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

Socioeconomic deprivation, urban-rural location and alcohol-related mortality in England and Wales

Background: Many causes of death are directly attributable to the toxic effects of alcohol and deaths from these causes are increasing in the United Kingdom. The aim of this study was to investigate variation in alcohol-related mortality in relation to socioeconomic deprivation, urban-rural location and age within a national context. Methods: An ecological study design was used with data from 8797 standard table wards in England and Wales. The methodology included using the Carstairs Index as a measure of socioeconomic deprivation at the small-area level and the national harmonised classification system for urban and rural areas in England and Wales. Alcohol-related mortality was defined using the National Statistics definition, devised for tracking national trends in alcohol-related deaths. Deaths from liver cirrhosis accounted for 85% of all deaths included in this definition. Deaths from 1999-2003 were examined and 2001 census ward population estimates were used as the denominators. Results: The analysis was based on 28,839 deaths. Alcohol-related mortality rates were higher in men and increased with increasing age, generally reaching peak levels in middle-aged adults. The 45-64 year age group contained a quarter of the total population but accounted for half of all alcohol-related deaths. There was a clear association between alcohol-related mortality and socioeconomic deprivation, with progressively higher rates in more deprived areas. The strength of the association varied with age. Greatest relative inequalities were seen amongst people aged 25-44 years, with relative risks of 4.73 (95% CI 4.00 to 5.59) and 4.24 (95% CI 3.50 to 5.13) for men and women respectively in the most relative to the least deprived quintiles. People living in urban areas experienced higher alcohol-related mortality relative to those living in rural areas, with differences remaining after adjustment for socioeconomic deprivation. Adjusted relative risks for urban relative to rural areas were 1.35 (95% CI 1.20 to 1.52) and 1.13 (95% CI 1.01 to 1.25) for men and women respectively. Conclusions: Large inequalities in alcohol-related mortality exist between sub-groups of the population in England and Wales. These should be considered when designing public health policies to reduce alcohol-related harm

Gamma-Ray Telescopes (in "400 Years of Astronomical Telescopes")

The last half-century has seen dramatic developments in gamma-ray telescopes, from their initial conception and development through to their blossoming into full maturity as a potent research tool in astronomy. Gamma-ray telescopes are leading research in diverse areas such as gamma-ray bursts, blazars, Galactic transients, and the Galactic distribution of aluminum-26.Comment: 11 pages, 6 figures/ in "400 Years of Astronomical Telescopes: A Review of History, Science and Technology", ed. B.R. Brandl, R. Stuik, & J.K. Katgert-Merkeli (Exp. Astron. 26, 111-122 [2009]

Corn and wheat residue management effects on greenhouse gas emissions in the Mid-Atlantic USA

Greenhouse gas (GHG) emissions from crop residue management have been studied extensively, yet the effects of harvesting more than one crop residue in a rotation have not been reported. Here, we measured the short-term changes in methane (CH4), nitrous oxide (N2O), and carbon dioxide (CO2) emissions in response to residue removal from continuous corn (Zea mays L.) (CC) and corn-wheat (Triticum aestivum L.)-soybean (Glycine max L. Merr.) (CWS) rotations in the Mid-Atlantic USA. A first experiment retained five corn stover rates (0, 3.33, 6.66, 10, and 20 Mg ha-1) in a continuous corn (CC) in Blacksburg, VA, in 2016 and 2017. Two other experiments, initiated during the wheat and corn phases of the CWS rotation in New Kent, VA, utilized a factorial combination of retained corn (0, 3.33, 6.66, and 10.0 Mg ha-1) and wheat residue (0, 1, 2, and 3 Mg ha-1). Soybean residue was not varied. Different crop retention rates did not affect CO2 fluxes in any of the field studies. In Blacksburg, retaining 5 Mg ha-1 stover or more increased CH4 and N2O emissions by ~25%. Maximum CH4 and N2O fluxes (4.16 and 5.94 mg m-2 day-1) occurred with 200% (20 Mg ha-1) retention. Two cycles of stover management in Blacksburg, and one cycle of corn or wheat residue management in New Kent did not affect GHG fluxes. This study is the first to investigate the effects of crop residue on GHG emissions in a multi-crop system in humid temperate zones. Longer-term studies are warranted to understand crop residue management effects on GHG emissions in these systems

How do MNC R&D laboratory roles affect employee international assignments?

