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The exchange coupling between a hard magnetic layer MnBi and a soft magnetic layer Co-Fe has been found to significantly improve the maximum energy product. In this work, the spin structure of exchange-coupled MnBi:Co-Fe bilayers is experimentally investigated by X-ray magnetic circular dichroism (XMCD) and polarized neutron reflectometry (PNR). We find that the out-of-plane magnetization reversal process of the MnBi:Co-Fe bilayer structure involves formation of a curling-type twisting of the magnetization in the film plane at low or intermediate reversal fields. Micromagnetic simulations are further performed to provide a detailed view of the spins at the curling center. Reminiscent of chiral spin structures known as spin bobbers, this curling in the exchange-coupled hard-soft magnetic bilayers is a new type of skyrmionic spin structure and worth further investigation.

We use temperature-dependent Hall measurements to identify contributions of spin Hall, magnetic proximity, and sublattice effects to the anomalous Hall signal in heavy metal/ferrimagnetic insulator heterostructures with perpendicular magnetic anisotropy. This approach enables detection of both the magnetic proximity effect onset temperature and the magnetization compensation temperature and provides essential information regarding the interfacial exchange coupling. Onset of a magnetic proximity effect yields a local extremum in the temperature-dependent anomalous Hall signal, which occurs at higher temperature as magnetic insulator thickness increases. This magnetic proximity effect onset occurs at much higher temperature in Pt than W. The magnetization compensation point is identified by a sharp anomalous Hall sign change and divergent coercive field. We directly probe the magnetic proximity effect using x-ray magnetic circular dichroism and polarized neutron reflectometry, which reveal an antiferromagnetic coupling between W and the magnetic insulator. Finally, we summarize the exchange-coupling configurations and the anomalous Hall-effect sign of the magnetized heavy metal in various heavy metal/magnetic insulator heterostructures.

Control of materials through custom design of ionic distributions represents a powerful new approach to develop future technologies ranging from spintronic logic and memory devices to energy storage. Perovskites have shown particular promise for ionic devices due to their high ion mobility and sensitivity to chemical stoichiometry. In this work, we demonstrate a solid-state approach to control of ionic distributions in (La,Sr)CoO3 thin films. Depositing a Gd capping layer on the perovskite film, oxygen is controllably extracted from the structure, up to 0.5 O/u.c. throughout the entire 36-nm thickness. Commensurate with the oxygen extraction, the Co valence state and saturation magnetization show a smooth continuous variation. In contrast, magnetoresistance measurements show no change in the magnetic anisotropy and a rapid increase in the resistivity over the same range of oxygen stoichiometry. These results suggest significant phase separation, with metallic ferromagnetic regions and oxygen-deficient, insulating, nonferromagnetic regions, forming percolated networks. Indeed, x-ray diffraction identifies oxygen-vacancy ordering, including transformation to a brownmillerite crystal structure. The unexpected transformation to the brownmillerite phase at ambient temperature is further confirmed by high-resolution scanning transmission electron microscopy which shows significant structural - and correspondingly chemical - phase separation. This work demonstrates room-temperature ionic control of magnetism, electrical resistivity, and crystalline structure in a 36-nm-thick film, presenting opportunities for ionic devices that leverage multiple material functionalities.

We observe an induced switchable magnetic moment of 1.6±0.40μB/Fe for the nominally antiferromagnetic LaFeO3 extending two to four interface layers into the non-charge transfer system La0.7Sr0.3MnO3/LaFeO3/SrTiO3(111). Simultaneously a mismatch of oxygen octahedra rotations at the interface implies an atomic reconstruction of reduced symmetry at the interface, reaching two to five layers into LaFeO3. Density functional theory of a structure with atomic reconstruction and different correlation strength shows a ferrimagnetic state with a net Fe moment at the interface. Together these results suggest that engineered oxygen octahedra rotations, affecting the local symmetry, affect electron correlations and can be used to promote magnetic properties.

