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Aims: The reference nutrient intake for vitamin D in people aged ≥4 years is 10 μg/day (400 IU/day) in the UK, but the recommended daily allowance is 15 μg/day (600 IU/day) for people aged 1-70 years in the USA. Here, we aim to compare the 25-hydroxyvitamin D (25(OH)D) serum concentration profiles between the 2 doses., Methods: With world-wide trial data of adults aged ≥18 years, 45-93 kg, we constructed a minimal physiologically based pharmacokinetics model of serum concentrations of vitamin D and 25(OH)D using nonlinear mixed effects modelling. We used this model to forecast the mean, 2.5th and 97.5th percentiles for serum 25(OH)D concentrations in British adults aged ≥16 years., Results: Our final model used bodyweight to adjust volume of each compartment and maximum clearance of 25(OH)D. No other covariate was identified. The model accurately predicted independent data from trials of a broad range of dosing regimens. We simulated British adults and showed that circulating 25(OH)D concentrations in 95% of people taking 10 μg/day for a year is predicted to reach 50 nmol/L in 32 weeks, while 97.5% of those on 15 μg/day were predicted to attain this threshold within 28 weeks., Conclusion: Both doses are efficacious in >95% of the British population. The daily dose of 15 μg can help 97.5% of the British adults achieve 50 nmol/L serum 25(OH)D and reach the 25 nmol/L threshold in 4 weeks., (© 2024 Beyond Consulting Ltd. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Glutathione reductase (GR) is a two dinucleotide binding domain flavoprotein (tDBDF) that catalyzes the reduction of glutathione disulfide to glutathione coupled to the oxidation of NADPH to NADP + . An interesting feature of GR and other tDBDFs is the presence of a lysine residue (Lys-66 in human GR) at the active site, which interacts with the flavin group, but has an unknown function. To better understand the role of this residue, the dynamics of GR was studied using molecular dynamics simulations, and the reaction mechanism of FAD reduction by NADPH was studied using QM/MM molecular modeling. The two possible protonation states of Lys-66 were considered: neutral and protonated. Molecular dynamics results suggest that the active site is more structured for neutral Lys-66 than for protonated Lys-66. QM/MM modeling results suggest that Lys-66 should be in its neutral state for a thermodynamically favorable reduction of FAD by NADPH. Since the reaction is unfavorable with protonated Lys-66, the reverse reaction (the reduction of NADP + by FADH - ) is expected to take place. A phylogenetic analysis of various tDBDFs was performed, finding that an active site lysine is present in different the tDBDFs enzymes, suggesting that it has a conserved biological role. Overall, these results suggest that the protonation state of the active site lysine determines the energetics of the reaction, controlling its reversibility., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A series of 15 novel 1,3-thiazole amide derivatives of the pentacyclic triterpene Ochraceolide A ( 1 ) was synthesized, characterized, and evaluated in vitro against three human cancer cell lines (MCF-7, MDA-MB-231 and SiHa) and a normal cell line (Vero). Synthetic derivatives were obtained by acylation of the 2-aminothiazole triterpene 2 , previously reported. Remarkably, the 5-nitrofuramide derivative ( 2o ) showed better cytotoxic and antiproliferative activity than compound 2 and the other derivatives against the three cancer cell lines with CC 50 and IC 50 values of 1.6-12.7 µM. Furthermore, butyramide derivative ( 2c ) was approximately 25 times more selective than 2 , as well as 3.4 times more selective than Docetaxel, against SiHa cells in the cytotoxic assay, while the phenyl amide derivatives were inactive against the three cancer cell lines.

