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Abstract Background The molecular pathways involved in the interstitial lung diseases (ILDs) are poorly understood. Systems biology approaches, with global expression data sets, were used to identify perturbed gene networks, to gain some understanding of the underlying mechanisms, and to develop specific hypotheses relevant to these chronic lung diseases. Methods Lung tissue samples from patients with different types of ILD were obtained from the Lung Tissue Research Consortium and total cell RNA was isolated. Global mRNA and microRNA were profiled by hybridization and amplification-based methods. Differentially expressed genes were compiled and used to identify critical signaling pathways and potential biomarkers. Modules of genes were identified that formed a regulatory network, and studies were performed on cultured cells in vitro for comparison with the in vivo results. Results By profiling mRNA and microRNA (miRNA) expression levels, we found subsets of differentially expressed genes that distinguished patients with ILDs from controls and that correlated with different disease stages and subtypes of ILDs. Network analysis, based on pathway databases, revealed several disease-associated gene modules, involving genes from the TGF-β, Wnt, focal adhesion, and smooth muscle actin pathways that are implicated in advancing fibrosis, a critical pathological process in ILDs. A more comprehensive approach was also adapted to construct a putative global gene regulatory network based on the perturbation of key regulatory elements, transcription factors and microRNAs. Our data underscores the importance of TGF-β signaling and the persistence of smooth muscle actin-containing fibroblasts in these diseases. We present evidence that, downstream of TGF-β signaling, microRNAs of the miR-23a cluster and the transcription factor Zeb1 could have roles in mediating an epithelial to mesenchymal transition (EMT) and the resultant persistence of mesenchymal cells in these diseases. Conclusions We present a comprehensive overview of the molecular networks perturbed in ILDs, discuss several potential key molecular regulatory circuits, and identify microRNA species that may play central roles in facilitating the progression of ILDs. These findings advance our understanding of these diseases at the molecular level, provide new molecular signatures in defining the specific characteristics of the diseases, suggest new hypotheses, and reveal new potential targets for therapeutic intervention.

Abstract Introduction We report a rare case of an infected revision total knee replacement as a result of a Lactobacillus species infection. Lactobacillus infections have been associated with prolonged broad-spectrum antibiotic use. This can have implications in revision surgery, especially when patients have been on previous long-term suppressive antibiotic therapy. Case presentation An 81-year-old British man with a previous history of complex revision knee arthroplasty for infection presented with a hot, swollen knee joint. He had previously been on long-term suppressive antibiotic therapy. Aspiration of the knee joint yielded a culture of Lactobacillus species. Conclusion In patients undergoing revision joint arthroplasty, especially for previous infection, the presence of common and uncommon bacterial species must be excluded and eradicated before further surgical intervention.

Abstract Background The recruitment of mononuclear cells has important implications for tissue inflammation. Previous studies demonstrated enhanced CCR1 and CCR5 expression and decreased CCR2 expression during in vitro monocyte to macrophage differentiation. To date, no study examined the in vivo differences in chemokine receptor expression between human peripheral blood monocytes and alveolar macrophages. Methods We examined the expression of these receptors in human peripheral blood monocytes and alveolar macrophages using microarray analysis, reverse-transcriptase PCR, flow cytometry and migration analyses. Results In contrast to peripheral blood monocytes, alveolar macrophages did not express the CCL2 receptor, CCR2, and did not migrate toward CCL2. In contrast, monocytes and freshly isolated resident alveolar macrophages both migrated towards CCL3. However, up to 6-fold more monocytes migrated toward equivalent concentrations of CCL3 than did alveolar macrophages from the same donor. While peripheral blood monocytes expressed the CCL3 receptor, CCR1, alveolar macrophages expressed the alternate CCL3 receptor, CCR5. The addition of anti-CCR5 blocking antibodies completely abrogated CCL3-induced migration in alveolar macrophages, but did not affect the migration of peripheral blood monocytes. Conclusion These data support the specificity of CCL2 to selectively drive monocyte, but not alveolar macrophage recruitment to the lung and CCR5 as the primary macrophage receptor for CCL3.