We demonstrate substantial enhancement in the energy product of MnBi-based magnets by forming robust ferromagnetic exchange coupling between a MnBi layer and a thin CoFe layer in a unique perpendicular coupling configuration, which provides increased resistance to magnetization reversal. The measured nominal energy product of 172kJ/m3 at room temperature is the largest value experimentally attained for permanent magnets free of expensive raw materials. Our finding shows that exchange-coupled MnBi/CoFe magnets are a viable option for pursuing rare-earth-free magnets with energy products approaching those containing rare-earth elements.

Electric field control of magnetism provides a promising route towards ultralow power information storage and sensor technologies. The effects of magneto-ionic motion have been prominently featured in the modification of interface characteristics. Here, we demonstrate magnetoelectric coupling moderated by voltage-driven oxygen migration beyond the interface in relatively thick AlOx/GdOx/Co(15 nm) films. Oxygen migration and Co magnetization are quantitatively mapped with polarized neutron reflectometry under electro-thermal conditioning. The depth-resolved profiles uniquely identify interfacial and bulk behaviours and a semi-reversible control of the magnetization. Magnetometry measurements suggest changes in the microstructure which disrupt long-range ferromagnetic ordering, resulting in an additional magnetically soft phase. X-ray spectroscopy confirms changes in the Co oxidation state, but not in the Gd, suggesting that the GdOx transmits oxygen but does not source or sink it. These results together provide crucial insight into controlling magnetism via magneto-ionic motion, both at interfaces and throughout the bulk of the films.

Ionic transport in metal/oxide heterostructures offers a highly effective means to tailor material properties via modification of the interfacial characteristics. However, direct observation of ionic motion under buried interfaces and demonstration of its correlation with physical properties has been challenging. Using the strong oxygen affinity of gadolinium, we design a model system of GdxFe1-x/NiCoO bilayer films, where the oxygen migration is observed and manifested in a controlled positive exchange bias over a relatively small cooling field range. The exchange bias characteristics are shown to be the result of an interfacial layer of elemental nickel and cobalt, a few nanometres in thickness, whose moments are larger than expected from uncompensated NiCoO moments. This interface layer is attributed to a redox-driven oxygen migration from NiCoO to the gadolinium, during growth or soon after. These results demonstrate an effective path to tailoring the interfacial characteristics and interlayer exchange coupling in metal/oxide heterostructures.

We demonstrate reversible control of magnetization and anisotropy in La0.67Sr0.33MnO3 films through interfacial oxygen migration. Gd metal capping layers deposited onto La0.67Sr0.33MnO3 leach oxygen from the film through a solid-state redox reaction to form porous Gd2O3. X-ray absorption and polarized neutron reflectometry measurements show Mn valence alterations consistent with high oxygen vacancy concentrations, resulting in suppressed magnetization and increased coercive fields. Effects of the oxygen migration are observed both at the interface and also throughout the majority of a 40 nm thick film, suggesting extensive diffusion of oxygen vacancies. After Gd-capped La0.67Sr0.33MnO3 is exposed to atmospheric oxygen for a prolonged period of time, oxygen diffuses through the Gd2O3 layer and the magnetization of the La0.67Sr0.33MnO3 returns to the uncapped value. These findings showcase perovskite heterostructures as ideal candidates for developing functional interfaces through chemically-induced oxygen migration.

The US neutrino community gathered at the Workshop on the IntermediateNeutrino Program (WINP) at Brookhaven National Laboratory February 4-6, 2015 toexplore opportunities in neutrino physics over the next five to ten years.Scientists from particle, astroparticle and nuclear physics participated in theworkshop. The workshop examined promising opportunities for neutrino physics inthe intermediate term, including possible new small to mid-scale experiments,US contributions to large experiments, upgrades to existing experiments, R&Dplans and theory. The workshop was organized into two sets of parallel workinggroup sessions, divided by physics topics and technology. Physics workinggroups covered topics on Sterile Neutrinos, Neutrino Mixing, NeutrinoInteractions, Neutrino Properties and Astrophysical Neutrinos. Technologysessions were organized into Theory, Short-Baseline Accelerator Neutrinos,Reactor Neutrinos, Detector R&D and Source, Cyclotron and Meson Decay at Restsessions.This report summarizes discussion and conclusions from the workshop.

