Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues

Evaluation of multi element antennas in reverberation chamber

This paper focuses on the latest advances in the use of reverberation chambers for active device testing. Contained are description and comparison of different figure-of-merits that are applicable to multi element antennas, with a specific focus on LTE devices with MIMO capability. There are two new parameter concepts introduced: Modified Total Isotropic Sensitivity measurements to include MIMO signaling, and a Throughput Threshold Level for simplified quantification of data bit throughput measurement results

Changes in clinical indicators related to the transition from dialysis to kidney transplantation-data from the ERA-EDTA Registry

Background. Kidney transplantation should improve abnormalities that are common during dialysis treatment, like anaemia and mineral and bone disorder. However, its impact is incompletely understood. We therefore aimed to assess changes in clinical indicators after the transition from chronic dialysis to kidney transplantation. Methods. We used European Renal Association-European Dialysis and Transplant Association Registry data and included adult dialysis patients for whom data on clinical indicators before and after transplantation (2005-15) were available. Linear mixed models were used to quantify the effect of transplantation and of time after transplantation for each indicator. Results. In total, 16 312 patients were included. The mean age at transplantation was 50.1 (standard deviation 14.2) years, 62.9% were male and 70.2% were on haemodialysis before transplantation. Total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglycerides increased right after transplantation but decreased thereafter. All other indicators normalized or approached the target range soon after transplantation and these improvements were sustained for the first 4 years of follow-up. In patients with higher estimated glomerular filtration rate (eGFR) levels (30-60 and >60 mL/min/1.73 m(2)), the improvement of haemoglobin, ferritin, ionized calcium, phosphate, parathyroid hormone, HDL cholesterol, triglycerides, albumin and C-reactive protein levels was more pronounced than in patients with a lower eGFR ( Conclusions. Except for total cholesterol, LDL cholesterol and triglycerides, all clinical indicators improved after transplantation. These improvements were related to eGFR. Nevertheless, values remained out of range in a considerable proportion of patients and anaemia and hyperparathyroidism were still common problems. Further research is needed to understand the complex relationship between eGFR and the different clinical indicators.Peer reviewe

Demonstrating Benefit-Risk Profiles of Novel Therapeutic Strategies in Kidney Transplantation : Opportunities and Challenges of Real-World Evidence

While great progress has been made in transplantation medicine, long-term graft failure and serious side effects still pose a challenge in kidney transplantation. Effective and safe long-term treatments are needed. Therefore, evidence of the lasting benefit-risk of novel therapies is required. Demonstrating superiority of novel therapies is unlikely via conventional randomized controlled trials, as long-term follow-up in large sample sizes pose statistical and operational challenges. Furthermore, endpoints generally accepted in short-term clinical trials need to be translated to real-world (RW) care settings, enabling robust assessments of novel treatments. Hence, there is an evidence gap that calls for innovative clinical trial designs, with RW evidence (RWE) providing an opportunity to facilitate longitudinal transplant research with timely translation to clinical practice. Nonetheless, the current RWE landscape shows considerable heterogeneity, with few registries capturing detailed data to support the establishment of new endpoints. The main recommendations by leading scientists in the field are increased collaboration between registries for data harmonization and leveraging the development of technology innovations for data sharing under high privacy standards. This will aid the development of clinically meaningful endpoints and data models, enabling future long-term research and ultimately establish optimal long-term outcomes for transplant patients.Peer reviewe

Biological predictors of suicidality in schizophrenia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65166/1/j.1600-0447.1996.tb09883.x.pd

