The risk of stroke and stroke type in patients with atrial fibrillation and chronic kidney disease

Background: Atrial fibrillation (AF) and chronic kidney disease (CKD) are known to increase the risk of stroke. Objectives: We set out to examine the risk of stroke by kidney function and albuminuria in patients with and without AF. Design: Retrospective cohort study. Settings: Ontario, Canada. Participants: A total of 736 666 individuals (>40 years) from 2002 to 2015. Measurements: New-onset AF, albumin-to-creatinine ratio (ACR), and an estimated glomerular filtration rate (eGFR). Methods: A total of 39 120 matched patients were examined for the risk of ischemic, hemorrhagic, or any stroke event, accounting for the competing risk of all-cause mortality. Interaction terms for combinations of ACR/eGFR and the outcome of stroke with and without AF were examined. Results: In a total of 4086 (5.2%) strokes (86% ischemic), the presence of AF was associated with a 2-fold higher risk for any stroke event and its subtypes of ischemic and hemorrhagic stroke. Across eGFR levels, the risk of stroke was 2-fold higher with the presence of AF except for low levels of eGFR (eGFR < 30 mL/min/1.73 m2, hazard ratio [HR]: 1.38, 95% confidence interval [CI]: 0.99-1.92). Similarly across ACR levels, the risk of stroke was 2-fold higher except for high levels of albuminuria (ACR > 30 mg/g, HR: 1.61, 95% CI: 1.31-1.99). The adjusted risk of stroke with AF differed by combinations of ACR and eGFR categories (interaction P value = .04) compared with those without AF. Both stroke types were more common in patients with AF, and ischemic stroke rates differed significantly by eGFR and ACR categories. Limitations: Medication information was not included. Conclusions: Patients with CKD and AF are at a high risk of total, ischemic, and hemorrhagic strokes; the risk is highest with lower eGFR and higher ACR and differs based on eGFR and the degree of ACR

Impacts of center and clinical factors in antihypertensive medication use after kidney transplantation

Hypertension guidelines recommend calcium channel blockers (CCBs), thiazide diuretics, and angiotensin‐converting‐enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) as first‐line agents to treat hypertension. Hypertension is common among kidney transplant (KTx) recipients, but data are limited regarding patterns of antihypertensive medication (AHM) use in this population. We examined a novel database that links national registry data for adult KTx recipients (age > 18 years) with AHM fill records from a pharmaceutical claims warehouse (2007‐2016) to describe use and correlates of AHM use during months 7‐12 post‐transplant. For patients filling AHMs, individual agents used included: dihydropyridine (DHP) CCBs, 55.6%; beta‐blockers (BBs), 52.8%; diuretics, 30.0%; ACEi/ARBs, 21.1%; non‐DHP CCBs, 3.0%; and others, 20.1%. Both BB and ACEi/ARB use were significantly lower in the time period following the 2014 Eighth Joint National Committee (JNC‐8) guidelines (2014‐2016), compared with an earlier period (2007‐2013). The median odds ratios generated from case‐factor adjusted models supported variation in use of ACEi/ARBs (1.51) and BBs (1.55) across transplant centers. Contrary to hypertension guidelines for the general population, KTx recipients are prescribed relatively more BBs and fewer ACEi/ARBs. The clinical impact of this AHM prescribing pattern warrants further study.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154651/1/ctr13803.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154651/2/ctr13803_am.pd

Outcome implications of benzodiazepine and opioid co- prescription in kidney transplant recipients

The outcomes of benzodiazepine and opioid co- prescription are not well- defined in transplant populations. We examined linked national transplant registry and pharmaceutical records to characterize benzodiazepine and opioid use in the years before and after transplant in large US cohort of kidney transplant recipients (2007- 2016; N = 98 620), and associations (adjusted hazard ratio, LCLaHRUCL) with death and graft failure. Among the cohort, 15.6% filled benzodiazepine prescriptions in the year before transplant, and 14.0% filled benzodiazepine prescriptions in the year after transplant (short- acting, 9.5%; long- acting, 3.3%; both 1.1%). Use of short- acting benzodiazepines in the year before transplant was associated with a 22% increased risk of death in the year after transplant (aHR, 1.081.221.38), while use of all classes in the year after transplant was associated with increased risk of death from >1 to 5 years (aHR: short- acting 1.291.391.48; long- acting 1.121.251.40; both 1.461.742.07). Recipients who used benzodiazepines were also more likely to fill opioid prescriptions. Recipients who filled both classes of benzodiazepine and the highest level of opioids had a 2.9- fold increased risk of death compared to recipients who did not use either. Co- prescription of benzodiazepines and opioids in kidney transplant recipients is associated with increased mortality. Ongoing research is needed to understand mechanisms of risk relationships.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162821/2/ctr14005.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162821/1/ctr14005_am.pd