We have used polarized neutron reflectometry to show that controlled variation of growth pressure during deposition of Co/Pd multilayers can be used to achieve a significant vertical gradient in the effective anisotropy. This gradient is strongly dependent on deposition order (low to high pressure or vice versa), and is accompanied by a corresponding gradient in saturation magnetization. These results demonstrate pressure-grading as an attractively simple technique for tailoring the anisotropy profile of magnetic media.

Magnetization reversal mechanisms and depth-dependent magnetic profile have been investigated in Co/Pd thin films magnetron-sputtered under continuously varying pressure with opposite deposition orders. For samples grown under increasing pressure, magnetization reversal is dominated by domain nucleation, propagation, and annihilation; an anisotropy gradient is effectively established, along with a pronounced depth-dependent magnetization profile. However, in films grown under decreasing pressure, disorders propagate vertically from the bottom high-pressure region into the top low-pressure region, impeding domain wall motion and forcing magnetization reversal via rotation; depth-dependent magnetization varies in an inverted order, but the spread is much suppressed. © 2014 AIP Publishing LLC.

This study was designed to investigate the influence of sexual maturity on peak VO2 and blood lactate responses to exercise using serum testosterone levels as an objective measure of maturity. Testosterone levels were determined in venous blood samples obtained from 12- to 16-year-old males (n = 50). Peak VO2 and percentage of peak VO2 at blood lactate levels of 2.5 and 4.0 mmol x L to the negative first power were determined during incremental treadmill running. Standard multiple regression revealed that body mass, age, and height explained 74% of the variance in peak VO2 scores. The addition of serum testosterone to the equation failed to produce a significant increase in the explained variance. Correlation coefficients between testosterone and the lactate variables were not significant (p > .05). These findings do not support the hypothesis that hormonal changes per se during sexual maturation play an important role in the development of peak VO2 and blood lactate responses to exercise. [ABSTRACT FROM AUTHOR]

