Fulvestrant: pharmacokinetics and pharmacology

Fulvestrant is a new type of oestrogen receptor (ER) antagonist with no agonist activity and a novel pharmacological profile. Fulvestrant has been shown to significantly reduce cellular levels of the ER and progesterone receptor in both preclinical studies and in clinical trials of postmenopausal women with primary breast cancer. This paper reviews the pharmacokinetics and metabolism of fulvestrant, which support the rationale for drug delivery as a single, once-monthly intramuscular injection, and show that this agent has minimal potential to be the subject, or cause, of significant cytochrome p450-mediated drug interactions

Recovery of Breakthrough Asthma Attacks Treated With Oral Steroids while on monoclonal antibody therapy: protocol for a prospective observational study (BOOST)

Background: Asthma attacks are a common and important problem. Someone experiences an asthma attack in the United Kingdom every 10 seconds. Asthma attacks cause coughing, wheezing, breathlessness, and chest tightness and are highly stressful for patients. They result in reduced quality of life, with days lost from work or school. Asthma attacks are treated with oral corticosteroids (OCSs), but these have many short- and long-term side effects. Asthma monoclonal antibodies (mAbs) have revolutionized the treatment of severe asthma by reducing asthma attacks and OCS burden by over 50%, but some people still experience attacks while on mAbs. The MEX study showed that residual asthma attacks are broadly eosinophilic (high fractional exhaled nitric oxide [FeNO]) or noneosinophilic (low FeNO), but it did not measure response to OCS treatment. There is an evidence gap in understanding the clinical and inflammatory responses that occur when using OCSs to treat residual asthma attacks in patients taking asthma mAbs. Objective: The primary objective is to compare the clinical recovery between high-FeNO and low-FeNO attacks after acute treatment with oral prednisolone among people established on long-term asthma mAb treatment. The exploratory objective is to compare the inflammatory response to acute treatment with oral prednisolone between high-FeNO and low-FeNO attacks. Methods: BOOST (Breakthrough Asthma Attacks Treated With Oral Steroids) is a single-center, prospective observational study of 60 adults established on long-term asthma mAb treatment who receive acute treatment with oral prednisolone (usual care) for an asthma attack. The primary outcome will be the proportion of treatment failure (the need to start oral prednisolone or antibiotics or an unscheduled health care visit for asthma, following an attack) at day 28. The secondary outcomes will be the change in forced expiratory volume in 1 second and the change in visual analogue scale symptom score between the stable state, attack, day 7, and day 28 visits. The exploratory outcomes include the changes in sputum, nasal, and blood inflammometry between the stable state, attack, day 7, and day 28 visits. Results: The last asthma attack visit is anticipated to occur in December 2023. Data analysis and publication will take place in 2024. Conclusions: We will test the hypothesis that there is a difference in the rate of recovery of clinical and inflammatory measures between high-FeNO and low-FeNO asthma attacks that occur in patients on mAb therapy. The study data will help power a future randomized placebo-controlled trial of prednisolone treatment for nonsevere attacks in patients treated with asthma mAbs and will provide important information on whether corticosteroid treatment should be FeNO-directed. International Registered Report Identifier (IRRID): DERR1-10.2196/4674

Co-infection with <i>Fasciola hepatica</i> may increase the risk of <i>Escherichia coli</i> O157 shedding in British cattle destined for the food chain

© 2017 The Authors Escherichia coli O157 is a zoonotic bacterium that can cause haemorrhagic diarrhoea in humans and is of worldwide public health concern. Cattle are considered to be the main reservoir for human infection. Fasciola hepatica is a globally important parasite of ruminant livestock that is known to modulate its host's immune response and affect susceptibility to bacterial pathogens such as Salmonella Dublin. Shedding of E. coli O157 is triggered by unknown events, but the immune system is thought to play a part. We investigated the hypothesis that shedding of E. coli O157 is associated with F. hepatica infection in cattle. Three hundred and thirty four cattle destined for the food chain, from 14 British farms, were tested between January and October 2015. E. coli O157 was detected by immunomagnetic separation and bacterial load enumerated. F. hepatica infection status was assessed by copro-antigen ELISA. A significant association (p = 0.01) was found between the log percent positivity (PP) of the F. hepatica copro-antigen ELISA and E. coli O157 shedding when the fixed effects of day of sampling and the age of the youngest animal in the group, plus the random effect of farm were adjusted for. The results should be interpreted cautiously due to the lower than predicted level of fluke infection in the animals sampled. Nevertheless these results indicate that control of F. hepatica infection may have an impact on the shedding of E. coli O157 in cattle destined for the human food chain

Combined Monte Carlo/torsion-angle molecular dynamics for ensemble modeling of proteins, nucleic acids and carbohydrates

We describe a general method to use Monte Carlo simulation followed by torsion-angle molecular dynamics simulations to create ensembles of structures to model a wide variety of soft-matter biological systems. Our particular emphasis is focused on modeling low-resolution small-angle scattering and reflectivity structural data. We provide examples of this method applied to HIV-1 Gag protein and derived fragment proteins, TraI protein, linear B-DNA, a nucleosome core particle, and a glycosylated monoclonal antibody. This procedure will enable a large community of researchers to model low-resolution experimental data with greater accuracy by using robust physics based simulation and sampling methods which are a significant improvement over traditional methods used to interpret such data

