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Bioactivation of vitamin D consists of two sequential hydroxylation steps to produce 1α,25-dihydroxyvitamin D ₃. It is clear that the second or 1α-hydroxylation step is carried out by a single enzyme, 25-hydroxyvitamin D 1α-hydroxylase CYP27B1. However, it is not certain what enzyme or enzymes are responsible for the initial 25-hydroxylation. An excellent case has been made for vitamin D 25-hydroxylase CYP2R1, but this hypothesis has not yet been tested. We have now produced Cyp2r1 ⁻/⁻ mice. These mice had greater than 50% reduction in serum 25-hydroxyvitamin D ₃. Curiously, the 1α,25-dihydroxyvitamin D ₃ level in the serum remained unchanged. These mice presented no health issues. A double knockout of Cyp2r1 and Cyp27a1 maintained a similar circulating level of 25-hydroxyvitamin D ₃ and 1α,25-dihydroxyvitamin D ₃. Our results support the idea that the CYP2R1 is the major enzyme responsible for 25-hydroxylation of vitamin D, but clearly a second, as-yet unknown, enzyme is another contributor to this important step in vitamin D activation.

Answer Set Programming (ASP) is a declarative problem solving approach, initially tailored to modeling problems in the area of Knowledge Representation and Reasoning (KRR). More recently, its attractive combination of a rich yet simple modeling language with high-performance solving capacities has sparked interest in many other areas even beyond KRR. This book presents a practical introduction to ASP, aiming at using ASP languages and systems for solving application problems. Starting from the essential formal foundations, it introduces ASP's solving technology, modeling language and methodology, while illustrating the overall solving process by practical examples.

Atomic hydrogen (H) is crucial for understanding photochemistry and the energy budget in the mesopause region. However, there is still no consensus on the H abundance in this region. This study presents a new hydrogen data set derived from Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY) OH(9–6) band spectra, collocated with temperature and ozone profiles from other remote sensing instruments. H number densities peak at 82–87 km and range from 1.5×108 $1.5\\times 1{0}^{8}$ to 4×108 $4\\times 1{0}^{8}$ cm−3 ${\\mathrm{c}\\mathrm{m}}^{-3}$, depending on season and latitude. Two other H data sets obtained from the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) are presented for comparison: those from Mlynczak et al. (2018, https://doi.org/10.1029/2018GL077377) and Panka et al. (2021, https://doi.org/10.1029/2020GL091053) are approximately 30% lower and 50% higher than the SCIAMACHY data at peak altitudes, respectively. Additionally, the H number density retrieved in this study partly shows better agreement with the only direct rocket in situ measurements than those from SABER.