Inactivation of 24-hydroxylase (CYP24A1) causes mild hypercalcemia in humans that becomes severe and life-threatening during pregnancy through unclear mechanisms. We studied Cyp24a1 null mice during pregnancy, lactation, and post-weaning. We hypothesized that Cyp24a1 nulls have a much greater increase in calcitriol during pregnancy and lactation, leading to markedly increased intestinal calcium absorption and reduced lactational bone loss. WT and Cyp24a1 null sisters were mated to Cyp24a1+/- males. Timepoints included baseline (BL), late pregnancy (LP), mid-lactation (ML), late lactation (LL), and weekly x4 weeks of post-weaning recovery (R1-4). Assessments included intestinal calcium absorption (IntCaAbs) by gavage of 45Ca, bone mineral content (BMC) by DXA, microCT of femurs, 3-point bending tests of tibias, serum hormones, serum and urine minerals, milk analysis, and intestinal gene expression. At LP, whole body BMC increased equally by ~12% in null and WT. Calcitriol was 2.5-fold higher in nulls vs WT, accompanied by 3-fold increased IntCaAbs, hypercalcemia, hypercalciuria, and 6.5-fold higher FGF23. PTH was suppressed in both. Twenty percent of null dams died during delivery but their serum calcium at LP did not differ from Cyp24a1 nulls that survived. At ML, calcitriol, IntCaAbs, and FGF23 declined in both genotypes but remained higher than BL values in Cyp24a1 nulls. By LL, nulls were still hypercalcemic vs WT, and had lost less mean whole body BMC (11% vs. 21%, P<.02), but by micro-CT there were no differences from WT in cortical or trabecular bone mass. Lactational losses in BMC, cortical thickness, and trabecular number were restored by R4 in both genotypes. In summary, ablation of Cyp24a1 increased IntCaAbs and caused hypercalcemia during pregnancy and lactation, late gestational mortality in some nulls, and reduced lactational BMC loss. Treating women with gestational hypercalcemia from CYP24A1 mutations should focus on reducing calcitriol or IntCaAbs, since increased bone resorption is not the cause., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: Physical activity is associated with improved disease-free survival in colorectal cancer survivors. This report describes the purpose, design, recruitment, and exercise adherence results of the National Cancer Institute (NCI)-sponsored Exercise and Colorectal Cancer Treatment (EXACT) trial., Methods: The primary objective of the EXACT trial is to determine if randomization to 150 min per week of moderate-intensity aerobic exercise reduces systemic inflammation among stage I-III colorectal cancer survivors compared with a waitlist control group over 12 weeks. Participants were provided with an in-home treadmill and heart rate monitor. Characteristics associated with randomization were identified using χ 2 or Fisher's exact test for categorical variables and t-tests or analysis of covariance (ANCOVA). Exercise adherence was calculated as the total minutes exercised by total minutes prescribed., Results: Between August 2019 and February 2023, 3082 colorectal cancer survivors were invited to participate, 89 were screened, and 60 were randomized to the study protocol. Younger age (P = 0.02), female sex (P = 0.002), white race (P = 0.01), proximal time since tumor resection (P = 0.02), and regional tumor stage (P < 0.001) were associated with study participation. Average exercise adherence was 92.2 % (95 % CI: 85.5, 98.8) and all study participants achieved ≥80 % exercise adherence. Endpoint data collection was completed for all participants in May 2023., Conclusion: The results from the EXACT trial will characterize the changes that occur from exercise to advance our understanding of the biological mechanisms by which exercise may prevent tumor recurrence and death in colorectal cancer survivors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Ablation of Cyp27b1 eliminates calcitriol but does not disturb fetal mineral homeostasis or skeletal development. However, independent of fetal genotypes, maternal loss of Cyp27b1 altered fetal mineral and hormonal levels compared to offspring of WT dams. We hypothesized that these maternal influences would alter postnatal skeletal development. Cyp27b1 null and WT females were mated to bear only Cyp27b1+/- offspring. Forty-eight hours after birth, pups were cross-fostered to dams of the same or opposite genotype that bore them. Maternal and offspring samples were collected on days 21 (weaning) and 42. Offspring measurements included minerals and hormones, BMC by DXA, ash weight and mineral content, gene expression, 3-point bending tests, and microCT. Maternal lactational behavior was evaluated. Milk was analyzed for nutritional content. At day 21, offspring fostered by nulls, independent of birth dam, had ~20% lower weight, BMC, ash weight, and ash calcium than pups fostered by WT dams. Adjustment for body weight accounted for the lower BMC but not the lower ash weight and ash calcium. Hormones and serum/urine minerals did not differ across offspring groups. Offspring fostered by nulls had shorter femurs and lower cortical thickness, mean polar moment of inertia, cortical area, trabecular bone volume, and trabecular number. Dam lactational behaviors and milk nutritional content did not differ between groups. At day 42, body weight, ash weight, lengths, BMC, and tibial bone strength were no longer different between pups fostered by null vs WT dams. In summary, pups fostered by Cyp27b1 nulls, regardless of birth dam, have proportionately smaller skeletons at 21 d, impaired microstructure, but normal mineral homeostasis. The skeletal effects are largely recovered by day 42 (3 wk after weaning). In conclusion, maternal loss of calcitriol impairs early postnatal cortical bone growth and trabecular bone mass, but affected offspring catch up after weaning., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: Increased utilization of artificial intelligence (AI)-driven search and large language models by the lay and medical community requires us to evaluate the accuracy of AI responses to common hand surgery questions. We hypothesized that the answers to most hand surgery questions posed to an AI large language model would be correct. Methods: Using the topics covered in Green's Operative Hand Surgery 8 th Edition as a guide, 56 hand surgery questions were compiled and posed to ChatGPT (OpenAI, San Francisco, CA). Two attending hand surgeons then independently reviewed ChatGPT's answers for response accuracy, completeness, and usefulness. A Cohen's kappa analysis was performed to assess interrater agreement. Results: An average of 45 of the 56 questions posed to ChatGPT were deemed correct (80%), 39 responses were deemed useful (70%), and 32 responses were deemed complete (57%) by the reviewers. Kappa analysis demonstrated "fair to moderate" agreement between the two raters. Reviewers disagreed on 11 questions regarding correctness, 16 questions regarding usefulness, and 19 questions regarding completeness. Conclusions: Large language models have the potential to both positively and negatively impact patient perceptions and guide referral patterns based on the accuracy, completeness, and usefulness of their responses. While most responses fit these criteria, more precise responses are needed to ensure patient safety and avoid misinformation. Individual hand surgeons and surgical societies must understand these technologies and interface with the companies developing them to provide our patients with the best possible care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The effect of oxygen reduction on the magnetic properties of LaFeO 3-δ (LFO) thin films was studied to better understand the viability of LFO as a candidate for magnetoionic memory. Differences in the amount of oxygen lost by LFO and its magnetic behavior were observed in nominally identical LFO films grown on substrates prepared using different common methods. In an LFO film grown on as-received SrTiO 3 (STO) substrate, the original perovskite film structure was preserved following reduction, and remnant magnetization was only seen at low temperatures. In a LFO film grown on annealed STO, the LFO lost significantly more oxygen and the microstructure decomposed into La- and Fe-rich regions with remnant magnetization that persisted up to room temperature. These results demonstrate an ability to access multiple, distinct magnetic states via oxygen reduction in the same starting material and suggest LFO may be a suitable materials platform for nonvolatile multistate memory.

