Valganciclovir for Cytomegalovirus Prevention in Solid Organ Transplant Patients: An Evidence-Based Reassessment of Safety and Efficacy

Background

Several anti-viral drugs have demonstrated efficacy in preventing Cytomegalovirus (CMV) infections in solid organ transplant (SOT) patients. The recently approved valganciclovir is the most commonly used and most expensive drug for CMV prevention. The safety and efficacy data have been drawn from a single trial. We hypothesized that valganciclovir may not be as safe as nor more effective than other therapies for CMV prevention.

Methods

All experimental and analytical studies that compared valganciclovir with other therapies for prevention of CMV infection after SOT were selected. Based on meta-analytic and multivariate regression methodologies we critically analyzed all available evidence.

Findings

Nine studies were included (N = 1,831). In trials comparing valganciclovir with ganciclovir, the risk for CMV disease is 0.98 (95% Confidence Interval (95%CI) 0.67 to 1.43; P = 0.92; I² = 0%). Valganciclovir was significantly associated with the risk of absolute neutropenia (<1,500/mm³) compared with all therapies (Odds Ratio (OR) 3.63 95%CI 1.75 to 7.53; P = 0.001; I² = 0%); with ganciclovir only (OR 2.88, 95%CI 1.27 to 6.53; P = 0.01; I² = 0%); or with non-ganciclovir therapies (OR 8.30, 95%CI 1.51 to 45.58; P = 0.01; I² = 10%). For a neutropenia cut-off of <1,000/mm³, the risk remained elevated (OR 1.97, 95%CI 1.03 to 3.67; P = 0.04; I² = 0%). For every 24 patients who receive valganciclovir prophylaxis, one more will develop neutropenia compared to other therapies. The risk of late-onset CMV disease with valganciclovir was similar to ganciclovir and higher than those with non-ganciclovir therapies (OR 8.95, 95%CI 1.07 to 74.83; P = 0.04; I² = 0%]. One more patient will develop late-onset CMV disease for every 25 who receive valganciclovir compared to treatment with non-ganciclovir therapies. The risk of CMV tissue-invasive disease in liver recipients receiving valganciclovir was 4.5 times the risk seen with ganciclovir [95%CI 1.00 to 20.14] (p = 0.04). All results remained consistent across different study designs, valganciclovir doses, and CMV serostatus.

Conclusions

Valganciclovir shows no superior efficacy and significantly higher risk of absolute neutropenia, CMV late-onset disease, and CMV tissue-invasive disease compared to other standard therapies. Due to the availability of efficacious, safer, and lower cost drugs (high-dose acyclovir, valacyclovir, ganciclovir), our results do not favor the use of valganciclovir as a first-line agent for CMV preemptive or universal prophylaxis in SOT patients.     

Primary coronary intervention for ST-elevation myocardial infarction in Indonesia and the Netherlands: a comparison

Background. Although the beneficial effects of primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) have been demonstrated in a number of trials, most studies were conducted in Western countries. Experience, logistics and patient characteristics may differ in other parts of the world. Methods. Consecutive patients treated with primary PCI in Cinere Hospital, Jakarta, Indonesia, between January 2008 and October 2008 were compared with those treated in the Isala Clinics, Zwolle, the Netherlands. Results. During the study period, a total of 596 patients were treated by primary PCI, 568 in Zwolle and 28 in Jakarta. Patients in Indonesia were younger (54 vs 63 years), more often had diabetes (36 vs. 12%) and high lipids and were more often smokers (68 vs. 31%). Time delay between symptom onset and admission was longer in Indonesia. Patients from Indonesia more often had signs of heart failure at admission. The time between admission and balloon inflation was longer in Indonesia. At angiography, patients from Indonesia more often had multivessel disease. There was no difference in the percentage of restoration of TIMI 3 flow by primary PCI between the two hospitals. Conclusion. Patients with STEMI in Indonesia have a higher risk profile compared with those in the Netherlands, according to prevalence of coronary risk factors, signs of heart failure, multivessel disease and patient delay. Time delay between admission and balloon inflation was much longer in Indonesia, because of both logistic and financial reasons. (Neth Heart J 2009;17:418–21.)     