The assay of vitamin D that began in the 1970s with the quantification of one or two metabolites, 25‐OH‐D or 1,25‐(OH)2D, continues to evolve with the emergence of liquid chromatography tandem mass spectrometry (LC‐MS/MS) as the technique of choice. This highly accurate, specific, and sensitive technique has been adopted by many fields of endocrinology for the measurement of multiple other components of the metabolome, and its advantage is that it not only makes it feasible to assay 25‐OH‐D or 1,25‐(OH)2D but also other circulating vitamin D metabolites in the vitamin D metabolome. In the process, this broadens the spectrum of vitamin D metabolites, which the clinician can use to evaluate the many complex genetic and acquired diseases of calcium and phosphate homeostasis involving vitamin D. Several examples are provided in this review that additional metabolites (eg, 24,25‐(OH)2D3, 25‐OH‐D3‐26,23‐lactone, and 1,24,25‐(OH)3D3) or their ratios with the main forms offer valuable additional diagnostic information. This approach illustrates that biomarkers of disease can also include metabolites devoid of biological activity. Herein, a case is presented that the decision to switch to a LC‐MS/MS technology permits the measurement of a larger number of vitamin D metabolites simultaneously and does not need to lead to a dramatic increase in cost or complexity because the technique uses a highly versatile tandem mass spectrometer with plenty of reserve analytical capacity. Physicians are encouraged to consider adding this rapidly evolving technique aimed at evaluating the wider vitamin D metabolome toward streamlining their approach to calcium‐ and phosphate‐related disease states. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Recommendations for vitamin D supplementation for preterm infants span a wide range of doses. Response to vitamin D supplementation and impact on outcomes in preterm infants is not well understood. Evaluate serum 25(OH)D3 concentration changes after 4 weeks in response to two different doses of vitamin D3 supplementation in a population of premature infants and quantify the impact on NICU outcomes. 32 infants born at 24-32 weeks gestation were prospectively randomized to receive 400 or 800 IU/day vitamin D3 supplementation. Serum 25(OH)D3 levels were measured every 4 weeks. The Wilcoxon signed rank test was used to compare serum levels of 25(OH)D3 at 4 weeks and each subsequent time point. A p-value of <0.05 was considered statistically significant. Serum 25(OH)D3 levels at birth were 41.9 and 42.9 nmol/l for infants in the 400 IU group and 800 IU group, respectively (p = 0.86). Cord 25(OH)D3 concentrations significantly correlated with gestational age (r = 0.40, p = 0.04). After 4 weeks of D3 supplementation, median 25(OH)D3 levels increased in both groups (84.6vs. 105.3 nmol/l for 400 vs. 800 IU/day respectively, with significantly more improvement in the higher dose (p = 0.048). Infants in the 400 IU group were significantly more likely to have dual energy x-ray absorptiometry (DEXA) bone density measurements <10 percentile (56% vs 16%, p = 0.04). Improvement in 25(OH)D3 levels at 4 weeks, bone density, and trends towards improvement in linear growth support consideration of a daily dose of 800 IU of vitamin D for infants <32 weeks cared for in the NICU.

Detection of the Doppler shift of airglow radiation in the middle and upper atmosphere is one of the most important methods for remote sensing of the atmospheric wind field. Laboratory and routine field calibration of an optical interferometer for wind measurement is very important. We report a novel calibration system that simulates a frequency shift of airglow emission lines introduced by wind in the middle and upper atmosphere for calibrating passive optical interferometers. The generator avoids the shortcomings of traditional motor-driven Doppler-shift generators in terms of stability and security while improving accuracy and simplifying assemblies. A simulated wind speed can be determined simultaneously using the light-beat method. The wind error simulated by the generator mainly comes from the light source, which is about 0.63 m/s. An experimental demonstration was conducted using a calibrated Fabry–Perot interferometer and showed that the root mean square of the measurement uncertainty is 0.91 m/s. The novel calibration system was applied to calibrate an asymmetric spatial heterodyne spectrometer (ASHS)-type interferometer successfully. The results demonstrate the feasibility of the system.