Calcitriol circulates at low levels in normal human and rodent fetuses, in part due to increased 24-hydroxylation of calcitriol and 25-hydroxyvitamin D by 24-hydroxylase (CYP24A1). Inactivating mutations of CYP24A1 cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia type 1, but whether the fetus is disturbed by the loss of CYP24A1 is unknown. We hypothesized that loss of Cyp24a1 in fetal mice will cause high calcitriol, hypercalcemia, and increased placental calcium transport. The Cyp24a1 +/- mice were mated to create pregnancies with wildtype, Cyp24a1 +/- , and Cyp24a1 null fetuses. The null fetuses were hypercalcemic, modestly hypophosphatemic (compared to Cyp24a1 +/- fetuses only), with 3.5-fold increased calcitriol, 4-fold increased fibroblast growth factor 23 (FGF23), and unchanged parathyroid hormone. The quantitative RT-PCR confirmed the absence of Cyp24a1 and 2-fold increases in S100g , sodium-calcium exchanger type 1, and calcium-sensing receptor in null placentas but not in fetal kidneys; these changes predicted an increase in placental calcium transport. However, placental 45 Ca and 32 P transport were unchanged in null fetuses. Fetal ash weight and mineral content, placental weight, crown-rump length, and skeletal morphology did not differ among the genotypes. Serum procollagen 1 intact N-terminal propeptide and bone expression of sclerostin and Blgap were reduced while calcitonin receptor was increased in nulls. In conclusion, loss of Cyp24a1 in fetal mice causes hypercalcemia, modest hypophosphatemia, and increased FGF23, but no alteration in skeletal development. Reduced incorporation of calcium into bone may contribute to the hypercalcemia without causing a detectable decrease in the skeletal mineral content. The results predict that human fetuses bearing homozygous or compound heterozygous inactivating mutations of CYP24A1 will also be hypercalcemic in utero but with normal skeletal development., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Jacobs syndrome is a rare trisomy (47, XYY) found in ~1 in 1000 male children associated with infertility, autism spectrum disorders, macrocephaly, hypertelorism, tall stature, and macroorchidism. Diagnosis is often delayed due to relatively subtle phenotypic changes. Craniosynostosis, a fusion of the cranial sutures, has been described in ~1 in 2000 live births, of which 25% are related to a diagnosed syndrome with the most common being Apert and Crouzon. Craniosynostosis does not have a known association with Jacobs syndrome and no prior cases have been reported. This case report seeks to describe the presentation and treatment of a patient with Jacobs syndrome and metopic craniosynostosis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Competing Interests: Declaration of Competing Interest The authors declare that there are no relevant conflicts of interest.

