Determining the Locations of Dust Sources in FeLoBAL Quasars

We conduct a spectroscopic search of quasars observed by the Sloan Digital Sky Survey (SDSS) with broad absorption line (BAL) troughs due to Mg II and troughs due to Fe II that simultaneously exhibit strong Balmer narrow emission lines (NELs). We find that in a redshift range of 0.4 less than or equal to z less than or equal to 0.9 approximately 23 of the 70 Mg II BALs and 4 of a subset of 15 Fe II BALs exhibit strong Balmer emission. We also find significant fractions of Mg II BALs (approximately 23%) and those Mg II BALs with Fe II troughs (approximately 27%) have strong continuum reddening, E(B - V) greater than or equal to 0.1. From measurements of the Balmer decrement in three objects, we find similarly significant reddening of the NEL region in three of the four objects; the NELs in the fourth object are not measurable. We also include one object in this study not taken from the SDSS sample that shows Fe II absorption and strong narrow emission, but due to measurement uncertainty and low continuum reddening the comparison is consistent but inconclusive. We find a trend in both the Mg II and Fe II BAL samples between the NEL reddening and continuum reddening. Because the narrow line reddening is consistent with the continuum reddening in every object in the two SDSS samples, it suggests that the reddening sources in these objects likely exist at larger radial distances than the narrow line regions from the central nucleus.Comment: 40 manuscript pages, accepted in ApJ (July

Calcitriol suppression of parathyroid hormone fails to improve skeletal properties in an animal model of chronic kidney disease

BACKGROUND: Chronic kidney disease (CKD) leads to complex metabolic changes and an increased risk of fracture. Currently, calcitriol is the standard of care as it effectively suppresses parathyroid hormone (PTH) levels in CKD patients. While calcitriol and its analogs improve BMD and reduce fractures in the general population, the extension of these benefits to patients with advanced kidney disease is unclear. Here, the impact of calcitriol on the skeleton was examined in the setting of reduction in PTH. METHODS: Male Cy/+ rats, a PKD-like CKD model, were treated with either vehicle or calcitriol for 5 weeks. Their normal littermates served as controls. Animals were assessed for changes in mineral metabolism and skeletal parameters (microCT, histology, whole bone mechanics and bone quality). RESULTS: PTH levels were significantly higher (12-fold) in animals with CKD compared to normal controls. CKD animals also exhibited negative changes in bone structural and mechanical properties. Calcitriol treatment resulted in a 60% suppression of PTH levels in animals with CKD. Despite these changes, it had no impact on bone volume (cortical or cancellous), bone turnover, osteoclast number or whole bone mechanical properties. CONCLUSIONS: These data indicate that while calcitriol effectively lowered PTH in rats with CKD, it did little to prevent the negative effects of secondary hyperparathyroidism on the skeleton

The Quasar Outflow Contribution to AGN Feedback: VLT Measurements of SDSS J0318-0600

We present high spectral resolution VLT observations of the BAL quasar SDSS J0318-0600. This high quality data set allows us to extract accurate ionic column densities and determine an electron number density of n_e=10^3.3 +/- 0.2 cm^-3 for the main outflow absorption component. The heavily reddened spectrum of SDSS J0318-0600 requires purely silicate dust with a reddening curve characteristic of predominately large grains, from which we estimate the bolometric luminosity. We carry out photoionization modeling to determine the total column density, ionization parameter and distance of the gas and find that the photionization models suggest abundances greater than solar. Due to the uncertainty in the location of the dust extinction, we arrive at two viable distances for the main ouflow component from the central source, 6 and 18 kpc, where we consider the 6 kpc location as somewhat more physically plausable. Assuming the canonical global covering of 20% for the outflow and a distance of 6 kpc, our analysis yields a mass flux of 120 M_sun yr^-1 and a kinetic luminosity that is ~0.1% of the bolometric luminosity of the object. Should the dust be part of the outflow, then these values are ~4x larger. The large mass flux and kinetic luminosity make this outflow a significant contributor to AGN feedback processes.Comment: Accepted for publication in ApJ, 57 pages, 14 figure

Raloxifene improves skeletal properties in an animal model of cystic chronic kidney disease

Patients with chronic kidney disease (CKD) have an increased risk of fracture. Raloxifene is a mild antiresorptive agent that reduces fracture risk in the general population. Here we assessed the impact of raloxifene on the skeletal properties of animals with progressive CKD. Male Cy/+ rats that develop autosomal dominant cystic kidney disease were treated with either vehicle or raloxifene for five weeks. They were assessed for changes in mineral metabolism and skeletal parameters (microCT, histology, whole-bone mechanics, and material properties). Their normal littermates served as controls. Animals with CKD had significantly higher parathyroid hormone levels compared with normal controls, as well as inferior structural and mechanical skeletal properties. Raloxifene treatment resulted in lower bone remodeling rates and higher cancellous bone volume in the rats with CKD. Although it had little effect on cortical bone geometry, it resulted in higher energy to fracture and modulus of toughness values than vehicle-treated rats with CKD, achieving levels equivalent to normal controls. Animals treated with raloxifene had superior tissue-level mechanical properties as assessed by nanoindentation, and higher collagen D-periodic spacing as assessed by atomic force microscopy. Thus, raloxifene can positively impact whole-bone mechanical properties in CKD through its impact on skeletal material properties

Skeletal levels of bisphosphonate in the setting of chronic kidney disease are independent of remodeling rate and lower with fractionated dosing

