Cytomegalovirus Serology and Replication Remain Associated With Solid Organ Graft Rejection and Graft Loss in the Era of Prophylactic Treatment

BACKGROUND Cytomegalovirus (CMV) replication has been associated with more risk for solid organ graft rejection. We wondered whether this association still holds when patients at risk receive prophylactic treatment for CMV. METHODS We correlated CMV infection, biopsy-proven graft rejection, and graft loss in 1,414 patients receiving heart (n=97), kidney (n=917), liver (n=237), or lung (n=163) allografts reported to the Swiss Transplant Cohort Study. RESULTS Recipients of all organs were at an increased risk for biopsy-proven graft rejection within 4 weeks after detection of CMV replication (hazard ratio [HR] after heart transplantation, 2.60; 95% confidence interval [CI], 1.34-4.94, P<0.001; HR after kidney transplantation, 1.58; 95% CI, 1.16-2.16, P=0.02; HR after liver transplantation, 2.21; 95% CI, 1.53-3.17, P<0.001; HR after lung transplantation, 5.83; 95% CI, 3.12-10.9, P<0.001. Relative hazards were comparable in patients with asymptomatic or symptomatic CMV infection. The CMV donor or recipient serological constellation also predicted the incidence of graft rejection after liver and lung transplantation, with significantly higher rates of rejection in transplants in which donor or recipient were CMV seropositive (non-D-/R-), compared with D- transplant or R- transplant (HR, 3.05; P=0.002 for liver and HR, 2.42; P=0.01 for lung transplants). Finally, graft loss occurred more frequently in non-D- or non-R- compared with D- transplant or R- transplant in all organs analyzed. Valganciclovir prophylactic treatment seemed to delay, but not prevent, graft loss in non-D- or non-R- transplants. CONCLUSION Cytomegalovirus replication and donor or recipient seroconstellation remains associated with graft rejection and graft loss in the era of prophylactic CMV treatment.

Decoding Delay Minimization in Inter-Session Network Coding

Intra-session network coding has been shown to offer significant gains in terms of achievable throughput and delay in settings where one source multicasts data to several clients. In this paper, we consider a more general scenario where multiple sources transmit data to sets of clients over a wireline overlay network. We propose a novel framework for efficient rate allocation in networks where intermediate network nodes have the opportunity to combine packets from different sources using randomized network coding. We formulate the problem as the minimization of the average decoding delay in the client population and solve it with a gradient-based stochastic algorithm. Our optimized inter-session network coding solution is evaluated in different network topologies and is compared with basic intra-session network coding solutions. Our results show the benefits of proper coding decisions and effective rate allocation for lowering the decoding delay when the network is used by concurrent multicast sessions.

Why Some People Discount More than Others: Baseline Activation in the Dorsal PFC Mediates the Link between COMT Genotype and Impatient Choice

Individuals differ widely in how steeply they discount future rewards. The sources of these stable individual differences in delay discounting (DD) are largely unknown. One candidate is the COMT Val158Met polymorphism, known to modulate prefrontal dopamine levels and affect DD. To identify possible neural mechanisms by which this polymorphism may contribute to stable individual DD differences, we measured 73 participants' neural baseline activation using resting electroencephalogram (EEG). Such neural baseline activation measures are highly heritable and stable over time, thus an ideal endophenotype candidate to explain how genes may influence behavior via individual differences in neural function. After EEG-recording, participants made a series of incentive-compatible intertemporal choices to determine the steepness of their DD. We found that COMT significantly affected DD and that this effect was mediated by baseline activation level in the left dorsal prefrontal cortex (DPFC): (i) COMT had a significant effect on DD such that the number of Val alleles was positively correlated with steeper DD (higher numbers of Val alleles means greater COMT activity and thus lower dopamine levels). (ii) A whole-brain search identified a cluster in left DPFC where baseline activation was correlated with DD; lower activation was associated with steeper DD. (iii) COMT had a significant effect on the baseline activation level in this left DPFC cluster such that a higher number of Val alleles was associated with lower baseline activation. (iv) The effect of COMT on DD was explained by the mediating effect of neural baseline activation in the left DPFC cluster. Our study thus establishes baseline activation level in left DPFC as salient neural signature in the form of an endophenotype that mediates the link between COMT and DD.

Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort

BACKGROUND AND AIMS Limited data from large cohorts are available on tumor necrosis factor (TNF) antagonists (infliximab, adalimumab, certolizumab pegol) switch over time. We aimed to evaluate the prevalence of switching from one TNF antagonist to another and to identify associated risk factors. METHODS Data from the Swiss Inflammatory Bowel Diseases Cohort Study (SIBDCS) were analyzed. RESULTS Of 1731 patients included into the SIBDCS (956 with Crohn's disease [CD] and 775 with ulcerative colitis [UC]), 347 CD patients (36.3%) and 129 UC patients (16.6%) were treated with at least one TNF antagonist. A total of 53/347 (15.3%) CD patients (median disease duration 9 years) and 20/129 (15.5%) of UC patients (median disease duration 7 years) needed to switch to a second and/or a third TNF antagonist, respectively. Median treatment duration was longest for the first TNF antagonist used (CD 25 months; UC 14 months), followed by the second (CD 13 months; UC 4 months) and third TNF antagonist (CD 11 months; UC 15 months). Primary nonresponse, loss of response and side effects were the major reasons to stop and/or switch TNF antagonist therapy. A low body mass index, a short diagnostic delay and extraintestinal manifestations at inclusion were identified as risk factors for a switch of the first used TNF antagonist within 24 months of its use in CD patients. CONCLUSION Switching of the TNF antagonist over time is a common issue. The median treatment duration with a specific TNF antagonist is diminishing with an increasing number of TNF antagonists being used.

Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity.

We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30-6.09, p = 2 × 10(-5)) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.1129-5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p = 5 × 10(-6)), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129-5923C>G/hapB3 variant is a major contributor to severe early-onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.1679T>G and c.2846A>T). Pre-therapeutic DPYD testing may prevent 20-30% of life-threatening or lethal episodes of FP toxicity in Caucasian patients.

Terrestrial Radar Interferometric Measurement of Hillslope Deformation and Atmospheric Disturbances in the Illgraben Debris-Flow Catchment, Switzerland

We describe a method for rapid identification and precise quantification of slope deformation using a portable radar interferometer. A rockslide with creep-like behavior was identified in the rugged and inaccessible headwaters of the Illgraben debris-flow catchment, located in the Central Swiss Alps. The estimated volume of the moving rock mass was approximately 0.5 x 10(6) m(3) with a maximum daily (3-D) displacement rate of 3 mm. Fast scene acquisition in the order of 6 s/scene led to uniquely precise mapping of spatial and temporal variability of atmospheric phase delay. Observations led to a simple qualitative model for prediction of atmospheric disturbances using a simple model for solar radiation, which can be used for advanced campaign planning for short observation periods (hours to days).

Total Thyroidectomy for Amiodarone-induced Thyrotoxicosis in the Hyperthyroid State.

Amiodarone is a potent antiarrhythmic agent, indicated for the treatment of refractory arrhythmias, which may lead to thyrotoxicosis. In these patients, thyroidectomy is a valid therapeutic option. Antithyroid therapy in the immediate preoperative setting and the subsequently accepted minimal delay until thyroidectomy have not been clearly defined yet. The aim of the present study was to show, that total thyroidectomy under general anaesthesia in patients with amiodarone-induced thyrotoxicosis (AIT) is safe without necessarily obtaining an euthyroid state preoperatively.We conducted a retrospective cohort study of prospectively gathered data on 11 patients undergoing total thyroidectomy under general anaesthesia between January 2008 and December 2013 for AIT at our University Hospital.All patients were preoperatively treated with carbimazole, steroids and β-receptor antagonists. Additionally, 3 patients received potassium perchlorate and in one patient carbimazole was changed to propylthiouracil. Plasmapheresis was performed in 3 patients. Only one patient was euthyroid at the time of operation. There were no significant intra- and postoperative complications, especially no signs of thyroid storm. One patient could postoperatively be removed from the cardiac transplant waiting list due to improved cardiac function.Improvements in the interdisciplinary surgical management for AIT between cardiologists, endocrinologists, anaesthetists and endocrine surgeons provide the basis of safe total thyroidectomy under general anaesthesia in hyperthyroid state. Early surgery without long delay for medical antithyroid treatment (with its potential negative side effects) is recommended.

Characterization and age determination of Quaternary volcanism in the southern Ankaratra region (central Madagascar) through novel approaches in luminescence dating

This work introduces two novel approaches for the application of luminescence dating techniques to Quaternary volcanic eruptions: crystalline xenoliths from lava flows are demonstrated to be basically suitable for luminescence dating, and a set of phreatic explosion deposits from the Late Quaternary Vakinankaratra volcanic field in central Madagascar is successfully dated with infrared stimulated luminescence (IRSL). Using a numerical model approach and experimental verification, the potential for thermal resetting of luminescence signals of xenoliths in lava flows is demonstrated. As microdosimetry is an important aspect when using sample material extracted from crystalline whole rocks, autoradiography using image plates is introduced to the field of luminescence dating as a method for detection and assessment of spatially resolved radiation inhomogeneities. Determinations of fading rates of feldspar samples have been observed to result in aberrant g-values if the pause between preheat and measurement in the delayed measurements was kept short. A systematic investigation reveals that the phenomenon is caused by the presence of three signal components with differing individual fading behaviour. As this is restricted to short pauses, it is possible to determine a minimal required delay between preheating and measurement after which the aberrant behaviour disappears. This is applied in the measuring of 12 samples from phreatic explosion deposits from the Antsirabe – Betafo region in the Late Quaternary Vakinankaratra volcanic field. The samples were taken from stratigraphically correlatable sections and appear to represent at least three phreatic events, one of which created the Lac Andraikiba maar near Antsirabe. The obtained ages indicate that the eruptive activity in the region started in the Late Pleistocene between 113.9 and 99.6 ka. A second layer in the Betafo area is dated at approximately 73 ka and the Lac Andraikiba deposits give an age between 63.9 and 50.7 ka. The youngest phreatic layer is dated between 33.7 and 20.7 ka. These ages are the first recorded direct ages of such volcanic deposits, as well as the first and only direct ages for the Late Quaternary volcanism in the Vakinankaratra volcanic field. This illustrates the huge potential of this new method for volcanology and geochronology, as it enables direct numerical dating of a type of volcanic deposit which has not been successfully directly dated by any other method so far.