Abstract Background: Blood monocytes play a central role in regulating host inflammatory processes through chemotaxis, phagocytosis, and cytokine production. However, the molecular details underlying these diverse functions are not completely understood. Understanding the proteomes of blood monocytes will provide new insights into their biological role in health and diseases. Results: In this study, monocytes were isolated from five healthy donors. Whole monocyte lysates from each donor were then analyzed by 2D gel electrophoresis, and proteins were detected using Sypro Ruby fluorescence and then examined for phosphoproteomes using ProQ phospho-protein fluorescence dye. Between 1525 and 1769 protein spots on each 2D gel were matched, analyzed, and quantified. Abundant protein spots were then subjected to analysis by mass spectrometry. This report describes the protein identities of 231 monocyte protein spots, which represent 164 distinct proteins and their respective isoforms or subunits. Some of these proteins had not been previously characterized at the protein level in monocytes. Among the 231 protein spots, 19 proteins revealed distinct modification by protein phosphorylation. Conclusion: The results of this study offer the most detailed monocyte proteomic database to date and provide new perspectives into the study of monocyte biology.

Abstract TGF-β plays an important role in the genesis and progression of pulmonary fibrosis. We sought to determine the role of mononuclear phagocytes in the activation of TGF-β and found that freshly isolated peripheral blood monocytes spontaneously released TGF-β. Stimulating these monocytes with GM-CSF or LPS, but not MCSF, augmented the activation of TGF-β. In human monocytes, the free thiol compounds DTT and NAC decreased the activity of TGF-β, without affecting TGF-β mRNA transcription. Both NAC and DTT lessened the biological activity of recombinant active TGF-β in a cell-free system. We found that NAC and DTT reduced dimeric active TGF-β from a 25 kDa protein to 12.5 kDa inactive monomer. This conversion was reversed using the oxidizing agent diamide. Diamide also restored biological activity to NAC or DTT-treated TGF-β. Reduction of TGF-β to monomers could competitively inhibit active dimeric TGF-β and block intracellular signaling events. Our observations suggest that modulation of the oxidative state of TGF-β may be a novel therapeutic approach for patients with pulmonary fibrosis.

Introduction: Children with ADHD demonstrate difficulties on many different neuropsychological tests. However, it remains unclear whether this pattern reflects a large number of distinct deficits or a small number of deficit(s) that broadly impact test performance. The current study is among the first experiments to systematically manipulate demands on both working memory and inhibition, with implications for competing conceptual models of ADHD pathogenesis., Method: A clinically evaluated, carefully phenotyped sample of 110 children with ADHD, anxiety disorders, or co-occurring ADHD+anxiety ( M age =10.35, 44 girls; 69% White Not Hispanic/Latino) completed a counterbalanced, double dissociation experiment, with two tasks each per inhibition (low vs. high) x working memory (low vs. high) condition., Results: Bayesian and frequentist models converged in indicating that both manipulations successfully increased demands on their target executive function (BF 10 >5.33x10 8 , p <.001). Importantly, occupying children's limited capacity working memory system produced slower response times and reduced accuracy on inhibition tasks (BF 10 >317.42, p <.001, d =0.67-1.53). It also appeared to differentially reduce inhibition (and non-inhibition) accuracy for children with ADHD relative to children with anxiety (BF 10 =2.03, p =.02, d =0.50). In contrast, there was strong evidence against models that view working memory deficits as secondary outcomes of underlying inhibition deficits in ADHD (BF 01 =18.52, p =.85)., Discussion: This pattern indicates that working memory broadly affects children's ability to inhibit prepotent tendencies and maintain fast/accurate performance, and may explain the errors that children with ADHD make on inhibition tests. These findings are broadly consistent with models describing working memory as a causal mechanism that gives rise to secondary impairments. In contrast, these findings provide evidence against models that view disinhibition as a cause of working memory difficulties or view working memory as a non-causal correlate or epiphenomenon in ADHD., Competing Interests: The principal investigator MK holds a patent for neurocognitive interventions that target central executive working memory and inhibitory control. These interventions were not used in the current study. MK discloses travel reimbursement from the American Professional Society for ADHD and Related Disorders APSARD and consulting payments from Sky Therapeutics and Boys Town National Research Hospital in the past 2 years (no prior disclosures). None of the other investigators have potential conflicts to report., (Copyright © 2024 Kofler, Groves, Chan, Marsh, Cole, Gaye, Cibrian, Tatsuki and Singh.)