Background Chronic kidney disease (CKD) results in a dramatic increase in skeletal fracture risk. Bisphosphates (BP) are an effective treatment for reducing fracture risk but they are not recommended in advanced CKD. We have recently shown higher acute skeletal accumulation of fluorescently-tagged zoledronate (ZOL) in the setting of CKD but how this accumulation is retained/lost over time is unclear. Furthermore, it is unknown if alternative dosing approaches can modulate accumulation in the setting of CKD. Methods To address these two questions normal (NL) and Cy/+ (CKD) rats were divided into control groups (no dosing), a single dose of a fluorescent-tagged ZOL (FAM-ZOL), a single dose of non-labelled zoledronate (ZOL) or ten weekly doses of FAM-ZOL each at 1/10th the dose of the single dose group. Half of the CKD animals in each group were provided water with 3% calcium in drinking water (CKD + Ca) to suppress PTH and remodeling. At 30 or 35 weeks of age, serum, tibia, ulna, radius, vertebra, femora, and mandible were collected and subjected to assessment methods including biochemistry, dynamic histomorphometry and multi-spectral fluorescence levels (using IVIS SpectrumCT). Results FAM-ZOL did not significantly reduce bone remodeling in either NL or CKD animals while Ca supplementation in CKD produced remodeling levels comparable to NL. At five- and ten-weeks post-dosing, both CKD and CKD + Ca groups had higher levels of FAM-ZOL in most, but not all, skeletal sites compared to NL with no difference between the two CKD groups suggesting that the rate of remodeling did not affect skeletal retention of FAM-ZOL. Fractionating the FAM-ZOL into ten weekly doses led to 20–32% less (p < 0.05) accumulation/retention of compound in the vertebra, radius, and ulna compared to administration as a single dose. Conclusions The rate of bone turnover does not have significant effects on levels of FAM-ZOL accumulation/retention in animals with CKD. A lower dose/more frequent administration paradigm results in lower levels of accumulation/retention over time. These data provide information that could better inform the use of bisphosphonates in the setting of CKD in order to combat the dramatic increase in fracture risk

Skeletal accumulation of fluorescently-tagged zoledronate is higher in animals with early stage chronic kidney disease

This work examines the skeletal accumulation of fluorescently-tagged zoledronate in an animal model of chronic kidney disease. The results show higher accumulation 24-hours post-dose in animals with lower kidney function due to greater amounts of binding at individual surfaces.NIH F30 DK115162; NIH T32 AR065971; NIH P30 DK 07931

Supply chain risk management strategies in normal and abnormal times:Policymakers’ role in reducing generic medicine shortages

Purpose – This paper links supply chain risk management to medicine supply chains to explore the role ofpolicymakers in employing supply chain risk management strategies (SCRMS) to reduce generic medicineshortages.Design/methodology/approach – Using secondary data supplemented with primary data, the authors mapand compare seven countries’ SCRMS for handling shortage risks in their paracetamol supply chains beforeand during the first two waves of the COVID-19 pandemic.Findings – Consistent with recent research, the study finds that policymakers had implemented few SCRMSspecifically for responding to disruptions caused by COVID-19. However, shortages were largely avoided sincemultiple strategies for coping with business-as-usual disruptions had been implemented prior to the pandemic.The authors did find that SCRMS implemented during COVID-19 were not always aligned with thoseimplemented pre-pandemic. The authors also found that policymakers played both direct and indirect roles.Research limitations/implications – Combining longitudinal secondary data with interviews sheds lighton how, regardless of the level of preparedness during normal times, SCRMS can be leveraged to avertshortages in abnormal times. However, the problem is highly complex, which warrants further research.Practical implications – Supply chain professionals and policymakers in the healthcare sector can use thefindings when developing preparedness and response plans.Social implications – The insights developed can help policymakers improve the availability of high-volumegeneric medicines in (ab)normal times.Originality/value – The authors contribute to prior SCRM research in two ways. First, the authorsoperationalize SCRMS in the medicine supply chain context in (ab)normal times, thereby opening avenues forfuture research on SCRM in this context. Second, the authors develop insights on the role policymakers playand how they directly implement and indirectly influence the adoption of SCRMS. Based on the study findings,the authors develop a framework that captures the diverse roles of policymakers in SCRM

Reversing cortical porosity: Cortical pore infilling in preclinical models of chronic kidney disease

Purpose Chronic kidney disease (CKD) patients have a high incidence of fracture due in part to cortical porosity. The goal of this study was to study cortical pore infilling utilizing two rodent models of progressive CKD. Methods Exp 1: Female C57Bl/6J mice (16-week-old) were given dietary adenine (0.2%) to induce CKD for 10 weeks after which calcium water supplementation (Ca-H2O; 1.5% and 3%) was given to suppress PTH for another 4 weeks. Exp 2: Male Cy/+ rats were aged to ~30 weeks with baseline porosity assessed using in vivo μCT. A second in vivo scan followed 5-weeks of Ca-H2O (3%) supplementation. Results Exp 1: Untreated adenine mice had elevated blood urea nitrogen (BUN), parathyroid hormone (PTH), and cortical porosity (~2.6% porosity) while Ca-H2O lowered PTH and cortical porosity (0.5–0.8% porosity). Exp 2: Male Cy/+ rats at baseline had variable porosity (0.5%–10%), but after PTH suppression via Ca-H2O, cortical porosity in all rats was lower than 0.5%. Individual pore dynamics measured via a custom MATLAB code demonstrated that 85% of pores infilled while 12% contracted in size. Conclusion Ca-H2O supplementation causes net cortical pore infilling over time and imparted mechanical benefits. While calcium supplementation is not a viable clinical treatment for CKD, these data demonstrate pore infilling is possible and further research is required to examine clinically relevant therapeutics that may cause net pore infilling in CKD