Prognostic Value of Exercise Capacity in Kidney Transplant Candidates

BACKGROUND: Exercise stress testing for cardiovascular assessment in kidney transplant candidates has been shown to be a feasible alternative to pharmacologic methods. Exercise stress testing allows the additional assessment of exercise capacity, which may have prognostic value for long-term cardiovascular outcomes in pre-transplant recipients. This study aimed to evaluate the prognostic value of exercise capacity on long-term cardiovascular outcomes in kidney transplant candidates. METHODS AND RESULTS: We retrospectively evaluated exercise capacity in 898 consecutive kidney transplant candidates between 2013 and 2020 who underwent symptom-limited exercise stress echocardiography for pre-transplant cardiovascular assessment. Exercise capacity was measured by age-and sex-predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events, defined as cardiac death, non-fatal myocardial infarction, and stroke. Cox proportional hazard multivariable modeling was performed to define major adverse cardiovascular events predictors with transplantation treated as a time-varying covariate. A total of 429 patients (48%) achieved predicted METs. During follow-up, 93 (10%) developed major adverse cardiovascular events and 525 (58%) underwent transplantation. Achievement of predicted METs was independently associated with reduced major adverse cardiovascular events (hazard ratio [HR] 0.49; [95% CI 0.29–0.82], P=0.007), as was transplantation (HR, 0.52; [95% CI 0.30–0.91], P=0.02). Patients achieving predicted METs on pre-transplant exercise stress echocardiography had favorable outcomes that were independent (HR, 0.78; [95% CI 0.32–1.92], P=0.59) and of similar magnitude to subsequent transplantation (HR, 0.97; [95% CI 0.42–2.25], P=0.95). CONCLUSIONS: Achievement of predicted METs on pre-transplant exercise stress echocardiography confers excellent prognosis independent of and of similar magnitude to subsequent kidney transplantation. Future studies should assess the benefit on exercise training in this population.Sean Tan, MBBS, Yi Wen Thang, MBBS, William R. Mulley, BMed, PhD, Kevan R. Polkinghorne, MBChB, PhD, Satish Ramkumar, MBBS, PhD, Kevin Cheng, MBBS, Jasmine Chan, BSc, MBBS, John Galligan, MBBS, Mark Nolan, MBBS, PhD, Adam J. Brown, BSc, MB BChir, PhD, Stuart Moir, MBBS, PhD, James D. Cameron, MD, MEngSc, Stephen J. Nicholls, MBBS, PhD, Philip M. Mottram, MBBS, PhD, Nitesh Nerlekar, MBBS, MPH, Ph

The composition of the protosolar disk and the formation conditions for comets

Conditions in the protosolar nebula have left their mark in the composition of cometary volatiles, thought to be some of the most pristine material in the solar system. Cometary compositions represent the end point of processing that began in the parent molecular cloud core and continued through the collapse of that core to form the protosun and the solar nebula, and finally during the evolution of the solar nebula itself as the cometary bodies were accreting. Disentangling the effects of the various epochs on the final composition of a comet is complicated. But comets are not the only source of information about the solar nebula. Protostellar disks around young stars similar to the protosun provide a way of investigating the evolution of disks similar to the solar nebula while they are in the process of evolving to form their own solar systems. In this way we can learn about the physical and chemical conditions under which comets formed, and about the types of dynamical processing that shaped the solar system we see today. This paper summarizes some recent contributions to our understanding of both cometary volatiles and the composition, structure and evolution of protostellar disks.Comment: To appear in Space Science Reviews. The final publication is available at Springer via http://dx.doi.org/10.1007/s11214-015-0167-

Solid-phase library synthesis, screening, and selection of tight-binding reduced peptide bond inhibitors of a recombinant Leishmania mexicana cysteine protease B

A one-bead−two-compound inhibitor library was synthesized by the split−mix method for the identification of inhibitors of a recombinant cysteine protease from Leishmania mexicana, CPB2.8ΔCTE. The inhibitor library was composed of octapeptides with a centrally located reduced bond introduced by reductive amination of the resin-bound amines with Fmoc amino aldehydes. The library was screened on solid phase, and less than 1% of the library contained active compounds. The inhibitors displayed great specificity in the subsites flanking the enzyme catalytic triad with Cha and Ile/Leu preferred in P2, Phe in P1, Cha and Ile/Leu in P1‘, and Ile/Leu in P2‘. Some of the inhibitors were resynthesized, and the kinetics of inhibition were determined in solution-phase assays. Most of the inhibitors had micromolar Ki values, and a few inhibited the enzyme at nanomolar concentrations. One inhibitor, DKHF(CH2NH)LLVK (Ki = 1 μM), was tested for antiparasite efficacy and shown to affect parasite survival with an IC50 of approximately 50 μΜ