The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation

Purpose: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients. Methods: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition. Results: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p

Biliary atresia

Biliary atresia (BA) is a rare disease characterised by a biliary obstruction of unknown origin that presents in the neonatal period. It is the most frequent surgical cause of cholestatic jaundice in this age group. BA occurs in approximately 1/18,000 live births in Western Europe. In the world, the reported incidence varies from 5/100,000 to 32/100,000 live births, and is highest in Asia and the Pacific region. Females are affected slightly more often than males. The common histopathological picture is one of inflammatory damage to the intra- and extrahepatic bile ducts with sclerosis and narrowing or even obliteration of the biliary tree. Untreated, this condition leads to cirrhosis and death within the first years of life. BA is not known to be a hereditary condition. No primary medical treatment is relevant for the management of BA. Once BA suspected, surgical intervention (Kasai portoenterostomy) should be performed as soon as possible as operations performed early in life is more likely to be successful. Liver transplantation may be needed later if the Kasai operation fails to restore the biliary flow or if cirrhotic complications occur. At present, approximately 90% of BA patients survive and the majority have normal quality of life

The role of complex cues in social and reproductive plasticity

Phenotypic plasticity can be a key determinant of fitness. The degree to which the expression of plasticity is adaptive relies upon the accuracy with which information about the state of the environment is integrated. This step might be particularly beneficial when environments, e.g. the social and sexual context, change rapidly. Fluctuating temporal dynamics could increase the difficulty of determining the appropriate level of expression of a plastic response. In this review, we suggest that new insights into plastic responses to the social and sexual environment (social and reproductive plasticity) may be gained by examining the role of complex cues (those comprising multiple, distinct sensory components). Such cues can enable individuals to more accurately monitor their environment in order to respond adaptively to it across the whole life course. We briefly review the hypotheses for the evolution of complex cues and then adapt these ideas to the context of social and sexual plasticity. We propose that the ability to perceive complex cues can facilitate plasticity, increase the associated fitness benefits and decrease the risk of costly ‘mismatches’ between phenotype and environment by (i) increasing the robustness of information gained from highly variable environments, (ii) fine-tuning responses by using multiple strands of information and (iii) reducing time lags in adaptive responses. We conclude by outlining areas for future research that will help to determine the interplay between complex cues and plasticity

Velocity-imaging the rapidly precessing planetary disc around the white dwarf HE1349-2305 using Doppler tomography

The presence of planetary material in white dwarf atmospheres, thought to be accreted from a dusty debris disc produced via the tidal disruption of a planetesimal, is common. Approximately 5 per cent of these discs host a co-orbital gaseous component detectable via emission from atomic transitions  –  usually the 8600 Å Ca II triplet. These emission profiles can be highly variable in both morphology and strength. Furthermore, the morphological variations in a few systems have been shown to be periodic, likely produced by an apsidally precessing asymmetric disc. Of the known gaseous debris discs, that around HE 1349–2305 has the most rapidly evolving emission-line morphology, and we present updated spectroscopy of the Ca II triplet of this system. The additional observations show that the emission-line morphologies vary periodically and consistently, and we constrain the period to two aliases of 459 ± 3 and 502 ± 3 d. We produce images of the Ca II triplet emission from the disc in velocity space using Doppler tomography  –  only the second such imaging of a white dwarf debris disc. We suggest that the asymmetric nature of these velocity images is generated by gas moving on eccentric orbits with radially dependent excitation conditions via photoionization from the white dwarf. We also obtained short-cadence (≃4 min) spectroscopy to search for variability on the time-scale of the disc’s orbital period (≃hours) due to the presence of a planetesimal, and rule out variability at a level of ≃1.4 per cent

Public v. Private Enforcement in the Electronic Communications Sector

The 2002 Common Regulatory Framework diversifies remedies to competition problems according to the market strength of telecoms providers. One set of remedies is particularly targeted at posing constraints on (pre-)existing significant market power (SMP) in the relevant market. Those remedies are provided for in the Access and Interconnection Directive and in ascending order of intrusiveness they are transparency obligation, non-discrimination obligation, accounting separation, access obligation and price control. A second set of measures are meant to apply to all telecoms providers irrespective whether they have market power or not. This set of measures is introduced by the Universal Service Directive (USD). This paper provides a comparison between sector-specific and competition law remedies and will examine the regulatory configurations in which either of the two regulatory regimes will give best results (Secion I). Having analysed the likely challenges for SMP remedies, it discusses the potential of number portability (NP) under the USD for enhancement of the state of competition (Section II). Remedies taken under a co-regulatory procedure are presented in Section III. Challenges to private enforcement of the competition rules in the telecoms sector are put forward and respective solutions to possible impediments to it are suggested in Section IV. Section V attempts to outline the predominant standard against which public and private enforcers will define harm from an antitrust violation