Increasing Obesity Prevalence in the United States End-Stage Renal Disease Population.

Background: Among ESRD patients, obesity may improve dialysis-survival but decreases likelihood of transplantation, and as such, obesity prevalence may directly affect growth of the dialysis population. Objective: The objective of this study was to assess BMI trends in the ESRD population as compared to the general population. Materials and Methods: Incident adult ESRD patients were identified from the United States Renal Data System from 01/01/1995-12/31/2010 (n=1,458,350). Data from the Behavioral Risk Factor Surveillance System (n=4,303,471) represented the US population. Trends in BMI, obesity classes I (BMI of 30-34.9), II (BMI of 35-39.9), and III (BMI ≥ 40), were examined by year of dialysis initiation. Trends in BMI slope were compared between the ESRD and US populations using linear regression. Results: Mean BMI of ESRD patients in 1995 was 25.2 as compared to 29.4 in 2010, a 16.7% increase, while the US population's mean BMI increased from 25.3 to 27.2, a 7.5% increase. BMI increase among the ESRD population was significantly more rapid than among the US population (ß: 0.16, 95% CI: 0.14-0.18, p<0.001). Conclusions and Recommendations: Mean BMI among the ESRD population is increasing more rapidly than the US population. Given decreased access to kidney transplantation among ESRD patients with obesity, future research should be directed at controlling healthcare expenditures by identifying strategies to address the obesity epidemic among the US ESRD population.

Impact of Protease Inhibitor-Based Anti-Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients.

Excellent outcomes have been demonstrated among select HIV-positive kidney transplant (KT) recipients with well-controlled infection, but to date, no national study has explored outcomes among HIV+ KT recipients by antiretroviral therapy (ART) regimen. Intercontinental Marketing Services (IMS) pharmacy fills (1/1/01-10/1/12) were linked with Scientific Registry of Transplant Recipients (SRTR) data. A total of 332 recipients with pre- and posttransplantation fills were characterized by ART at the time of transplantation as protease inhibitor (PI) or non-PI-based ART (88 PI vs. 244 non-PI). Cox proportional hazards models were adjusted for recipient and donor characteristics. Comparing recipients by ART regimen, there were no significant differences in age, race, or HCV status. Recipients on PI-based regimens were significantly more likely to have an Estimated Post Transplant Survival (EPTS) score of >20% (70.9% vs. 56.3%, p = 0.02) than those on non-PI regimens. On adjusted analyses, PI-based regimens were associated with a 1.8-fold increased risk of allograft loss (adjusted hazard ratio [aHR] 1.84, 95% confidence interval [CI] 1.22-2.77, p = 0.003), with the greatest risk observed in the first posttransplantation year (aHR 4.48, 95% CI 1.75-11.48, p = 0.002), and a 1.9-fold increased risk of death as compared to non-PI regimens (aHR 1.91, 95% CI 1.02-3.59, p = 0.05). These results suggest that whenever possible, recipients should be converted to a non-PI regimen prior to kidney transplantation.

Increased Mortality and Graft Loss With Kidney Retransplantation Among Human Immunodeficiency Virus (HIV)-Infected Recipients.

Excellent outcomes have been demonstrated in primary human immunodeficiency virus (HIV)-positive (HIV+) kidney transplant recipients, but a subset will lose their graft and seek retransplantation (re-KT). To date, no study has examined outcomes among HIV+ re-KT recipients. We studied risk for death and graft loss among 4149 (22 HIV+ vs. 4127 HIV-negative [HIV-]) adult re-KT recipients reported to the Scientific Registry of Transplant Recipients (SRTR) (2004-2013). Compared to HIV- re-KT recipients, HIV+ re-KT recipients were more commonly African American (63.6% vs. 26.7%, p < 0.001), infected with hepatitis C (31.8% vs. 5.0%, p < 0.001) and had longer median time on dialysis (4.8 years vs. 2.1 years, p = 0.02). There were no significant differences in length of time between the primary and re-KT events by HIV status (1.5 years vs. 1.4 years, p = 0.52). HIV+ re-KT recipients experienced a 3.11-fold increased risk of death (adjusted hazard ratio [aHR]: 3.11, 95% confidence interval [CI]: 1.82-5.34, p < 0.001) and a 1.96-fold increased risk of graft loss (aHR: 1.96, 95% CI: 1.14-3.36, p = 0.01) compared to HIV- re-KT recipients. Re-KT among HIV+ recipients was associated with increased risk for mortality and graft loss. Future research is needed to determine if a survival benefit is achieved with re-KT in this vulnerable population.