The ERA Registry Annual Report 2021: a summary

[EN] Background The European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with end-stage kidney disease (ESKD). This paper is a summary of the ERA Registry Annual Report 2021, including a comparison across treatment modalities.Methods Data was collected from 54 national and regional registries from 36 countries, of which 35 registries from 18 countries contributed individual patient data and 19 registries from 19 countries contributed aggregated data. Using this data, incidence and prevalence of KRT, kidney transplantation rates, survival probabilities and expected remaining lifetimes were calculated.Result In 2021, 533.2 million people in the general population were covered by the ERA Registry. The incidence of KRT was 145 per million population (pmp). In incident patients, 55% were 65 years or older, 64% were male, and the most common primary renal disease (PRD) was diabetes (22%). The prevalence of KRT was 1040 pmp. In prevalent patients, 47% were 65 years or older, 62% were male, and the most common PRDs were diabetes and glomerulonephritis/sclerosis (both 16%). On 31 December 2021, 56% of patients received haemodialysis, 5% received peritoneal dialysis, and 39% were living with a functioning graft. The kidney transplantation rate in 2021 was 37 pmp, a majority coming from deceased donors (66%). For patients initiating KRT between 2012-2016, 5-year survival probability was 52%. Compared to the general population, life expectancy was 65% and 68% shorter for males and females receiving dialysis, and 40% and 43% shorter for males and females living with a functioning graft.The ERA Registry is funded by the European Renal Association (ERA). This article was written by B.A. Boerstra et al. on behalf of the ERA Registry, which is an official body of the ERA. P.B. reports payments from AstraZeneca and Takeda. S.B. reports consulting fees from GSK, Bayer, and AstraZeneca. A.C.A. reports payments from Diaverum Spain. F.J. reports payments from AstraZeneca, Boehringer Ingelheim, Servier, and Merck; and support for attending meetings and/or travel from Servier, AstraZeneca, Pfizer, and Fresenius. J.M. reports receiving support for attending meetings and/or travel from CSL Vifor. M.F.S.-R. reports receiving consulting fees from Baxter, Fresenius, and Nipro; payments from Baxter and Fresenius; and support for attending meetings and/or travel from Vifor, Fresenius, and Palex. I.Z. reports consulting fees from Astellas, Pharma, and Bayer; and payments from AstraZeneca, Bayer, Behringer Ingelheim, Norameda, and Swixx Biopharma. A.O. reports receiving grants from Sanofi; and consultancy or speaker fees or travel support from Advicciene, Astellas Pharma, AstraZeneca, Amicus, Amgen, Boehringer Ingelheim, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Menarini, Mundipharma, Kyowa Kirin, Lilly, Alexion, Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk, Sysmex, and Vifor Fresenius Medical Care Renal Pharma. K.J.J. reports receiving funds from ERA during the conduct of the study and grants from ESPN. V.S.S. reports receiving funds from ERA.Boerstra, BA.; Boenink, R.; Astley, ME.; Bonthuis, M.; Elhafeez, SA.; Arribas Monzón, F.; Asberg, A.... (2024). The ERA Registry Annual Report 2021: a summary. Clinical Kidney Journal. 17(2). https://doi.org/10.1093/ckj/sfad28117

Measuring senescence rates of patients with end-stage renal disease while accounting for population heterogeneity : an analysis of data from the ERA-EDTA Registry

Purpose: Although a population's senescence rate is classically measured as the increase in mortality rate with age on a logarithmic scale, it may be more accurately measured as the increase on a linear scale. Patients on dialysis, who suffer from accelerated senescence, exhibit a smaller increase in their mortality rate on a logarithmic scale, but a larger increase on a linear scale than patients with a functioning kidney transplant. However, this comparison may be biased by population heterogeneity. Methods: Follow-up data on 323,308 patients on dialysis and 91,679 patients with a functioning kidney transplant were derived from the ERA-EDTA Registry. We measured the increases in their mortality rates using Gompertz frailty models that allow individual variation in this increase. Results: According to these models, the senescence rate measured as the increase in mortality rate on a logarithmic scale was smaller in patients on dialysis, while the senescence rate measured as the increase on a linear scale was larger in patients on dialysis than patients with a functioning kidney transplant. Conclusions: Also when accounting for population heterogeneity, a population's senescence rate is more accurately measured as the increase in mortality rate on a linear scale than a logarithmic scale. (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Population screening for hereditary haemochromatosis in Australia: Construction and validation of a state-transition cost-effectiveness model

