Experience with tacrolimus in children with steroid-resistant nephrotic syndrome

Children with steroid-resistant nephrotic syndrome (SRNS) are at risk of developing renal failure. We report here the results of a single-center retrospective observational study of the remission rate in pediatric patients with SNRS receiving tacrolimus. Serial renal biopsies from children on tacrolimus therapy were evaluated for tubulointerstitial fibrosis and transforming growth factor-β immunostaining. Of the 16 children with SRNS, 15 went into complete remission after a median of 120 days of therapy. Nine children were able to stop steroids, while the others were on tapering doses. Forty-seven percent had relapses, most of which were steroid-responsive. Serial renal biopsies were obtained from seven children after a median treatment duration of 24 months; two of these children had increased tubulointerstitial fibrosis and four showed increased transforming growth factor-β tissue staining. Children with worsening histological findings were younger. There was no significant association between tacrolimus exposure and biopsy changes, although the average trough level was higher in those children with worsening histological findings. In conclusion, tacrolimus may be a safe and effective alternative agent for inducing remission in children with SRNS. However, caution needs to be taken when prescribing this agent due to its narrow therapeutic index. Serial renal biopsies are necessary to check for subclinical nephrotoxicity, especially in younger children and those with higher trough levels

Donor-derived cell-free DNA monitoring for early diagnosis of antibody-mediated rejection after kidney transplantation: a randomized trial

BACKGROUND AND HYPOTHESIS: Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR.We hypothesized that monitoring dd-cfDNA in KTR with de novo donor-specific anti-HLA antibodies (dnDSA) and performing kidney biopsy in case of increased dd-cfDNA may reduce time to AMR diagnosis in comparison to clinical indication biopsy. METHODS: In this diagnostic, single-center, open-label, randomized clinical trial, we assigned 40 KTR with prevalent dnDSA and estimated glomerular filtration rate =20 mL/min/1.73m2, but without previous biopsy-proven AMR, to either dd-cfDNA-guided biopsy (intervention group) or clinician-guided biopsy (control group) over a 12-months period. In both groups, dd-cfDNA was assessed at inclusion and 1, 3, 6, 9, and 12 months. In the intervention group, dd-cfDNA > 50cp/mL indicated a biopsy. Biopsies for clinical indication could be performed at any point during the study period in both groups. A protocol biopsy was scheduled after 12 months for patients without dd-cfDNA-guided biopsy or clinical indication biopsy until study completion. The primary endpoint was time from study inclusion to diagnosis of active or chronic active AMR. RESULTS: 39/40 patients had functioning grafts at study completion. From these, 26 patients underwent biopsy, 13 in each group. AMR was diagnosed earlier in the intervention group than in the control group (median 2.8 months, IQR 1.7-5.3 vs. median 14.5 months, IQR 13.3-16.7, p = 0.003). Longitudinal dd-cfDNA monitoring had 77% positive predictive value and 85% negative predictive value for AMR. CONCLUSIONS: Dd-cfDNA-guided biopsy in KTR with prevalent dnDSA can reduce the time to AMR diagnosis and hereby expedite therapy initiation. (NCT04897438)

Nature’s nations: the shared conservation history of Canada and the USA

Historians often study the history of conservation within the confines of national borders, concentrating on the bureaucratic and political manifestations of policy within individual governments. Even studies of the popular expression of conservationist ideas are generally limited to the national or sub-national (province, state, etc.) scale. This paper suggests that conservationist discourse, policy and practice in Canada and the USA were the products of a significant cross-border movement of ideas and initiatives derived from common European sources. In addition, the historical development of common approaches to conservation in North America suggests, contrary to common assumptions, that Canada did not always lag behind the USA in terms of policy innovation. The basic tenets of conservation (i.e. state control over resource, class-based disdain for subsistence hunters and utilitarian approaches to resource management) have instead developed at similar time periods and along parallel ideological paths in Canada and the USA

Effects of Atmospheric Change and Agriculture on the Biogeochemistry and Microbial Ecology of Prairie Wetlands

Relatively little is known about the factors which regulate in water biogeochemical processes and food chains in prairie wetlands. Climatic warming, increased UV-radiation and agricultural activities will have interacting effects on these wetlands. We examined the effects of these processes on prairie wetland functioning and productivity with particular emphasis on production and cycling of organic carbon, especially dissolved organic carbon (DOC). Autotrophic and heterotrophic production are temperature dependent and temperature increases or decreases could affect production under more extreme climate change scenarios. DOC concentrations could decrease with increasing bacterial production and photolysis, leading to increases in UV-radiation penetration. This is pertinent to prairie wetlands because of their general shallowness. Considering the potential consequences of climatic warming, increased UV-radiation and agricultural activity on biogeochemistry and food chains, it is imperative that we obtain an understanding of the major rate processes in prairie wetlands and how these may be affected by external processes

Incentives, Burnout, and Turnover: Dynamic Compensation Design with Effort Cost Spillover

Employee burnout has long plagued firms. The prevalence of burnout shows that work-related effort is not only costly in the present but has carryover effects into the future. We incorporate this ‘effort cost spillover’ into a dynamic, two-period principal-agent model, where the worker’s effort cost in the second period increases in both their second-period and first-period efforts. We use this model to explore optimal compensation design and the connection between incentives, burnout, and turnover. Naturally, turnover may occur if it is easy to replace workers, or if firms fail to account for burnout when designing contracts. However, we show that even when turnover is very costly, and firms and workers properly understand effort cost spillover, the firm’s equilibrium strategy may be to offer high-powered incentives that induce workers to work so hard that they exit (i.e. reject any contract that the firm would offer) in the next period. Workplace measures that reduce spillover, such as flexible work arrangements, can limit turnover and improve profits dramatically. Committing to contracts for both periods in advance can also limit turnover (at the cost of reduced flexibility)