Systematic review of clinical practice guidelines in kidney transplantation.

BACKGROUND: Clinical practice guidelines (CPGs) are widely used to inform the development of protocols for clinical management. Previous work has demonstrated that the quality of CPGs varies widely. This systematic review aimed to determine the quality of CPGs in kidney transplantation in the UK. METHODS: CPGs in kidney transplantation published between 2010 and 2017 were identified through searches of MEDLINE, NHS NICE Evidence, and websites of relevant UK societies. Using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool, three appraisers rated the quality of CPGs across six domains, the overall quality of each CPG, and whether it should be recommended for future use. Domain scores were calculated, and inter-rater reliability using the intraclass correlation coefficient (ICC) was reported. RESULTS: Thirteen CPGs met the inclusion criteria. The domain 'clarity of presentation' scored highest, followed closely by 'scope and purpose'. The poorest scoring domains were 'applicability' and 'editorial independence'. Editorial independence also had the widest range of scores. Of the 13 CPGs, one was not recommended for future use, seven were recommended for use with modifications, and five for future use with no need for modification. Mean overall CPG quality was 5 (range 3-6) of a maximum score of 7, and mean inter-rater reliability was substantial with an ICC of 0·71. CONCLUSION: UK CPGs scored satisfactorily, although with wide variation in how well each domain scored both within and across CPGs. The quality of UK CPGs can still be improved.

Dosing Eculizumab for Antibody-Mediated Rejection in Kidney Transplantation: A Case Report.

Severe antibody-mediated rejection (AMR) of a blood type-incompatible (ABOi) living donor kidney transplantation (LDKT) can lead to graft failure, and aggressive therapies, such as the anticomplement antibody eculizumab, are often used to rescue the affected graft. Eculizumab therapy can be crippling financially. Current literature suggests a wide variation in the amount and timing of eculizumab given as rescue therapy in the setting of AMR. Herein we describe a limited-eculizumab regimen in the setting of severe AMR that is both clinically and cost effective. Treatment included escalation in plasmapheresis and intravenous immunoglobulin (PP/IVIg) and eculizumab. Eculizumab therapy was discontinued at the first sign of clinical improvement (2-fold decrease in anti-ABO titer and stabilization of serum creatinine). The current standard of care is to redose eculizumab after any PP treatment, and, in some series, continue with maintenance eculizumab doses. In these 2 cases, discontinuing eculizumab therapy upon observed clinical improvement saved 6 unnecessary doses at a cost of $90,000. Both patients have more than 1 year of follow-up and functioning allografts. Although this is a small and limited study, we suggest that a dosing regimen of eculizumab similar to that presented here may be effective in rescuing a graft following AMR while simultaneously limiting cost.

Identification of Optimal Donor-Recipient Combinations Among Human Immunodeficiency Virus (HIV)-Positive Kidney Transplant Recipients.