INTRODUCTION: HFE-associated haemochromatosis, the most common monogenic disorder amongst populations of northern European ancestry, is characterised by iron overload. Excess iron is stored in parenchymal tissues, leading to morbidity and mortality. Population screening programmes are likely to improve early diagnosis, thereby decreasing associated disease. Our aim was to develop and validate a health economics model of screening using utilities and costs from a haemochromatosis cohort. METHODS: A state-transition model was developed with Markov states based on disease severity. Australian males (aged 30 years) and females (aged 45 years) of northern European ancestry were the target populations. The screening strategy was the status quo approach in Australia; the model was run over a lifetime horizon. Costs were estimated from the government perspective and reported in 2015 Australian dollars ($A); costs and quality-adjusted life-years (QALYs) were discounted at 5$A22,737 (3670-85,793) for males and $A13,840 (1335-67,377) for females. Sensitivity analyses revealed discount rates and prevalence had the greatest impacts on outcomes. CONCLUSION: We have developed a transparent, validated health economics model of C282Y homozygote haemochromatosis. The model will be useful to decision makers to identify cost-effective screening strategies

Recovery of kidney function in patients treated with maintenance dialysis-a report from the ERA-EDTA Registry

Background. Literature on recovery of kidney function (RKF) in patients with end-stage kidney disease treated with maintenance dialysis (i.e. >90days) is limited. We assessed the incidence of RKF and its associated characteristics in a European cohort of dialysis patients. Methods. We included adult patients from the European Renal Association-European Dialysis and Transplant Association Registry who started maintenance dialysis in 1997-2016. Sustained RKF was defined as permanent discontinuation of dialysis. Temporary discontinuation of >= 30days (non-sustained RKF) was also evaluated. Factors associated with RKF adjusted for potential confounders were studied using Cox regression analyses. Results. RKF occurred in 7657 (1.8%) of 440996 patients, of whom 71% experienced sustained RKF. Approximately 90% of all recoveries occurred within the first 2years after Day 91 of dialysis. Of patients with non-sustained RKF, 39% restarted kidney replacement therapy within 1year. Sustained RKF was strongly associated with the following underlying kidney diseases (as registered by the treating physician): tubular necrosis (irreversible) or cortical necrosis {adjusted hazard ratio [aHR] 20.4 [95% confidence interval (CI) 17.9-23.1]}, systemic sclerosis [aHR 18.5 (95% CI 13.8-24.7)] and haemolytic uremic syndrome [aHR 17.3 (95% CI 13.9-21.6)]. Weaker associations were found for haemodialysis as a first dialysis modality [aHR 1.5 (95% CI 1.4-1.6)] and dialysis initiation at an older age [aHR 1.8 (95% CI 1.6-2.0)] or in a more recent time period [aHR 2.4 (95% CI 2.1-2.7)]. Conclusions. Definitive discontinuation of maintenance dialysis is a rare and not necessarily an early event. Certain clinical characteristics, but mostly the type of underlying kidney disease, are associated with a higher likelihood of RKF.Peer reviewe

Quality of life utility values for hereditary haemochromatosis in Australia

Background: Hereditary hemochromatosis (HH) is a common autosomal recessive disorder amongst persons of northern European heritage. If untreated, iron accumulates in parenchymal tissues causing morbidity and mortality. As diagnosis often follows irreversible organ damage, screening programs have been suggested to increase early diagnosis. A lack of economic evidence has been cited as a barrier to establishing such a program. Previous analyses used poorly estimated utility values. This study sought to measure utilities directly from people with HH in Australia. Methods: Volunteers with HH were recruited to complete a web-based survey. Utility was assessed using the Assessment of Quality of Life 4D (AQOL-4D) instrument. Severity of HH was graded into four categories. Multivariable regression analysis was performed to identify parameters associated with HSUV. Results: Between November 2013 and November 2014, 221 people completed the survey. Increasing severity of HH was negatively associated with utility. Mean (standard deviation) utilities were 0.76 (0.21), 0.81 (0.18), 0.60 (0.27), and 0.50 (0.27) for categories 1-4 HH respectively. Lower mean utility was found for symptomatic participants (categories 3 and 4) compared with asymptomatic participants (0.583 v. 0.796). Self-reported HH-related symptoms were negatively associated with HSUV (r = -0.685). Conclusions: Symptomatic stages of HH and presence of multiple self-reported symptoms were associated with decreasing utility. Previous economic analyses have used higher utilities which likely resulted in underestimates of the cost effectiveness of HH interventions. The utilities reported in this paper are the most robust available, and will contribute to improving the validity of future economic models for HH