Growing evidence suggests that childhood ADHD is associated with larger impairments in working memory relative to inhibition. However, most studies have not considered the role of co-occurring anxiety on these estimates - a potentially significant confound given prior evidence that anxiety may increase working memory difficulties but decrease inhibition difficulties for these children. The current study extends prior work to examine the extent to which co-occurring anxiety may be systematically affecting recent estimates of the magnitude of working memory/inhibitory control deficits in ADHD. The carefully-phenotyped sample included 197 children with ADHD and 142 children without ADHD between the ages of 8 and 13 years (N = 339; M age  = 10.31, SD = 1.39; 144 female participants). Results demonstrated that ADHD diagnosis predicted small impairments in inhibitory control (d = 0.31) and large impairments in working memory (d = 0.99). However, child trait anxiety assessed dimensionally across multiple informants (child, parent, teacher) did not uniquely predict either executive function, nor did it moderate estimates of ADHD-related working memory/inhibition deficits. When evaluating anxiety categorically and controlling for ADHD, anxiety diagnosis predicted slightly better working memory (d = 0.19) but not inhibitory control for clinically evaluated children generally. Findings from the current study indicate that trait anxiety, measured dimensionally or categorically, does not differentially affect estimates of executive dysfunction in pediatric ADHD. Further, results suggest that trait anxiety is generally not associated with executive dysfunction above and beyond the impact of co-occurring ADHD. Future research is needed to further assess the role of anxiety in ADHD behavioral symptomatology, neurocognitive functioning, and mechanisms underlying these relations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.63 2.07 2.65 , P < .001), lower DCGF (hazard ratio: 0.36 0.53 0.77 , P = .001), and AR (odds ratio: 0.39 0.54 0.74 , P < .001), and similar DGF (odds ratio: 0.46 1.03 2.33 , P = .9) and LOS (incidence rate ratio: 0.88 0.98 1.10 , P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Two event-related potentials (ERPs) elicited following errors, the error-related negativity (ERN) and error positivity (Pe), have been proposed to reflect cognitive control, though the specific processes remain debated. Few studies have examined the ERN and Pe's relations with individual differences in cognitive control/executive functioning using well-validated tests administered separately from the inhibition tasks used to elicit the ERN/Pe. Additionally, neurocognitive tests of executive functions tend to strongly predict ADHD symptoms, but the extent to which task-based and EEG-based estimates of executive functioning/cognitive control account for the same variance in ADHD symptoms remains unclear. The current study addressed these limitations by examining relations between the ERN/Pe and three core executive functions (working memory, inhibitory control, set shifting) in a clinically-evaluated sample of 53 children ages 8-12 (M age  = 10.36, SD = 1.42; 77.4% White/Non-Hispanic; 16 girls) with and without ADHD. Results demonstrated that neither the ERN nor Pe were related to overall cognitive control/executive functioning, or to working memory or set shifting specifically (all 95%CIs include 0.0). In contrast, a larger Pe was associated with better-developed inhibitory control (β=-.35, 95%CI excludes 0.0), but did not capture aspects of inhibitory control that are important for predicting ADHD symptoms. Neither the ERN nor Pe predicted ADHD symptoms (95%CIs include 0.0). Results were generally robust to control for age, sex, SES, ADHD symptom cluster, and anxiety, and emphasize the need for caution when interpreting the ERN/Pe as indices of broad-based cognitive control/executive functioning, as well as using the ERN/Pe to examine cognitive processes contributing to ADHD symptomatology.