Subaru FOCAS Spectroscopic Observations of High-Redshift Supernovae

We present spectra of high-redshift supernovae (SNe) that were taken with the Subaru low resolution optical spectrograph, FOCAS. These SNe were found in SN surveys with Suprime-Cam on Subaru, the CFH12k camera on the Canada-France-Hawaii Telescope (CFHT), and the Advanced Camera for Surveys (ACS) on the Hubble Space Telescope (HST). These SN surveys specifically targeted z>1 Type Ia supernovae (SNe Ia). From the spectra of 39 candidates, we obtain redshifts for 32 candidates and spectroscopically identify 7 active candidates as probable SNe Ia, including one at z=1.35, which is the most distant SN Ia to be spectroscopically confirmed with a ground-based telescope. An additional 4 candidates are identified as likely SNe Ia from the spectrophotometric properties of their host galaxies. Seven candidates are not SNe Ia, either being SNe of another type or active galactic nuclei. When SNe Ia are observed within a week of maximum light, we find that we can spectroscopically identify most of them up to z=1.1. Beyond this redshift, very few candidates were spectroscopically identified as SNe Ia. The current generation of super red-sensitive, fringe-free CCDs will push this redshift limit higher.Comment: 19 pages, 26 figures. PASJ in press. see http://www.supernova.lbl.gov/2009ClusterSurvey/ for additional information pertaining to the HST Cluster SN Surve

The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes

Aims: Biomarker‐driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub‐classify iMB, and proffer strategies for personalized, risk‐adapted therapies. Methods: We characterized the iMB molecular landscape, including second‐generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). Results: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second‐generation subtypes II/III/IV. Subtype II strongly associated with large‐cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very‐high‐risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4) and subtype IV tumours were standard risk (80% OS) using upfront CSI‐based therapies; randomized‐controlled trials of upfront radiation‐sparing and/or second‐line radiotherapy should be considered. Seventy‐five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non‐DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH. iMBSHH harboured two distinct subtypes (iMBSHH‐I/II). Within the discriminated favourable‐risk iMBSHH DN/MBEN patient group, iMBSHH‐II had significantly better progression‐free survival than iMBSHH‐I, offering opportunities for risk‐adapted stratification of upfront therapies. Both iMBSHH‐I and iMBSHH‐II showed notable rescue rates (56% combined post‐relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. Conclusions: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup‐dependent survival models highlight opportunities for biomarker‐directed therapies

Evo-devo of human adolescence: beyond disease models of early puberty

Despite substantial heritability in pubertal development, much variation remains to be explained, leaving room for the influence of environmental factors to adjust its phenotypic trajectory in the service of fitness goals. Utilizing evolutionary development biology (evo-devo), we examine adolescence as an evolutionary life-history stage in its developmental context. We show that the transition from the preceding stage of juvenility entails adaptive plasticity in response to energy resources, other environmental cues, social needs of adolescence and maturation toward youth and adulthood. Using the evolutionary theory of socialization, we show that familial psychosocial stress fosters a fast life history and reproductive strategy rather than early maturation being just a risk factor for aggression and delinquency. Here we explore implications of an evolutionary-developmental-endocrinological-anthropological framework for theory building, while illuminating new directions for research

Constraining dust and color variations of high-z SNe using NICMOS on Hubble Space Telescope

We present data from the Supernova Cosmology Project for five high redshift Type Ia supernovae (SNe Ia) that were obtained using the NICMOS infrared camera on the Hubble Space Telescope. We add two SNe from this sample to a rest-frame I-band Hubble diagram, doubling the number of high redshift supernovae on this diagram. This I-band Hubble diagram is consistent with a flat universe (Omega_Matter, Omega_Lambda= 0.29, 0.71). A homogeneous distribution of large grain dust in the intergalactic medium (replenishing dust) is incompatible with the data and is excluded at the 5 sigma confidence level, if the SN host galaxy reddening is corrected assuming R_V=1.75. We use both optical and infrared observations to compare photometric properties of distant SNe Ia with those of nearby objects. We find generally good agreement with the expected color evolution for all SNe except the highest redshift SN in our sample (SN 1997ek at z=0.863) which shows a peculiar color behavior. We also present spectra obtained from ground based telescopes for type identification and determination of redshift.Comment: 30 pages, 10 figures; accepted for publication in ApJ; v2: revised to match the version in the journa

The Role of Individual Variables, Organizational Variables and Moral Intensity Dimensions in Libyan Management Accountants’ Ethical Decision Making

This study investigates the association of a broad set of variables with the ethical decision making of management accountants in Libya. Adopting a cross-sectional methodology, a questionnaire including four different ethical scenarios was used to gather data from 229 participants. For each scenario, ethical decision making was examined in terms of the recognition, judgment and intention stages of Rest’s model. A significant relationship was found between ethical recognition and ethical judgment and also between ethical judgment and ethical intention, but ethical recognition did not significantly predict ethical intention—thus providing support for Rest’s model. Organizational variables, age and educational level yielded few significant results. The lack of significance for codes of ethics might reflect their relative lack of development in Libya, in which case Libyan companies should pay attention to their content and how they are supported, especially in the light of the under-development of the accounting profession in Libya. Few significant results were also found for gender, but where they were found, males showed more ethical characteristics than females. This unusual result reinforces the dangers of gender stereotyping in business. Personal moral philosophy and moral intensity dimensions were generally found to be significant predictors of the three stages of ethical decision making studied. One implication of this is to give more attention to ethics in accounting education, making the connections between accounting practice and (in Libya) Islam. Overall, this study not only adds to the available empirical evidence on factors affecting ethical decision making, notably examining three stages of Rest’s model, but also offers rare insights into the ethical views of practising management accountants and provides a benchmark for future studies of ethical decision making in Muslim majority countries and other parts of the developing world