The magnetic properties of permalloy-based trilayers of the form Py 0.8 Cu 0.2 /Py 0.4 Cu 0.6 /Py/IrMn were studied as the spacer layer undergoes a paramagnetic to ferromagnetic phase transition. We find the coupling between the free Py 0.8 Cu 0.2 layer and the exchange bias pinned Py to be strongly temperature-dependent: there is negligible coupling above the Curie temperature of the Py 0.4 Cu 0.6 spacer layer, strong ferromagnetic coupling below that temperature, and a tunable coupling between these extremes. Polarized neutron reflectometry was used to measure the depth profile of the magnetic order in the system, allowing us to correlate the order parameter with the coupling strength. The thickness dependence shows that these are interface effects with an inverse relationship to thickness, and that there is a magnetic proximity effect that enhances the Curie temperature of the spacer layer with characteristic length scale of about 7 nm. As a demonstration of potential functionality of such a system, the structure is shown to spontaneously flip from the antiparallel to parallel magnetic configuration once the spacer layer has developed long-range magnetic order., (© 2023. The Author(s).)

Thrombosis is a major complication that can occur in both blood-contacting devices and regions and in regions of vascular damage. Microfluidic devices are popular templates to model various thrombogenic settings and to assess conditions that lead to bulk channel occlusion. However, area-averaged measurements miss the opportunity to extract real-time information on thrombus evolution and early dynamics of thrombus formation and propagation, which result in late-stage bulk channel occlusion. To clarify these dynamics, we have developed a standalone tracking algorithm that uses consecutive image connectivity and minimal centroid distance mappings to uniquely index all appearing thrombi in fluorescence time-lapse videos http://links.lww.com/ASAIO/A887 , and http://links.lww.com/ASAIO/A888 . This leads to measurements of all individual aggregates that can in turn be studied as ensembles. We applied tracking to fluorescence time-lapse videos http://links.lww.com/ASAIO/A887 , and http://links.lww.com/ASAIO/A888 of thrombosis across both collagen-functionalized substrate and across the surface of a roughened titanium alloy (Ti6Al4V) at a shear rate of 4000 s -1 . When comparing ensemble-averaged measurements to area-averaged metrics, we unveil immediate, steady thrombus growth at early phases on collagen surfaces and unstable thrombus attachment to roughened Ti6Al4V surfaces on Ti6Al4V surfaces. Additionally, we introduce tracked thrombus eccentricity and fluorescence intensity as additional volumetric measures of thrombus growth that relate back to the primary thrombosis mechanism at play. This work advocates for the complementation of surface macrostate metrics with characteristic thrombus microstate growth patterns to accurately predict critical thrombosis events., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Spectral-temporal ripple tests in both adaptive and non-adaptive versions have been proposed for use in the audiology clinic. Though these methods have been found to yield repeatable results and to be correlated with each other in adults, similar information about test performance in children is lacking. In this preliminary study, children ages 6-12 years completed two repetitions of the adaptive spectral-temporally modulated ripple test (SMRT) and non-adaptive SMRT Lite for computeRless Measurement (SLRM) test. The first and second repetitions of the SLRM were correlated. Though mean performance on the SMRT was significantly correlated with the SLRM, the first and second repetitions of the SMRT were not significantly correlated., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Background and Objective: Cilofexor is a selective farnesoid X receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis and primary sclerosing cholangitis. Our objective was to evaluate potential drug-drug interactions of cilofexor as a victim and as a perpetrator., Methods: In this Phase 1 study, healthy adult participants (n = 18-24 per each of the 6 cohorts) were administered cilofexor in combination with either perpetrators or substrates of cytochrome P-450 (CYP) enzymes and drug transporters., Results: In total, 131 participants completed the study. As a victim, cilofexor area under the curve (AUC) was 651%, 795%, and 175% when administered following single-dose cyclosporine (600 mg; organic anion transporting polypeptide [OATP]/P-glycoprotein [P-gp]/CYP3A inhibitor), single-dose rifampin (600 mg; OATP1B1/1B3 inhibitor), and multiple-dose gemfibrozil (600 mg twice daily [BID]; CYP2C8 inhibitor), respectively, compared with the administration of cilofexor alone. Cilofexor AUC was 33% when administered following multiple-dose rifampin (600 mg; OATP/CYP/P-gp inducer). Multiple-dose voriconazole (200 mg BID; CYP3A4 inhibitor) and grapefruit juice (16 ounces; intestinal OATP inhibitor) did not affect cilofexor exposure. As a perpetrator, multiple-dose cilofexor did not affect the exposure of midazolam (2 mg; CYP3A substrate), pravastatin (40 mg; OATP substrate), or dabigatran etexilate (75 mg; intestinal P-gp substrate), but atorvastatin (10 mg; OATP/CYP3A4 substrate) AUC was 139% compared with atorvastatin administered alone., Conclusion: Cilofexor may be coadministered with inhibitors of P-gp, CYP3A4, or CYP2C8 without the need for dose modification. Cilofexor may be coadministered with OATP, BCRP, P-gp, and/or CYP3A4 substrates-including statins-without dose modification. However, coadministration of cilofexor with strong hepatic OATP inhibitors, or with strong or moderate inducers of OATP/CYP2C8, is not recommended., (© 2023. The Author(s).)