Research and development (R&D) employees are important human resources for multinational corporations (MNCs) as they are the driving force behind the advancement of innovative ideas and products. International assignments of these employees can be a unique way to upgrade their expertise; allowing them to effectively recombine their unique human resources to progress existing knowledge and advance new ones. This study aims to investigate the effect of the roles of R&D laboratories in which these employees work on the international assignments they undertake. We categorise R&D laboratory roles into those of the support laboratory, the locally integrated laboratory and the internationally interdependent laboratory. Based on the theory of resource recombinations, we hypothesise that R&D employees in support laboratories are not likely to assume international assignments, whereas those in locally integrated and internationally interdependent laboratories are likely to assume international assignments. The empirical evidence, which draws from research conducted on 559 professionals in 66 MNC subsidiaries based in Greece, provides support to our hypotheses. The resource recombinations theory that extends the resource based view can effectively illuminate the international assignment field. Also, research may provide more emphasis on the close work context of R&D scientists rather than analyse their demographic characteristics, the latter being the focus of scholarly practice hitherto

The Interplay Between GUT and Flavour Symmetries in a Pati-Salam x S4 Model

Both Grand Unified symmetries and discrete flavour symmetries are appealing ways to describe apparent structures in the gauge and flavour sectors of the Standard Model. Both symmetries put constraints on the high energy behaviour of the theory. This can give rise to unexpected interplay when building models that possess both symmetries. We investigate on the possibility to combine a Pati-Salam model with the discrete flavour symmetry $S_4$ that gives rise to quark-lepton complementarity. Under appropriate assumptions at the GUT scale, the model reproduces fermion masses and mixings both in the quark and in the lepton sectors. We show that in particular the Higgs sector and the running Yukawa couplings are strongly affected by the combined constraints of the Grand Unified and family symmetries. This in turn reduces the phenomenologically viable parameter space, with high energy mass scales confined to a small region and some parameters in the neutrino sector slightly unnatural. In the allowed regions, we can reproduce the quark masses and the CKM matrix. In the lepton sector, we reproduce the charged lepton masses, including bottom-tau unification and the Georgi-Jarlskog relation as well as the two known angles of the PMNS matrix. The neutrino mass spectrum can present a normal or an inverse hierarchy, and only allowing the neutrino parameters to spread into a range of values between $\lambda^{-2}$ and $\lambda^2$, with $\lambda\simeq0.2$. Finally, our model suggests that the reactor mixing angle is close to its current experimental bound.Comment: 62 pages, 4 figures; references added, version accepted for publication in JHE

Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours

Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions

When to Start Antiretroviral Therapy

The question of when to start combination antiretroviral therapy for treatment-naïve patients has always been controversial. This is particularly true in the current era, with major guidelines recommending very different treatment strategies. Despite a lack of clarity regarding the optimal time to begin therapy, there has been a recent shift toward earlier initiation. This more aggressive approach is driven by several observations. First, effective viral suppression with therapy can prevent non-AIDS-related morbidity and mortality. Second, therapy can prevent irreversible harm to the human immune system. Third, therapy may prevent transmission of HIV to others, and thus have a potential public health benefit. For patients who are motivated and willing to initiate early treatment, the collective benefits of early therapy may outweigh the well-documented risks of antiretroviral medications

Novel avian paramyxovirus isolated from gulls in Caspian seashore in Kazakhstan.

Three isolates APMV/gull/Kazakhstan/5976/2014, APMV/gull/Kazakhstan/ 5977/2014 and APMV/gull/Kazakhstan/5979/2014, were obtained from independent samples during annual surveillance for avian influenza and paramyxoviruses in wild birds from the Caspian Sea coast in Western Kazakhstan, and were initially identified as putative paramyxoviruses on the basis of electron microscopy. Hemagglutination Inhibition Assays with antisera to nine known APMV serotypes (APMV1-9) indicated no relation to any of them. Next generation sequencing of whole genome sequences indicated the three isolates were genetically identical, and had a nucleotide structure typical for all APMVs, consisting of six genes 3'-NP-P-M-F-HN-L-5'. Phylogenetic analyses, and assessment of amino acid identities, suggested the most closely related lineages to be APMV-2, 8, 10 and 15, but the novel isolate had less than 64% identity to them and all other known avian paramyxoviruses. This value was above levels considered to generally define other APMV serotypes. Estimates of the evolutionary divergence of the nucleotide sequences of the genomes of APMVs have shown that novel Kazakhstan APMV strain was closest to APMV-2, APMV-8, APMV-10 and APMV-15, with calculated distance values of 2.057, 2.058, 2.026 and 2.286 respectively, which is above values considered to differentiate other serotypes (observed minimum was 1.108 between APMV-1 and recently isolated APMV/UPO216/Korea). Together, the data suggest that isolate APMV/gull/Kazakhstan/5976/2014 and other two should be considered as the first representative of a novel APMV-20 group, and is the first time that avian paramyxoviruses have been found infecting members of the gull family, extending the known taxonomic host range

Cardiovascular Risk Factors and Knowledge of Symptoms Among Vietnamese Americans

BACKGROUND: There are few population-based studies of cardiovascular risk factors, knowledge, and related behaviors among Vietnamese Americans. OBJECTIVE: To describe cardiovascular risk factors, knowledge, and related behaviors among Vietnamese Americans and compare the results to non-Hispanic whites. DESIGN: Comparison of data from two populationbased, cross-sectional telephone surveys