For some patient subgroups, human immunodeficiency virus (HIV) infection has been associated with worse outcomes after kidney transplantation (KT); potentially modifiable factors may be responsible. The study goal was to identify factors that predict a higher risk of graft loss among HIV-positive KT recipients compared with a similar transplant among HIV-negative recipients. In this study, 82 762 deceased donor KT recipients (HIV positive: 526; HIV negative: 82 236) reported to the Scientific Registry of Transplant Recipients (SRTR) (2001-2013) were studied by interaction term analysis. Compared to HIV-negative recipients, the hepatitis C virus (HCV) amplified risk 2.72-fold among HIV-positive KT recipients (adjusted hazard ratio [aHR]: 2.72, 95% confidence interval [CI]: 1.75-4.22, p < 0.001). Forty-three percent of the excess risk was attributable to the interaction between HIV and HCV (attributable proportion of risk due to the interaction [AP]: 0.43, 95% CI: 0.23-0.63, p = 0.02). Among HIV-positive recipients with more than three HLA mismatches (MMs), risk was amplified 1.80-fold compared to HIV-negative (aHR: 1.80, 95% CI: 1.31-2.47, p < 0.001); 42% of the excess risk was attributable to the interaction between HIV and more than three HLA MMs (AP: 0.42, 95% CI: 0.24-0.60, p = 0.01). High-HIV-risk (HIV-positive/HCV-positive HLAwith more than three MMs) recipients had a 3.86-fold increased risk compared to low-HIV-risk (HIV-positive/HCV-negative HLA with three or fewer MMs)) recipients (aHR: 3.86, 95% CI: 2.37-6.30, p < 0.001). Avoidance of more than three HLA MMs in HIV-positive KT recipients, particularly among coinfected patients, may mitigate the increased risk of graft loss associated with HIV infection.

Center-Level Experience and Kidney Transplant Outcomes in HIV-Infected Recipients.

Excellent outcomes among HIV+ kidney transplant (KT) recipients have been reported by the NIH consortium, but it is unclear if experience with HIV+ KT is required to achieve these outcomes. We studied associations between experience measures and outcomes in 499 HIV+ recipients (SRTR data 2004-2011). Experience measures examined included: (1) center-level participation in the NIH consortium; (2) KT experiential learning curve; and (3) transplant era (2004-2007 vs. 2008-2011). There was no difference in outcomes among centers early in their experience (first 5 HIV+ KT) compared to centers having performed >6 HIV+ KT (GS adjusted hazard ratio [aHR]: 1.05, 95% CI: 0.68-1.61, p = 0.82; PS aHR: 0.93; 95% CI: 0.56-1.53, p = 0.76), and participation in the NIH-study was not associated with any better outcomes (GS aHR: 1.08, 95% CI: 0.71-1.65, p = 0.71; PS aHR: 1.13; 95% CI: 0.68-1.89, p = 0.63). Transplant era was strongly associated with outcomes; HIV+ KTs performed in 2008-2011 had 38% lower risk of graft loss (aHR: 0.62; 95% CI: 0.42-0.92, p = 0.02) and 41% lower risk of death (aHR: 0.59; 95% CI: 0.39-0.90, p = 0.01) than that in 2004-2007. Outcomes after HIV+ KT have improved over time, but center-level experience or consortium participation is not necessary to achieve excellent outcomes, supporting continued expansion of HIV+ KT in the US.

The impact of proposed changes in liver allocation policy on cold ischemia times and organ transportation costs.

Changes to the liver allocation system have been proposed to decrease regional variation in access to liver transplant. It is unclear what impact these changes will have on cold ischemia times (CITs) and donor transportation costs. Therefore, we performed a retrospective single center study (2008-2012) measuring liver procurement CIT and transportation costs. Four groups were defined: Local-within driving distance (Local-D, n = 262), Local-flight (Local-F, n = 105), Regional-flight <3 h (Regional <3 h, n = 61) and Regional-Flight >3 h (Regional >3 h, n = 53). The median travel distance increased in each group, varying from zero miles (Local-D), 196 miles (Local-F), 384 miles (Regional <3 h), to 1647 miles (Regional >3 h). Increasing travel distances did not significantly increase CIT until the flight time was >3 h. The average CIT ranged from 5.0 to 6.0 h for Local-D, Local-F and Regional <3 h, but increased to 10 h for Regional >3 h (p < 0.0001). Transportation costs increased with greater distance traveled: Local-D $101, Local-F $1993, Regional <3 h $8324 and Regional >3 h $27 810 (p < 0.0001). With proposed redistricting, local financial modeling suggests that the average liver donor procurement transportation variable direct costs will increase from $2415 to $7547/liver donor, an increase of 313%. These findings suggest that further discussion among transplant centers and insurance providers is needed prior to policy implementation.

doublesex is a mimicry supergene.