Individuals usually develop a sense of place through lived experiences or travel. Here we introduce new and innovative tools to measure sense of place for remote, far-away locations, such as Greenland. We apply this methodology within place-based education to study whether we can distinguish a sense of place between those who have visited Greenland or are otherwise strongly connected to the place from those who never visited. Place-based education research indicates that an increased sense of place has a positive effect on learning outcomes. Thus, we hypothesize that vicarious experiences with a place result in a measurably stronger sense of place when compared to the sense of place of those who have not experienced the place directly. We studied two distinct groups; the first are people with a strong Greenland connection (experts, n = 93). The second are students who have never been there (novices, n = 142). Using i) emotional value attribution of words, ii) thematic analysis of phrases and iii) categorization of words, we show significant differences between novice's and expert's use of words and phrases to describe Greenland as a proxy of sense of place. Emotional value of words revealed statistically significant differences between experts and novices such as word power (dominance), feeling pleasantness (valence), and degree of arousal evoked by the word. While both groups have an overall positive impression of Greenland, 31% of novices express a neutral view with little to no awareness of Greenland (experts 4% neutral). We found differences between experts and novices along dimensions such as natural features; cultural attributes; people of Greenland; concerns, importance, or interest in and feeling connected to Greenland. Experts exhibit more complex place attributes, frequently using emotional words, while novices present a superficial picture of Greenland. Engaging with virtual environments may shift novice learners to a more expert-like sense of place, for a far-away places like Greenland, thus, we suggest virtual field trips can supplement geoscience teaching of concepts in far-away places like Greenland and beyond., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Understanding factors that promote resilience in pediatric ADHD is important though highly understudied., Aims: The current study sought to provide a preliminary 'shortlist' of key individual, family, and social-community assets among children with ADHD., Methods and Procedures: The study included well-characterized, clinically-evaluated samples of children with (n=108) and without ADHD (n=98) ages 8-13 years (M=10.31; 41.3% girls; 66.5% White/Non-Hispanic). All subsets regression and dominance analysis identified the subset of predictors that accounted for the most variance in broad-based resilience for children with ADHD and their relative importance. Findings were compared for children with versus without ADHD as preliminary evidence regarding the extent to which identified assets are promotive, protective, or conditionally helpful., Outcomes and Results: Higher levels of peer acceptance, social skills, and academic performance were top predictors of resilience among children with ADHD. Better child working memory, attention, higher levels of hyperactivity, older age, and fewer parent self-reported mental health concerns were also identified as predictors of resilience in ADHD. Both overlapping and unique factors were associated with resilience for children with versus without ADHD. Conclusions and Results: These results, if replicated, provide a strong preliminary basis for strength-based basic/applied research on key assets that promote resilience in ADHD., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Children with ADHD show impairments in set shifting task performance. However, the limited available evidence suggests that directly training shifting may not improve shifting performance in this population. We hypothesized that this incongruence may be because impairments exhibited by children with ADHD during shifting tasks are due to deficits in other executive functions, as shifting tasks also engage children's working memory and/or inhibitory control abilities. This randomized controlled trial examined the extent to which neurocognitive training of working memory vs. inhibitory control can produce downstream (far-transfer) improvements in set shifting task performance. Children with ADHD ages 8-12 ( M = 10.41, SD = 1.46; 12 girls; 74% White/Non-Hispanic) were randomized to either central executive training (CET; n = 25) or inhibitory control training (ICT; n = 29), two next-generation digital therapeutics previously shown to improve their intended neurocognitive targets. Two criterion set shifting tests were administered at pre- and post-treatment. Results indicated that ICT was superior to CET for improving shifting accuracy (treatmentxtime: p = .03, BF 10 = 3.01, η 2 = .09, d = 0.63). ICT was also superior to CET for improving shifting speed, albeit on only one of the two outcome tasks ( p = .02, BF 10 = 4.53, η 2 = .08, d = 0.59). CET did not produce improvements in shifting speed or accuracy on either task ( p > .52, BF 01 > 2.62), but showed evidence for more general (non-shifting-specific) improvement in response times on one of the outcome tasks (shift trials, d = 0.70; non-shift trials, d = 0.68). Taken together, these findings confirm that inhibitory control is important for successful performance on shifting tests, and suggest that training inhibitory control may reflect a method for improving set shifting difficulties in children with ADHD.