Routine prophylactic platelet transfusion is the standard of care for patients with severe thrombocytopenia. We assessed the effect of a new strategy of therapeutic platelet transfusion on the number of transfusions and safety in patients with hypoproliferative thrombocytopenia. We did a multicentre, open-label, randomised parallel-group trial at eight haematology centres in Germany. Patients aged 16–80 years, who were undergoing intensive chemotherapy for acute myeloid leukaemia or autologous haemopoietic stem-cell transplantation for haematological cancers, were randomly assigned via a computer-generated randomisation sequence to receive either platelet transfusion when bleeding occurred (therapeutic strategy) or when morning platelet counts were 10×109 per L or lower (prophylactic strategy). Investigators undertaking interventions were not masked to group assignment. The primary endpoint was the number of platelet transfusions. Analysis was by intention to treat. This trial is registered, NCT00521664. 197 patients were assigned the prophylactic strategy and 199 the therapeutic strategy. Of 391 patients analysed, the therapeutic strategy reduced the mean number of platelet transfusions by 33·5% (95% CI 22·2–43·1; p<0·0001) in all patients (2·44 [2·22–2·67] in prophylactic group vs 1·63 [1·42–1·83] in therapeutic group), 31·6% (18·6–42·6; p<0·0001) in those with acute myeloid leukaemia (2·68 [2·35–3·01] vs 1·83 [1·58–2·10]), and 34·2% (6·6–53·7; p=0·0193) in those who had had autologous transplantation (1·80 [1·45–2·15] vs 1·18 [0·82–1·55]. We noted no increased risk of major haemorrhage in patients who had undergone autologous transplantation. In those with acute myeloid leukaemia, risk of non-fatal grade 4 (mostly CNS) bleeding was increased. We recorded 15 cases of non-fatal haemorrhage: four retinal in each transfusion group, and one vaginal and six cerebral in the therapeutic group. 12 patients died in the study: two from fatal cerebral haemorrhages in the therapeutic group, and ten (five in each treatment group) unrelated to major bleeding. The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia. The new strategy should be used by some haematology centres only if the staff are well educated and experienced in the new approach and can react in a timely way to first signs of CNS bleeding. Deutsche Krebshilfe eV (German Cancer Aid).

Metabolomic profiling can aid in understanding crucial biological processes in cancer development and progression and can also yield diagnostic biomarkers. Desorption electrospray ionization coupled to mass spectrometry imaging (DESI-MSI) has been proposed as a potential adjunct to diagnostic surgical pathology, particularly for prostate cancer. However, due to low resolution sampling, small numbers of mass spectra, and little validation, published studies have yet to test whether this method is sufficiently robust to merit clinical translation. We used over 900 spatially resolved DESI-MSI spectra to establish an accurate, high-resolution metabolic profile of prostate cancer. We identified 25 differentially abundant metabolites, with cancer tissue showing increased fatty acids (FAs) and phospholipids, along with utilization of the Krebs cycle, and benign tissue showing increased levels of lyso-phosphatidylethanolamine (PE). Additionally, we identified, for the first time, two lyso-PEs with abundance that decreased with cancer grade and two phosphatidylcholines (PChs) with increased abundance with increasing cancer grade. Importantly, we developed and internally validated a multivariate metabolomic classifier for prostate cancer using 534 spatial regions of interest (ROIs) in the training cohort and 430 ROIs in the test cohort. With excellent statistical power, the training cohort achieved a balanced accuracy of 97% and validation on testing data set demonstrated 85% balanced accuracy. Given the validated accuracy of this classifier and the correlation of differentially abundant metabolites with established patterns of prostate cancer cell metabolism, we conclude that DESI-MSI is an effective tool for characterizing prostate cancer metabolism with the potential for clinical translation.

Clinical research relies on high-quality patient data, however, obtaining big data sets is costly and access to existing data is often hindered by privacy and regulatory concerns. Synthetic data generation holds the promise of effectively bypassing these boundaries allowing for simplified data accessibility and the prospect of synthetic control cohorts. We employed two different methodologies of generative artificial intelligence – CTAB-GAN+ and normalizing flows (NFlow) – to synthesize patient data derived from 1606 patients with acute myeloid leukemia, a heterogeneous hematological malignancy, that were treated within four multicenter clinical trials. Both generative models accurately captured distributions of demographic, laboratory, molecular and cytogenetic variables, as well as patient outcomes yielding high performance scores regarding fidelity and usability of both synthetic cohorts ( n  = 1606 each). Survival analysis demonstrated close resemblance of survival curves between original and synthetic cohorts. Inter-variable relationships were preserved in univariable outcome analysis enabling explorative analysis in our synthetic data. Additionally, training sample privacy is safeguarded mitigating possible patient re-identification, which we quantified using Hamming distances. We provide not only a proof-of-concept for synthetic data generation in multimodal clinical data for rare diseases, but also full public access to synthetic data sets to foster further research.