One of the most striking examples of sexual dimorphism is sex-limited mimicry in butterflies, a phenomenon in which one sex--usually the female--mimics a toxic model species, whereas the other sex displays a different wing pattern. Sex-limited mimicry is phylogenetically widespread in the swallowtail butterfly genus Papilio, in which it is often associated with female mimetic polymorphism. In multiple polymorphic species, the entire wing pattern phenotype is controlled by a single Mendelian 'supergene'. Although theoretical work has explored the evolutionary dynamics of supergene mimicry, there are almost no empirical data that address the critical issue of what a mimicry supergene actually is at a functional level. Using an integrative approach combining genetic and association mapping, transcriptome and genome sequencing, and gene expression analyses, we show that a single gene, doublesex, controls supergene mimicry in Papilio polytes. This is in contrast to the long-held view that supergenes are likely to be controlled by a tightly linked cluster of loci. Analysis of gene expression and DNA sequence variation indicates that isoform expression differences contribute to the functional differences between dsx mimicry alleles, and protein sequence evolution may also have a role. Our results combine elements from different hypotheses for the identity of supergenes, showing that a single gene can switch the entire wing pattern among mimicry phenotypes but may require multiple, tightly linked mutations to do so.

A partitioned likelihood analysis of swallowtail butterfly phylogeny (Lepidoptera:Papilionidae).

Although it is widely agreed that data from multiple sources are necessary to confidently resolve phylogenetic relationships, procedures for accommodating and incorporating heterogeneity in such data remain underdeveloped. We explored the use of partitioned, model-based analyses of heterogeneous molecular data in the context of a phylogenetic study of swallowtail butterflies (Lepidoptera: Papilionidae). Despite substantial basic and applied study, phylogenetic relationships among the major lineages of this prominent group remain contentious. We sequenced 3.3 kb of mitochondrial and nuclear DNA (2.3 kb of cytochrome oxidase I and II and 1.0 kb of elongation factor-1 alpha, respectively) from 22 swallowtails, including representatives of Baroniinae, Parnassiinae, and Papilioninae, and from several moth and butterfly outgroups. Using parsimony, we encountered considerable difficulty in resolving the deepest splits among these taxa. We therefore chose two outgroups with undisputed relationships to each other and to Papilionidae and undertook detailed likelihood analyses of alternative topologies. Following from previous studies that have demonstrated substantial heterogeneity in the evolutionary dynamics among process partitions of these genes, we estimated evolutionary parameters separately for gene-based and codon-based partitions. These values were then used as the basis for examining the likelihoods of possible resolutions and rootings under several partitioned and unpartitioned likelihood models. Partitioned models gave markedly better fits to the data than did unpartitioned models and supported different topologies. However, the most likely topology varied from model to model. The most likely ingroup topology under the best-fitting, six-partition GTR + gamma model favors a paraphyletic Parnassiinae. However, when examining the likelihoods of alternative rootings of this tree relative to rootings of the classical hypothesis, two rootings of the latter emerge as most likely. Of these two, the most likely rooting is within the Papilioninae, although a rooting between Baronia and the remaining Papilionidae is only nonsignificantly less likely.

Interaction of process partitions in phylogenetic analysis: an example from the swallowtail butterfly genus Papilio.