Center practice drives variation in choice of US kidney transplant induction therapy: a retrospective analysis of contemporary practice

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141776/1/tri13079_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141776/2/tri13079.pd

Associations of obesity with antidiabetic medication use after living kidney donation: An analysis of linked national registry and pharmacy fill records

We examined a novel linkage of national US donor registry data with records from a pharmacy claims warehouse (2007‐2016) to examine associations (adjusted hazard ratio, LCLaHRUCL) of post‐donation fills of antidiabetic medications (ADM, insulin or non‐insulin agents) with body mass index (BMI) at donation and other demographic and clinical factors. In 28 515 living kidney donors (LKDs), incidence of ADM use at 9 years rose in a graded manner with higher baseline BMI: underweight, 0.9%; normal weight, 2.1%; overweight, 3.5%; obese, 8.5%. Obesity was associated with higher risk of ADM use compared with normal BMI (aHR, 3.364.596.27). Metformin was the most commonly used ADM and was filled more often by obese than by normal weight donors (9‐year incidence, 6.87% vs 1.85%, aHR, 3.555.007.04). Insulin use was uncommon and did not differ significantly by BMI. Among a subgroup with BMI data at the 1‐year post‐donation anniversary (n = 19 528), compared with stable BMI, BMI increase >0.5 kg/m2 by year 1 was associated with increased risk of subsequent ADM use (aHR, 1.031.482.14, P = .04). While this study did not assess the impact of donation on the development of obesity, these data support that among LKD, obesity is a strong correlate of ADM use.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152001/1/ctr13696_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152001/2/ctr13696.pd

Appearance Modeling of Living Human Tissues

This is the peer reviewed version of the following article: Nunes, A.L.P., Maciel, A., Meyer, G.W., John, N.W., Baranoski, G.V.G., & Walter, M. (2019). Appearance Modeling of Living Human Tissues, Computer Graphics Forum, which has been published in final form at https://doi.org/10.1111/cgf.13604. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-ArchivingThe visual fidelity of realistic renderings in Computer Graphics depends fundamentally upon how we model the appearance of objects resulting from the interaction between light and matter reaching the eye. In this paper, we survey the research addressing appearance modeling of living human tissue. Among the many classes of natural materials already researched in Computer Graphics, living human tissues such as blood and skin have recently seen an increase in attention from graphics research. There is already an incipient but substantial body of literature on this topic, but we also lack a structured review as presented here. We introduce a classification for the approaches using the four types of human tissues as classifiers. We show a growing trend of solutions that use first principles from Physics and Biology as fundamental knowledge upon which the models are built. The organic quality of visual results provided by these Biophysical approaches is mainly determined by the optical properties of biophysical components interacting with light. Beyond just picture making, these models can be used in predictive simulations, with the potential for impact in many other areas

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Validation of kidney transplantation using administrative data

Abstract Background Administrative data are increasingly being used to assess outcomes in kidney transplant recipients. Objective To assess the validity of transplant data in healthcare administrative databases compared to the reference standard of information collected directly from transplant centres. Design Retrospective cohort study. Setting One of three major transplant centres in Ontario (Toronto General Hospital, University Hospital – London, and Ottawa Hospital). Patients Recipients who received a kidney-only transplant between 2008 and 2011. Measurements For each data source, we identified kidney transplants performed. We calculated the sensitivity and positive predictive value (PPV) of the administrative data for the reference standard data. Methods The data collected from transplant centres were compared with data from the Canadian Organ Replacement Register (CORR) database, a hospital procedural code from the Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD), and provincial physician billing claims from the Ontario Health Insurance Plan (OHIP) database. Results During the study period, the three centres reported a total of 1112 kidney transplants performed. The probability of identifying kidney transplant recipients in CORR, CIHI, and OHIP, given they were identified by the transplant centres (sensitivity), was 96%, 98%, and 98% respectively. The probability that the database code correctly identified a transplant recipient (positive predictive value) in CORR, CIHI, and OHIP was 98%, 98%, and 96% respectively. Limitations We validated the information from 2008 to 2011 and cannot attest to the reliability of the data beyond the study period. Specifically, we would not regard this as evidence that applies to the earlier years, shortly after the inception of the databases. Secondly, we were unable to distinguish between first and repeat transplantation. Conclusions Codes in CORR, CIHI, and OHIP each operate well in the detection of kidney transplant recipients. These data sources can be used to efficiently identify and follow kidney transplant recipients for post-transplant outcomes