The von Hippel-Lindau (VHL) disease is an autosomal dominant cancer syndrome caused by mutations in the VHL tumor suppressor gene. VHL protein (pVHL) forms a complex (VBC) with Elongins B-C, Cullin2, and Rbx1. Although other functions have been discovered, the most described function of pVHL is to recognize and target hypoxia-inducible factor (HIF) for degradation. This work comprises the functional characterization of two novel variants of the VHL gene (P138R and L163R) that have been described in our center in patients with VHL disease by in vitro , in vivo , and in silico approaches. In vitro , we found that these variants have a significantly shorter half-life compared to wild-type VHL but still form a functional VBC complex. Altered fibronectin deposition was evidenced for both variants using immunofluorescence. In vivo studies revealed that both variants failed to suppress tumor growth. By means of molecular dynamics simulations, we inspected in silico the nature of the changes introduced by each variant in the VBC complex. We have demonstrated the pathogenicity of P138R and L163R novel variants, involving HIF-dependent and HIF-independent mechanisms. These results provide the basis for future studies regarding the impact of structural alterations on posttranslational modifications that drive pVHL's fate and functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mathó, Fernández, Bonanata, Liu, Martin, Vieites, Sansó, Barontini, Jonasch, Coitiño and Pennisi.)

Background: The awake prone positioning strategy for patients with acute respiratory distress syndrome is a safe, simple and cost-effective technique used to improve hypoxaemia. We aimed to evaluate intubation and mortality risk in patients with coronavirus disease 2019 (COVID-19) who underwent awake prone positioning during hospitalisation., Methods: In this retrospective, multicentre observational study conducted between 1 May 2020 and 12 June 2020 in 27 hospitals in Mexico and Ecuador, nonintubated patients with COVID-19 managed with awake prone or awake supine positioning were included to evaluate intubation and mortality risk through logistic regression models; multivariable and centre adjustment, propensity score analyses, and E-values were calculated to limit confounding., Results: 827 nonintubated patients with COVID-19 in the awake prone (n=505) and awake supine (n=322) groups were included for analysis. Fewer patients in the awake prone group required endotracheal intubation (23.6% versus 40.4%) or died (19.8% versus 37.3%). Awake prone positioning was a protective factor for intubation even after multivariable adjustment (OR 0.35, 95% CI 0.24-0.52; p<0.0001, E=2.12), which prevailed after propensity score analysis (OR 0.41, 95% CI 0.27-0.62; p<0.0001, E=1.86) and mortality (adjusted OR 0.38, 95% CI 0.26-0.55; p<0.0001, E=2.03). The main variables associated with intubation among awake prone patients were increasing age, lower baseline peripheral arterial oxygen saturation/inspiratory oxygen fraction ratio ( P aO 2 / F IO 2 ) and management with a nonrebreather mask., Conclusions: Awake prone positioning in hospitalised nonintubated patients with COVID-19 is associated with a lower risk of intubation and mortality., Competing Interests: Conflict of interest: O.R. Perez-Nieto has nothing to disclose. Conflict of interest: D. Escarraman-Martínez has nothing to disclose. Conflict of interest: M.A. Guerrero-Gutierrez has nothing to disclose. Conflict of interest: E.I. Zamarron-Lopez has nothing to disclose. Conflict of interest: J. Mancilla-Galindo has nothing to disclose. Conflict of interest: A. Kammar-García has nothing to disclose. Conflict of interest: M.A. Martinez-Camacho has nothing to disclose. Conflict of interest: E. Deloya-Tomás has nothing to disclose. Conflict of interest: J.S. Sanchez-Díaz has nothing to disclose. Conflict of interest: L.A. Macías-García has nothing to disclose. Conflict of interest: R. Soriano-Orozco has nothing to disclose. Conflict of interest: G. Cruz-Sánchez has nothing to disclose. Conflict of interest: J.D. Salmeron-Gonzalez has nothing to disclose. Conflict of interest: M.A. Toledo-Rivera has nothing to disclose. Conflict of interest: I. Mata-Maqueda has nothing to disclose. Conflict of interest: L.A. Morgado-Villaseñor has nothing to disclose. Conflict of interest: J.J. Martinez-Mazariegos has nothing to disclose. Conflict of interest: R. Flores Ramirez has nothing to disclose. Conflict of interest: J.L. Medina-Estrada has nothing to disclose. Conflict of interest: S.A. Ñamendys-Silva has nothing to disclose., (Copyright ©The authors 2022.)