Background: Continuous-flow ventricular assist devices (cfVADs) are implanted in patients with end-stage heart failure to assist with blood circulation. However, VAD implantation is associated with dangerous thrombotic complications. Our goal was to determine the impact of micron and sub-micron scale Ti6Al4V surface roughness on adherent platelet aggregate properties under clinically relevant shear rates., Methods: We used fluorescence microscopy to visualize platelets in real time as they adhered to Ti6Al4V coupons of varying degrees of roughness, including a smooth control, in microfluidic channels and quantified deposition using an image processing algorithm. We systematically characterized roughness using spatial frequencies to generalize results for more blood-biomaterial contact applications., Results: We observed that on the control and sub-micron rough surfaces, at 1000 s -1 , platelets adhered uniformly on the surface. At 2000 s -1 , we observed small and stably adherent platelet aggregates. At 5500 s -1 , platelet aggregates were large, unstable and interconnected via fibrillar structures. On a surface with micron-scale roughness features, at all three shear rates, platelets deposited in the troughs of the roughened surface, and formed aggregates. Thrombus height at 2000 s -1 and 5500 s -1 was greatest on the roughest surface and lowest on the mirror-finished surface, as indicated by the mean fluorescence intensity., Conclusions: These results demonstrated that at high shear rates, thrombi form regardless of surface topography at the scales applied. At lower shear rates, micron-scale surface features cause thrombus formation, whereas submicron features result in innocuous platelet adhesion. These findings have implications for manufacturing costs and other considerations., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Cilofexor is a nonsteroidal farnesoid X receptor (FXR) agonist being evaluated for treatment of nonalcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC). This work characterized the pharmacokinetics, pharmacodynamic, safety, and tolerability of cilofexor in healthy participants. Cilofexor single and multiple once-daily doses (10 to 300 mg fasting or fed and twice-daily doses [15 and 50 mg; fed]; tablet formulation) were evaluated. In each cohort, participants were randomized to active drug or placebo in a 4:1 ratio (planned n = 15/cohort). Multiple dosing was for 14 days. Pharmacokinetic and pharmacodynamic samples were collected and safety and tolerability were assessed. Overall, 120 participants were enrolled in the study and 118 participants received at least one dose of study drug. Cilofexor pharmacokinetics followed bi-exponential disposition and its exposure increased in a less-than-dose-proportional manner over the 10 to 300 mg dose range, with no significant accumulation with repeated dosing. Moderate-fat meal reduced cilofexor area under the plasma concentration versus time curve (AUC) by 21% to 45%. Cilofexor increased plasma levels of fibroblast growth factor19 (FGF19) and reduced the serum bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) and bile acids in an exposure-dependent manner. Cilofexor doses >30 mg appeared to achieve the plateau of intestinal FXR activation. Cilofexor was generally well tolerated; all treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE. The pharmacokinetics pharmacodynamic safety, and tolerability results from this study supported further evaluations, and informed dose selection, of cilofexor in phase II studies in patients with NASH and PSC., (© 2022 Gilead Sciences, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Cobalt oxides have long been understood to display intriguing phenomena known as spin-state crossovers, where the cobalt ion spin changes vs. temperature, pressure, etc. A very different situation was recently uncovered in praseodymium-containing cobalt oxides, where a first-order coupled spin-state/structural/metal-insulator transition occurs, driven by a remarkable praseodymium valence transition. Such valence transitions, particularly when triggering spin-state and metal-insulator transitions, offer highly appealing functionality, but have thus far been confined to cryogenic temperatures in bulk materials (e.g., 90 K in Pr 1-x Ca x CoO 3 ). Here, we show that in thin films of the complex perovskite (Pr 1-y Y y ) 1-x Ca x CoO 3-δ , heteroepitaxial strain tuning enables stabilization of valence-driven spin-state/structural/metal-insulator transitions to at least 291 K, i.e., around room temperature. The technological implications of this result are accompanied by fundamental prospects, as complete strain control of the electronic ground state is demonstrated, from ferromagnetic metal under tension to nonmagnetic insulator under compression, thereby exposing a potential novel quantum critical point., (© 2022. The Author(s).)

