or on dialysis and, with that, to avoid exposing vulnerable participants in a clinical trial. EudraCT number: 2018-002426-23

The atomic structure of neptunium (Np) was investigated by two-step resonance ionization spectroscopy. The study involved exploring ground-state transitions as well as following transitions to high-lying states just below the ionization potential (IP) or auto-ionizing states above the IP. That resulted in the identification of two-step ionization schemes, suitable for trace analysis and nuclear structure investigations. The lifetimes of two excited states located at 25,342.48 cm-1\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\, \ ext {cm}^{-1} $$\\end{document} and 25,277.64 cm-1\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\, \ ext {cm}^{-1} $$\\end{document} were determined as 230(12) ns and 173(9) ns, respectively. Because of the absence of Rydberg series in wide-ranging spectra recorded, the first IP was determined through the field ionization of high-lying, weakly-bound states using a well-controlled static electric field. By applying the saddle-point model, an IP value of 50,535.54(15) cm-1\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{-1}$$\\end{document} [6.265608(19) eV] was derived. This value agrees with the current literature value of 50,535(2) cm-1\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{-1}$$\\end{document}, while providing a more than ten times higher precision.Graphic abstract

ABSTRACT Many chromosome abnormalities are commonly observed and can lead to early pregnancy loss, miscarriage, or the birth of children with chromosomal defects. Such abnormalities are considered a major factor in the low pregnancy rate after assisted reproductive technology and natural conception. Preimplantation genetic testing for aneuploidy (PGT-A) aims to minimize the transfer of aneuploid embryos. Embryonic aneuploidies arising from errors in meiosis have an incidence of approximately 25% in embryos from women younger than 35 years, to more than half in embryos from women aged older than 35 years. Although these embryos are able to develop to the blastocyst stage, they tend to be of lower morphological quality. A recent multicenter randomized clinical trial (ESTEEM) analyzed polar bodies (PBs) from women after intracytoplasmic sperm injection aged between 36 and 40 years using microarrays in 205 cycles and found that the transfer of embryos from euploid oocytes did not lead to a higher live birth rate but was associated with a reduction in the number of embryo transfers and miscarriages. This study aimed to evaluate all PB results from this RCT and characterize the types of chromosomal abnormalities and the chromosomes most frequently affected. The ESTEEM trial obtained biopsy of first (PB1) and second (PB2) PB in the cohort receiving PGT-A and analyzed them using array comparative genomic hybridization (aCGH). A total of 693 PB pairs had full results available, including 676 confirmed fertilized oocytes. Chromosome segregations, including likely underlying mechanisms, from these pairs are reported here. To estimate the reliability of the aCGH procedure, 72 PB pairs from a single center were reanalyzed using next-generation sequencing (NGS). Embryos were classified into 4 categories based on morphology: good, fair, poor, and degenerated. A comparative analysis was performed to assess the association between chromosome status and embryo quality as well as study group (PGT-A vs control) and embryo quality. A total of 213/676 oocytes were euploid and 413/676 were aneuploid, whereas in the remaining 50 oocytes, an abnormality observed in PB1 was compensated by an abnormality in PB2. A total of 693 PB pairs reported chromatic numbers with results for 15,939 chromosomes. An abnormal segregation, in PB1 and/or PB2, was observed in 1162 chromosomes (7.3%) in 461 PB pairs. Chromosomes 22 (16.7%), 16 (16.6%), 19 (14.4%), 21 (13.7%), and 15 (12.4%) had the highest frequencies for abnormal segregations. The abnormal segregations were compatible with precocious separation of sister chromatids in meiosis 1 (M1) (n = 568; 48.9%), nondisjunction of chromatics in meiosis 2 (M2) or reverse segregation (n = 417; 35.9%), and nondisjunction in M1 (n = 65; 5.6%). However, 112 chromosomes had segregation patterns that could not be categorized into 1 of the 9 known mechanisms causing aneuploidy in oocytes. Concordance between aCGH and NGS was obtained for both PBs for 1650 of 1656 analyzed chromosomes (99.6%). Embryos predicted to be aneuploid had significantly worse quality scores on day 3 (adjusted odds ratio [aOR], 0.62; 95% confidence interval [CI], 0.43–0.90), day 4 (aOR, 0.15; 95% CI, 0.06–0.39), and day 5 (aOR, 0.28; 95% CI, 0.14–0.58). This study represents one of the largest analyses of chromosomal copy number in both PBs to date and highlights the frequent unexplained chromosome copy numbers underscoring the gap of knowledge into the mechanisms causing aneuploidy in oocytes.

