Population pharmacokinetics of ganciclovir after intravenous ganciclovir and oral valganciclovir administration in solid organ transplant patients infected with cytomegalovirus

A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CL(CR)) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49.(CL(CR)/57) liter/h (57 was the mean population value of CL(CR)); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h(-1); bioavailability was 0.825; and lag time was 0.382 h. The CL(CR) was the best predictor of CL, making dose adjustment by this covariate important to achieve the most efficacious ganciclovir exposure

Cellular Immunity to Predict the Risk of Cytomegalovirus Infection in Kidney Transplantation: A Prospective, Interventional, Multicenter Clinical Trial

Background: Improving cytomegalovirus (CMV) immune-risk stratification in kidney transplantation is highly needed to establish guided preventive strategies. Methods: This prospective, interventional, multicenter clinical trial assessed the value of monitoring pretransplant CMV-specific cell-mediated immunity (CMI) using an interferon-γrelease assay to predict CMV infection in kidney transplantation. One hundred sixty donor/recipient CMV-seropositive (D+/R+) patients, stratified by their baseline CMV (immediate-early protein 1)-specific CMI risk, were randomized to receive either preemptive or 3-month antiviral prophylaxis. Also, 15-day posttransplant CMI risk stratification and CMI specific to the 65 kDa phosphoprotein (pp65) CMV antigen were investigated. Immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids in 80% of patients, whereas 20% received thymoglobulin induction therapy. Results: Patients at high risk for CMV based on pretransplant CMI developed significantly higher CMV infection rates than those deemed to be at low risk with both preemptive (73.3% vs 44.4%; odds ratio [OR], 3.44 [95% confidence interval {CI}, 1.30-9.08]) and prophylaxis (33.3% vs 4.1%; OR, 11.75 [95% CI, 2.31-59.71]) approaches. The predictive capacity for CMV-specific CMI was only found in basiliximab-treated patients for both preemptive and prophylaxis therapy. Fifteen-day CMI risk stratification better predicted CMV infection (81.3% vs 9.1%; OR, 43.33 [95% CI, 7.89-237.96]). Conclusions: Pretransplant CMV-specific CMI identifies D+/R+ kidney recipients at high risk of developing CMV infection if not receiving T-cell-depleting antibodies. Monitoring CMV-specific CMI soon after transplantation further defines the CMV infection prediction risk. Monitoring CMV-specific CMI may guide decision making regarding the type of CMV preventive strategy in kidney transplantation. Clinical Trials Registration: NCT02550639

Steppes, savannahs, forests and phytodiversity reservoirs during the Pleistocene in the Iberian Peninsula

A palaeobotanical analysis of the Pleistocene floras and vegetation in the Iberian Peninsula shows the existence of patched landscapes with Pinus woodlands, deciduous and mixed forests, parklands (savannah-like), shrublands, steppes and grasslands. Extinctions of Arctotertiary woody taxa are recorded during the Early and Middle Pleistocene, but glacial refugia facilitated the survival of a number of temperate, Mediterranean and Ibero-North African woody angiosperms. The responses of Iberian vegetation to climatic changes during the Pleistocene have been spatially and temporarily complex, including rapid changes of vegetation in parallel to orbital and suborbital variability, and situations of multi-centennial resilience or accommodation to climatic changes. Regional characteristics emerged as soon as for the Middle Pleistocene, if not earlier: Ericaceae in the Atlantic coast indicating wetter climate, thermo-mediterranean elements in the south as currently, and broad-leaf trees in the northeastern. Overall, steppe landscapes and open Pinus woodlands prevailed over many continental regions during the cold spells of the Late Pleistocene. The maintenance of a high phytodiversity during the glacials was linked to several refuge zones in the coastal shelves of the Mediterranean and intramountainous valleys. Northern Iberia, especially on coastal areas, was also patched with populations of tree species, and this is not only documented by palaeobotanical data (pollen, charcoal) but also postulated by phylogeographical models

Mountain strongholds for woody angiosperms during the Late Pleistocene in SE Iberia

Mediterranean mountains played an essential role during glacial periods as vegetation refugia. The SE Iberia Late Pleistocene woody angiosperm fossil and floristic evidences are reviewed in the context of phylogeographical studies aiming to identify (i) spatial patterns related to woody angiosperms glacial survival, (ii) structural and functional characteristics of montane refugia, and (iii) gaps in knowledge on the woody angiosperm patterns of survival in Mediterranean mountains. The distribution of palaeobotanical data for SE Iberia refugia has been found to be taphonomically biased due to the scarcity of available and/or studied high-altitude Late Pleistocene sites. However, Siles Lake data together with floristic inference provide evidences for woody angiosperms’ survival in a high-altitude Mediterranean area. The main features boosting survival at montane contexts are physiographic complexity and water availability. Phylogeography studies have mainly been conducted at a continental scale. Although they cohere with palaeobotanical data to a broad scale, a general lack of sampling of SE Iberian range-edge populations, as well as misconceptions about the origin of the populations sampled, impede to infer the proper location of woody angiosperms’ mountain refugia and their importance in the post-glacial European colonisation. We conclude that floristic, geobotanical, palaeobotanical, ethnographical and genetic evidence should be merged to gain a deeper understanding on the role played by Mediterranean mountains as glacial refugia in order to explain the current distribution of many plants and the large biodiversity levels encountered in Mediterranean mountain areas. This is hallmark for effective and efficient conservation and management