Efficient hydrogen production from the lignocellulosic energy crop Miscanthus by the extreme thermophilic bacteria Caldicellulosiruptor saccharolyticus and Thermotoga neapolitana

Background  

The production of hydrogen from biomass by fermentation is one of the routes that can contribute to a future sustainable hydrogen economy. Lignocellulosic biomass is an attractive feedstock because of its abundance, low production costs and high polysaccharide content.     

Modeled ecohydrological responses to climate change at seven small watersheds in the northeastern United States

A cross‐site analysis was conducted on seven diverse, forested watersheds in the northeastern United States to evaluate hydrological responses (evapotranspiration, soil moisture, seasonal and annual streamflow, and water stress) to projections of future climate. We used output from four atmosphere–ocean general circulation models (AOGCMs; CCSM4, HadGEM2‐CC, MIROC5, and MRI‐CGCM3) included in Phase 5 of the Coupled Model Intercomparison Project, coupled with two Representative Concentration Pathways (RCP 8.5 and 4.5). The coarse resolution AOGCMs outputs were statistically downscaled using an asynchronous regional regression model to provide finer resolution future climate projections as inputs to the deterministic dynamic ecosystem model PnET‐BGC. Simulation results indicated that projected warmer temperatures and longer growing seasons in the northeastern United States are anticipated to increase evapotranspiration across all sites, although invoking CO₂ effects on vegetation (growth enhancement and increases in water use efficiency (WUE)) diminish this response. The model showed enhanced evapotranspiration resulted in drier growing season conditions across all sites and all scenarios in the future. Spruce‐fir conifer forests have a lower optimum temperature for photosynthesis, making them more susceptible to temperature stress than more tolerant hardwood species, potentially giving hardwoods a competitive advantage in the future. However, some hardwood forests are projected to experience seasonal water stress, despite anticipated increases in precipitation, due to the higher temperatures, earlier loss of snow packs, longer growing seasons, and associated water deficits. Considering future CO₂ effects on WUE in the model alleviated water stress across all sites. Modeled streamflow responses were highly variable, with some sites showing significant increases in annual water yield, while others showed decreases. This variability in streamflow responses poses a challenge to water resource management in the northeastern United States. Our analyses suggest that dominant vegetation type and soil type are important attributes in determining future hydrological responses to climate change.     

Relationship between blood velocity and conduit artery diameter and the effects of smoking on vascular responsiveness.

Transient changes in arterial diameter in response to transient ischemia-induced changes in arterial blood velocity have been used as an index of vascular health. The purpose of this study was to determine the relationship between blood velocity and diameter in the brachial artery by different methods of increasing blood velocity. Acute cigarette smoking was used with otherwise healthy young occasional smokers to determine the influence of endothelial-nitric oxide pathways on the arterial diameter-blood velocity relationship. Nine nonsmokers and 12 occasional smokers (<1 pack/wk) were tested. Blood flow to the forearm was manipulated to indirectly investigate the relationship between blood velocity and diameter in the brachial artery. Blood flow to forearm was manipulated through the use of 1) 5-min ischemia; 2) handgrip exercise; 3) indirect local heating; and 4) 5-min ischemia plus indirect local heating. A strong relationship was observed between blood velocity and diameter independent of the method used to increase blood velocity (R(2) = 0.89). The mean slope of the velocity-diameter relationship was not different between nonsmokers and occasional smokers who abstained from smoking at least 2 days. Acute smoking did not alter the slope of the velocity-diameter relationship although the mean intercept was decreased as a result of consistent vasoconstriction (7-10%). The mechanisms by which smoking impairs vascular health are largely unknown. These findings differ from previous smoking studies that used chronic and/or heavier smokers. The velocity-diameter relationship appears independent of the method for increasing velocity. Acute smoking in occasional smokers results in vasoconstriction without altering vascular responsiveness. The velocity-diameter relationship may be a useful measure of the progression of vascular disease.     