Abstract Data-based process monitoring in injection molding plays an important role in compensating disturbances in the process and the associated impairment of part quality. Selecting appropriate features for a successful online quality prediction based on machine learning methods is crucial. Time series such as the injection pressure and injection flow curve are particularly suitable for this purpose. Predicting quality as early as possible during a cycle has many advantages. In this paper it is shown how the recording length of the time series affects the prediction performance when using machine learning algorithms. For this purpose, two successful molding quality prediction algorithms (k Nearest Neighbors and Ridge Regression) are trained with time series of different lengths on extensive data sets. Their prediction performances for part weight and a geometric dimension are evaluated. The evaluations show that recording time series until the end of a cycle is not necessary to obtain good prediction results. These findings indicate that early reliable quality prediction is possible within a cycle, which speeds up prediction, allows timely part handling at the end of the cycle and provides the basis for automated corrective interventions within the same cycle.

While contrast-enhanced MR imaging is the criterion standard in meningioma diagnosis and treatment response assessment, gallium 68Ga-DOTATATE PET/MR imaging has increasingly demonstrated utility in meningioma diagnosis and management. Integrating 68Ga-DOTATATE PET/MR imaging in postsurgical radiation planning reduces the planning target volume and organ-at-risk dose. However, 68Ga-DOTATATE PET/MR imaging is not widely implemented in clinical practice due to higher perceived costs. Our study analyzes the cost-effectiveness of 68Ga-DOTATATE PET/MR imaging for postresection radiation therapy planning in patients with intermediate-risk meningioma. We developed a decision-analytical model based on both recommended guidelines on meningioma management and our institutional experience. Markov models were implemented to estimate quality-adjusted life-years (QALY). Cost-effectiveness analyses with willingness-to-pay thresholds of $50,000/QALY and $100,000/QALY were performed from a societal perspective. Sensitivity analyses were conducted to validate the results. Model input values were based on published literature. The cost-effectiveness results demonstrated that 68Ga-DOTATATE PET/MR imaging yields higher QALY (5.47 versus 5.05) at a higher cost ($404,260 versus $395,535) compared with MR imaging alone. The incremental cost-effectiveness ratio analysis determined that 68Ga-DOTATATE PET/MR imaging is cost-effective at a willingness to pay of $50,000/QALY and $100,000/QALY. Furthermore, sensitivity analyses showed that 68Ga-DOTATATE PET/MR imaging is cost-effective at $50,000/QALY ($100,000/QALY) for specificity and sensitivity values above 76% (58%) and 53% (44%), respectively. 68Ga-DOTATATE PET/MR imaging as an adjunct imaging technique is cost-effective in postoperative treatment planning in patients with meningiomas. Most important, the model results show that the sensitivity and specificity cost-effective thresholds of 68Ga-DOTATATE PET/MR imaging could be attained in clinical practice.

Process-data-supported process monitoring in injection molding plays an important role in compensating for disturbances in the process. Until now, scalar process data from machine controls have been used to predict part quality. In this paper, we investigated the feasibility of incorporating time series of sensor measurements directly as features for machine learning models, as a suitable method of improving the online prediction of part quality. We present a comparison of several state-of-the-art algorithms, using extensive and realistic data sets. Our comparison demonstrates that time series data allow significantly better predictions of part quality than scalar data alone. In future studies, and in production-use cases, such time series should be taken into account in online quality prediction for injection molding.