Purpose: Myocardial extracellular volume fraction (ECV) using cardiovascular magnetic resonance (CMR) can identify diffuse lesions not detected by late gadolinium enhancement (LGE). We aimed to determine the prevalence of increased ECV and its relation to other CMR findings., Materials and Methods: Consecutive patients (n=609, age median [interquartile range] 53 [39 to 66] y, 62% male) underwent CMR at 1.5 T. Focal lesions on LGE images were noted. ECV in regions without focal LGE findings defined diffuse changes. Pronounced increases in left ventricular (LV) end-diastolic volume index and LV mass index, and pronounced decreases in LV ejection fraction were defined as >3 SD from the sex-specific mean in healthy volunteers., Results: Of 609 patients without amyloidosis or hypertrophic cardiomyopathy, 8% had diffusely increased ECV and 5% of all patients had diffusely increased ECV without any focal LGE findings. Multivariate analysis showed that a pronounced increase in the LV end-diastolic volume index was associated with increased ECV (P=0.001), but not LGE (P=0.52). A pronounced decrease in LV ejection fraction was associated with the presence of LGE (P<0.001), but not with increased ECV (P=0.41)., Conclusions: Eight percent of patients in this clinical cohort with known or suspected heart disease had diffusely increased ECV and 60% of these lacked focal LGE findings. LV size is independently associated with increased ECV, whereas systolic dysfunction is independently associated with LGE. This image-based clinical study demonstrates that ECV-CMR provides additional information negligibly related to the results of LGE imaging, and thereby increases the diagnostic yield of CMR., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: We aimed to compare outcomes of patients with middle cerebral artery (MCA) aneurysms treated by either microsurgical clipping or endovascular therapy and provide a treatment algorithm based on available evidence., Materials and Methods: We performed a retrospective analysis of 77 patients with 95 MCA aneurysms. Demographic, clinical, and aneurysm morphological variables were collected. Patients were divided into two groups depending on the received treatment. Clinical and radiological outcomes were collected at the end of a 1-year follow-up period and compared between both treatment groups., Results: Mean age was 51.4 years. Fifty patients (65%) underwent microsurgical clipping and 27 (35%) were treated by endovascular therapy. Fifty-four patients (70%) presented with subarachnoid hemorrhage, while 23 (30%) were treated for unruptured aneurysms. Patients with subarachnoid hemorrhage were more frequently treated by microsurgical clipping than patients with unruptured aneurysms. Clinical outcomes, including functional status, were similar between treatment groups after 1-year follow-up even when adjusting for clinical presentation. Residual aneurysms were found less frequently in the microsurgical group (OR = 0.09; p < 0.001)., Conclusions: In patients with MCA aneurysms, clinical outcomes at 1 year are similar between microsurgical clipping and endovascular therapy. However, microsurgery is associated with a lower risk of residual aneurysms., (Copyright: © 2022 Permanyer.)

After unsuccessful outpatient conservative treatment or invasive inpatient treatment and after cystectomy in interstitial cystitis/bladder pain syndrome (IC/BPS), an inpatient discipline-specific urological rehabilitation (rehab) should be proposed according to the German guideline on IC/BPS. During rehab, diagnostic results will be completed. Multimodal therapy includes the optimisation of lifestyle and medication. Intensive psychotherapy may frequently improve the processing of the disease. Various forms of exercise therapy and physical therapy with water applications, thermotherapy, several forms of massage and electrical or magnetic therapies as well as nutritional advice frequently alleviate complaints in IC/BPS. The different therapies are modified during rehab, if necessary. Social medicine evaluation and advice, e.g. on grade of handicap or ability to work, are also important issues in rehab. Two-thirds of patients show an essential improvement after rehab, which lasts for a prolonged period in about 50% of patients., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)