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Are long gamma-ray bursts biased tracers of star formation? Clues from the host galaxies of the Swift/BAT6 complete sample of bright LGRBs: II. Star formation rates and metallicities at z &lt; 1

Aims. Long gamma-ray bursts (LGRBs) are associated with the deaths of massive stars and might therefore be a potentially powerful tool for tracing cosmic star formation. However, especially at low redshifts (z < 1.5) LGRBs seem to prefer particular types of environment. Our aim is to study the host galaxies of a complete sample of bright LGRBs to investigate the effect of the environment on GRB formation. Methods. We studied host galaxy spectra of the Swift/BAT6 complete sample of 14 z < 1 bright LGRBs. We used the detected nebular emission lines to measure the dust extinction, star formation rate (SFR), and nebular metallicity (Z) of the hosts and supplemented the data set with previously measured stellar masses M∗. The distributions of the obtained properties and their interrelations (e.g. mass-metallicity and SFR-M∗ relations) are compared to samples of field star-forming galaxies. Results. We find that LGRB hosts at z < 1 have on average lower SFRs than if they were direct star formation tracers. By directly comparing metallicity distributions of LGRB hosts and star-forming galaxies, we find a good match between the two populations up to 12 + log (O/H) ∼ 8.4-8.5, after which the paucity of metal-rich LGRB hosts becomes apparent. The LGRB host galaxies of our complete sample are consistent with the mass-metallicity relation at similar mean redshift and stellar masses. The cutoff against high metallicities (and high masses) can explain the low SFR values of LGRB hosts. We find a hint of an increased incidence of starburst galaxies in the Swift/BAT6 z < 1 sample with respect to that of a field star-forming population. Given that the SFRs are low on average, the latter is ascribed to low stellar masses. Nevertheless, the limits on the completeness and metallicity availability of current surveys, coupled with the limited number of LGRB host galaxies, prevents us from investigating more quantitatively whether the starburst incidence is such as expected after taking into account the high-metallicity aversion of LGRB host galaxies. © 2016 ESO

GRB hosts through cosmic time: VLT/X-Shooter emission-line spectroscopy of 96 γ -ray-burst-selected galaxies at 0.1 &lt; z &lt; 3.6

We present data and initial results from VLT/X-Shooter emission-line spectroscopy of 96 galaxies selected by long γ-ray bursts (GRBs) at 0.1 V), oxygen abundances (12 + log (O/H)), and emission-line widths (σ). We study GRB hosts up to z ∼ 3.5 and find a strong change in their typical physical properties with redshift. The median SFR of our GRB hosts increases from SFRmed ∼ 0.6 M yr-1 at z ∼ 0.6 up to SFRmed ∼ 15 M yr-1 at z ∼ 2. A higher ratio of [O iii]/[O ii] at higher redshifts leads to an increasing distance of GRB-selected galaxies to the locus of local galaxies in the Baldwin-Phillips-Terlevich diagram. There is weak evidence for a redshift evolution in AV and σ, with the highest values seen at z ∼ 1.5 (AV) or z ∼ 2 (σ). Oxygen abundances of the galaxies are distributed between 12 + log (O/H) = 7.9 and 12 + log (O/H) = 9.0 with a median 12 + log (O/H)med ∼ 8.5. The fraction of GRB-selected galaxies with super-solar metallicities is ∼20% at zV (12 + log (O/H) 0.17·AV), line width (12 + log (O/H) σ0.6), and SFR (12 + log (O/H) SFR0.2). In the last two cases, the normalization of the relations shift to lower metallicities at z> 2 by ∼0.4 dex. These properties of GRB hosts and their evolution with redshift can be understood in a cosmological context of star-forming galaxies and a picture in which the hosts' properties at low redshift are influenced by the tendency of GRBs to avoid the most metal-rich environments. © ESO, 2015

Pluto's lower atmosphere and pressure evolution from ground-based stellar occultations, 1988-2016

Context. The tenuous nitrogen (N2) atmosphere on Pluto undergoes strong seasonal effects due to high obliquity and orbital eccentricity, and has recently (July 2015) been observed by the New Horizons spacecraft. Aims. The main goals of this study are (i) to construct a well calibrated record of the seasonal evolution of surface pressure on Pluto and (ii) to constrain the structure of the lower atmosphere using a central flash observed in 2015. Methods. Eleven stellar occultations by Pluto observed between 2002 and 2016 are used to retrieve atmospheric profiles (density, pressure, temperature) between altitude levels of ~5 and ~380 km (i.e. pressures from ~ 10 μbar to 10 nbar). Results. (i) Pressure has suffered a monotonic increase from 1988 to 2016, that is compared to a seasonal volatile transport model, from which tight constraints on a combination of albedo and emissivity of N2 ice are derived. (ii) A central flash observed on 2015 June 29 is consistent with New Horizons REX profiles, provided that (a) large diurnal temperature variations (not expected by current models) occur over Sputnik Planitia; and/or (b) hazes with tangential optical depth of ~0.3 are present at 4–7 km altitude levels; and/or (c) the nominal REX density values are overestimated by an implausibly large factor of ~20%; and/or (d) higher terrains block part of the flash in the Charon facing hemisphere