Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is ...presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes.
In vitro
dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of
in vitro
dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables,
in vivo
relevance of
in vitro
dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.
Anemia and thyroid dysfunction often co-occur, and both increase with age. Human data on relationships between thyroid disease and anemia are scarce.
To investigate the cross-sectional and ...longitudinal associations between clinical thyroid status and anemia.
Individual participant data meta-analysis.
Sixteen cohorts participating in the Thyroid Studies Collaboration (n = 42,162).
Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women).
Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants overt hypothyroidism, pooled OR 1.84 (95% CI 1.35 to 2.50), subclinical hypothyroidism 1.21 (1.02 to 1.43), subclinical hyperthyroidism 1.27 (1.03 to 1.57), and overt hyperthyroidism 1.69 (1.00 to 2.87). Hemoglobin levels were lower in all groups compared with participants with euthyroidism. In the longitudinal analyses (n = 25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 (95% CI 0.86 to 2.20) for overt hypothyroidism, 1.18 (1.00 to 1.38) for subclinical hypothyroidism, 1.15 (0.94 to 1.42) for subclinical hyperthyroidism, and 1.47 (0.91 to 2.38) for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups.
Higher odds of having anemia were observed in participants with both hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.
Measurement of the intracluster light at z∼1 Burke, Claire; Collins, Chris A.; Stott, John P. ...
Monthly notices of the Royal Astronomical Society,
21 September 2012, 2012-09-21, Letnik:
425, Številka:
3
Journal Article
Recenzirano
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ABSTRACT
A significant fraction of the total photospheric light in nearby galaxy clusters is thought to be contained within the diffuse intracluster light (ICL), which extends hundreds of kpc from ...cluster cores. The study of the ICL can reveal details of the evolutionary histories and processes occurring within galaxy clusters; however, since it has a very low surface brightness, it is often difficult to detect. We present here the first measurements of the ICL as a fraction of the total cluster light at z ∼ 1 using deep J‐band (1.2 μm) imaging from a high‐acuity wide‐field K‐band imager on the Very Large Telescope. We investigate the ICL in six X‐ray selected galaxy clusters at 0.8 ≤ z ≤ 1.2 and find that the ICL below isophotes μJ = 22 mag arcsec−2 constitutes 1–4 per cent of the total cluster light within a radius R500. This is broadly consistent with simulations of the ICL at a similar redshift and when compared to nearby observations suggests that the fraction of the total cluster light that is in the ICL has increased by a factor of 2–4 since z ∼ 1. We also find the fraction of the total cluster light contained within the brightest cluster galaxy (BCG) to be 2.0–6.3 per cent at these redshifts, which in five out of six cases is larger than the fraction of the ICL component, in contrast to the results from nearby clusters. This suggests that the evolution in cluster cores involves substantial stripping activity at late times, in addition to the early build‐up of the BCG stellar mass through merging. The presence of significant amount of stellar light at large radii from these BCGs may help towards solving the recent disagreement between the semi‐analytic model predictions of BCG mass growth and the observed large masses and scale sizes reported for BCGs at high redshift.
This paper presents both the result of a search for fossil systems (FSs) within the XMM Cluster Survey and the Sloan Digital Sky Survey and the results of a study of the stellar mass assembly and ...stellar populations of their fossil galaxies. In total, 17 groups and clusters are identified at z < 0.25 with large magnitude gaps between the first and fourth brightest galaxies. All the information necessary to classify these systems as fossils is provided. For both groups and clusters, the total and fractional luminosity of the brightest galaxy is positively correlated with the magnitude gap. The brightest galaxies in FSs (called fossil galaxies) have stellar populations and star formation histories which are similar to normal brightest cluster galaxies (BCGs). However, at fixed group/cluster mass, the stellar masses of the fossil galaxies are larger compared to normal BCGs, a fact that holds true over a wide range of group/cluster masses. Moreover, the fossil galaxies are found to contain a significant fraction of the total optical luminosity of the group/cluster within 0.5 R sub(200), as much as 85%, compared to the non-fossils, which can have as little as 10%. Our results suggest that FSs formed early and in the highest density regions of the universe and that fossil galaxies represent the end products of galaxy mergers in groups and clusters.
Abstract
Background
Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This ...study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.
Methods
Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.
Results
A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) −4.07 (−6.37 to −1.78) and −2.40 (−3.78 to −1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50–4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.
Conclusions
Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.
Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid ...hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
We measure the evolution of the velocity dispersion–temperature (σv–T
X) relation up to z = 1 using a sample of 38 galaxy clusters drawn from the XMM Cluster Survey. This work improves upon previous ...studies by the use of a homogeneous cluster sample and in terms of the number of high-redshift clusters included. We present here new redshift and velocity dispersion measurements for 12 z > 0.5 clusters observed with the Gemini Multi Object Spectographs instruments on the Gemini telescopes. Using an orthogonal regression method, we find that the slope of the relation is steeper than that expected if clusters were self-similar, and that the evolution of the normalization is slightly negative, but not significantly different from zero (σv ∝ T
0.86±0.14
E(z)−0.37±0.33). We verify our results by applying our methods to cosmological hydrodynamical simulations. The lack of evolution seen in our data is consistent with simulations that include both feedback and radiative cooling.
We study the ratio of luminous to faint red-sequence galaxies in both optically and X-ray selected galaxy clusters in the poorly studied redshift range 0.05 ≤z < 0.19. The X-ray-selected sample ...consists of 112 clusters based on the ROSAT All-Sky Survey, while the optical sample consists of 266 clusters from the Sloan Digital Sky Survey. Our results are consistent with the presence of a trend in luminous-to-faint ratio with redshift, confirming that downsizing is continuous from high to low redshift. After correcting for the variations with redshift using a partial Spearman analysis, we find no significant relationship between luminous-to-faint ratio and X-ray luminosity of the host cluster sample, in contrast to recent suggestions. Finally, we investigate the stacked colour–magnitude relations of these samples, finding no significant differences between the slopes for optically and X-ray selected clusters. The colour–magnitude slopes are consistent with the values obtained in similar studies, but not with predictions of theoretical models.
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