A morphological and genetic analysis of the European bitterling species complex

Bitterling fishes lay their eggs on the gills of living freshwater mussels and are valuable models in behavioural and evolutionary ecology. We used morphological and genetic data to resolve the taxonomic relationships of bitterling in Europe. Previous studies have suggested the European bitterling is either a single species with a wide but discontinuous geographic distribution, or a complex of species. Morphometric and meristic data identified differences between three putative species; with a clear distinction between the eastern Asian Rhodeus sericeus, western European bitterling Rhodeus amarus, and colchian bitterling, Rhodeus colchicus. Polymorphism in the mitochondrial DNA control region was predominantly due to insertion/deletion events, making phylogenetic inference difficult, but the single haplotype found in R. sericeus populations was detected at low frequency (one of 24 individuals) in R. amarus and R. colchicus populations. Eight control region haplotypes were found in R. amarus populations, which were distinct from the two haplotypes in a R. colchicus population. Cytochrome b data produced a phylogeny with strongly‐supported differentiation between a clade of two R. sericeus haplotypes and a clade of six R. amarus/colchicus haplotypes. The star‐like topology of the R. amarus/colchicus haplotypes in a minimum spanning network suggested a rapid radiation in this clade. Our results are consistent with an hypothesis of relatively ancient divergence of R. sericeus from R. amarus/colchicus and more recent and rapid differentiation between R. amarus and R. colchicus. © 2008 The Linnean Society of London, Biological Journal of the Linnean Society, 2008, 95 , 337–347.     

Analyses of Nuclear ldhA Gene and mtDNA Control Region Sequences of Atlantic Northern Bluefin Tuna Populations

There has been considerable debate about whether the Atlantic northern bluefin tuna exist as a single panmictic unit. We have addressed this issue by examining both mitochondrial DNA control region nucleotide sequences and nuclear gene ldhA allele frequencies in replicate size or year class samples of northern bluefin tuna from the Mediterranean Sea and the northwestern Atlantic Ocean. Pairwise comparisons of multiple year class samples from the 2 regions provided no evidence for population subdivision. Similarly, analyses of molecular variance of both mitochondrial and ldhA data revealed no significant differences among or between samples from the 2 regions. These results demonstrate the importance of analyzing multiple year classes and large sample sizes to obtain accurate estimates when using allele frequencies to characterize a population. It is important to note that the absence of genetic evidence for population substructure does not unilaterally constitute evidence of a single panmictic population, as genetic differentiation can be prevented by large population sizes and by migration.     

Apical Nonspecific Cation Channels in Everted Collecting Tubules of Potassium-Adapted Ambystoma

We observed intermediate conductance channels in approximately 20% of successful patch-clamp seals made on collecting tubules dissected from Ambystoma adapted to 50 mm potassium. These channels were rarely observed in collecting tubules taken from animals which were maintained in tap water. Potassium-adaptation either leads to an increase in the number of channels present or activates quiescent channels. In cell-attached patches the conductance averaged 30.3 ± 2.4 (9) pS. Since replacement of the chloride in the patch pipette with gluconate did not change the conductance, the channel carries cations, not anions. Notably, channel activity was observed at both positive and negative pipette voltages. When the pipette was voltage clamped at 0 mV or positive voltages, the current was directed inward, consistent with the movement of sodium into the cell. The pipette voltage at which the polarity of the current reversed (movement of potassium into the pipette) was −29.6 ± 6.5(9) mV. Open probability at 0 mV pipette voltage was 0.08 ± 0.03 and was unaffected when the apical membrane was exposed to either 2 × 10⁻⁶ or 2 × 10⁻⁵ m of amiloride. Exposure of the basolateral surface of the tubule to a saline containing 15 mm potassium caused a significant increase (P less than 0.001) in the open probability of these channels to 0.139 ± 0.002 without affecting the conductance of the apical channel. These data illustrate the presence of an intermediate conductance, poorly selective, amiloride-insensitive cation channel in native vertebrate collecting tubule. We postulate that, at least in amphibia, this channel may be used to secrete potassium. Received: 14 January 2000/Revised: 16 June 2000