Recovery from lactation-induced bone loss appears to be calcitriol-independent, since mice lacking 1-alpha-hydroxylase or vitamin D receptor (VDR) exhibit full skeletal recovery. However, in those studies mice consumed a calcium-, phosphorus-, and lactose-enriched "rescue" diet. Here we assessed whether postweaning skeletal recovery of Vdr null mice required that rescue diet. Wild type (WT) and Vdr null mice were raised on the rescue diet and switched to a normal (1% calcium) diet at Day 21 of lactation until 28 days after weaning. Unmated mice received the same regimen. In WT mice, cortical thickness was significantly reduced by 25% at 21 days of lactation and was completely restored by 28 days after weaning. Three-point bending tests similarly showed a significant reduction during lactation and full recovery of ultimate load and energy absorbed. Although Vdr null mice exhibited a similar lactational reduction in cortical thickness and mechanical strength, neither was even partially restored after weaning. Unmated mice showed no significant changes. In micro-computed tomography scans, diaphyses of Vdr null femora at 28 days after weaning were highly porous and exhibited abundant low-density bone extending into the marrow space from the endocortical surface. To quantify, we segregated bone into low-, mid-, and high-density components. In WT diaphyses, high-density bone was lost during lactation and restored after weaning. Vdr null mice also lost high-density bone during lactation but did not replace it; instead, they demonstrated a threefold increase in low-density bone mass. Histology revealed that intracortical and endocortical surfaces of Vdr null bones after weaning contained very thick (up to 20 micron) osteoid seams, covered with multiple layers of osteoblasts and precursors. We conclude that during the postweaning period, osteoblasts are potently stimulated to produce osteoid despite lacking VDRs, and that either calcitriol or a calcium-enriched diet are needed for this immature bone to become mineralized. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)