In this study, we explored how the concept of the process partition may be applied to phylogenetic analysis. Sequence data were gathered from 23 species and subspecies of the swallowtail butterfly genus Papilio, as well as from two outgroup species from the genera Eurytides and Pachliopta. Sequence data consisted of 1,010 bp of the nuclear protein-coding gene elongation factor-1 alpha (EF-1 alpha) as well as the entire sequences (a total of 2,211 bp) of the mitochondrial protein-coding genes cytochrome oxidase I and cytochrome oxidase II (COI and COII). In order to examine the interaction between the nuclear and mitochondrial partitions in a combined analysis, we used a method of visualizing branch support as a function of partition weight ratios. We demonstrated how this method may be used to diagnose error at different levels of a tree in a combined maximum-parsimony analysis. Further, we assessed patterns of evolution within and between subsets of the data by implementing a multipartition maximum-likelihood model to estimate evolutionary parameters for various putative process partitions. COI third positions have an estimated average substitution rate more than 15 times that of EF-1 alpha, while COII third positions have an estimated average substitution rate more than 22 times that of EF-1 alpha. Ultimately, we found that although the mitochondrial and nuclear data were not significantly incongruent, homoplasy in the fast-evolving mitochondrial data confounded the resolution of basal relationships in the combined unweighted parsimony analysis despite the fact that there was relatively strong support for the relationships in the nuclear data. We conclude that there may be shortcomings to the methods of "total evidence" and "conditional combination" because they may fail to detect or accommodate the type of confounding bias we found in our data.

A standards of care plan in the postanesthesia care unit.

Every patient is entitled to consistent, high-quality, individualized care. The PACU staff and former director of staff education at Southwestern Vermont Medical Center developed a documentation tool to achieve this end. The primary focus of the tool is on standards of care with an emphasis on outcome standards. Every patient received and cared for in the PACU is evaluated in terms of these outcome standards. If for any reason an outcome standard is not achieved, appropriate action is taken. The four-page bifold tool incorporates the nursing process. Potential nursing diagnostic problems are described and assessment and intervention data are integrated accordingly. The plan is further individualized vis à vis nursing progress notes. The tool has been in use for well over 1 year, and quality assurance studies demonstrate that outcome standards achieved and not achieved are consistently documented. The PACU staff believe this tool has enhanced professional practice and improved use of the nursing process and standards of care.

Energy status and oxidation-reduction status in rat liver at high altitude (3.8 km).

Adult male rats were exposed to 3.8-km altitude for intervals ranging from 1 h-60 d. Liver samples were taken under light ether anesthesia and were examined by enzymatic analyses. Within 1-6 h of hypoxic exposure, ATP levels decreased while ADP and AMP levels increased, producing a fall in calculated ATP/ADP and adenylate charge ratios. Concurrently, lactate/pyruvate and alpha-glycerophosphate/dihydroxyacetone phosphate ratios increased markedly. Direct measurements of cellular pyridine nucleotides indicated increased NADH/NAD and NADPH/NADP ratios. Levels of total adenosine phosphate and pyridine nucleotides decreased in a significant accompanying response. Many metabolite levels and calculated ratios returned to near-normal values within 1 week of exposure, indicating secondary intracellular adjustments to hypoxic stress; however, persistence of that stress is reflected in lactate conentrations and both substrate redox ratios. Results support and explore concepts that increased oxidation-reduction status and decreased energy status are primary events during hypoxia.

Energy status and oxidation-reduction status in rat liver at high altitude (3.8 km).

Adult male rats were exposed to 3.8-km altitude for intervals ranging from 1 h-60 d. Liver samples were taken under light ether anesthesia and were examined by enzymatic analyses. Within 1-6 h of hypoxic exposure, ATP levels decreased while ADP and AMP levels increased, producing a fall in calculated ATP/ADP and adenylate charge ratios. Concurrently, lactate/pyruvate and alpha-glycerophosphate/dihydroxyacetone phosphate ratios increased markedly. Direct measurements of cellular pyridine nucleotides indicated increased NADH/NAD and NADPH/NADP ratios. Levels of total adenosine phosphates and pyridine nucleotides decreased in a significant accompanying response. Many metabolite levels and calculated ratios returned to near-normal values within 1 week of exposure, indicating secondary intracellular adjustments to hypoxic stress; however, persistence of that stress is reflected in lactate concentrations and both substrate redox ratios. Results support and explore concepts that increased oxidation-reduction status and decreased energy status are primary events during hypoxia.