Steatotic livers represent a potentially underutilized resource to increase the donor graft pool; however, 1 barrier to the increased utilization of such grafts is the heterogeneity in the definition and the measurement of macrovesicular steatosis (MaS). Digital imaging software (DIS) may better standardize definitions to study posttransplant outcomes. Using HALO, a DIS, we analyzed 63 liver biopsies, from 3 transplant centers, transplanted between 2016 and 2018, and compared macrovesicular steatosis percentage (%MaS) as estimated by transplant center, donor hospital, and DIS. We also quantified the relationship between DIS characteristics and posttransplant outcomes using log-linear regression for peak aspartate aminotransferase, peak alanine aminotransferase, and total bilirubin on postoperative day 7, as well as logistic regression for early allograft dysfunction. Transplant centers and donor hospitals overestimated %MaS compared with DIS, with better agreement at lower %MaS and less agreement for higher %MaS. No DIS analyzed liver biopsies were calculated to be >20% %MaS; however, 40% of liver biopsies read by transplant center pathologists were read to be >30%. Percent MaS read by HALO was positively associated with peak aspartate aminotransferase (regression coefficient= 1.04 1.08 1.12 , p <0.001), peak alanine aminotransferase (regression coefficient = 1.04 1.08 1.12 , p <0.001), and early allograft dysfunction (OR= 1.10 1.40 1.78 , p =0.006). There was no association between HALO %MaS and total bilirubin on postoperative day 7 (regression coefficient = 0.99 1.01 1.04 , p =0.3). DIS provides reproducible quantification of steatosis that could standardize MaS definitions and identify phenotypes associated with good clinical outcomes to increase the utilization of steatite livers., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Introduction: Approximately 48-54% of children with attention-deficit/hyperactivity disorder (ADHD) have impairing difficulties with emotion regulation, and these difficulties are not ameliorated by first-line ADHD treatments. Working memory and inhibitory control represent promising intervention targets given their functional, if not causal, links with ADHD-related emotion dysregulation., Methods: This preregistered randomized controlled trial tested whether two digital therapeutic training protocols that have been previously shown to improve working memory (Central Executive Training [CET]) and inhibitory control (Inhibitory Control Training [ICT]) can improve emotion regulation in a sample of 94 children with ADHD aged 8-13 years ( M = 10.22, SD = 1.43; 76% White/non-Hispanic; 29 girls)., Results: Results of Bayesian mixed model ANOVAs indicated both treatment groups demonstrated significant decreases in emotion dysregulation relative to pre-treatment at immediate post-treatment (parent report; d = 1.25, BF 10 = 8.04 × 10 13 , p < 0.001), at 1-2 months after completing treatment (teacher report; d = 0.99, BF 10 = 1.22 × 10 6 , p < 0.001), and at 2-4-months follow-up (parent report; d = 1.22, BF 10 = 1.15 × 10 14 , p < 0.001). Contrary to our hypotheses, the CET and ICT groups demonstrated equivalent reductions in emotion dysregulation and maintenance of effects. Exploratory analyses revealed that results were robust to control for informant expectancies, ADHD medication status/changes, in-person vs. at-home treatment, child age, and time from treatment completion to post-treatment ratings., Discussion: To determine whether working memory and inhibitory control are causally linked with ADHD-related emotion dysregulation, future studies should include active control conditions that do not train executive functions prior to making decisions about the clinical utility of CET/ICT for the treatment of emotion dysregulation in ADHD., Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [NCT03324464]., Competing Interests: The principal investigator MK/Florida State University (FSU) was awarded U.S. Patent 11,210,967 for the Neurocognitive Interventions described in the present study. Central Executive Training was recently licensed to Sky Therapeutics, where MK is in negotiations to serve as Chief Science Officer and consultant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Groves, Chan, Marsh, Gaye, Jaisle and Kofler.)

Delayed graft function (DGF) after kidney transplantation is associated with higher rates of acute rejection and poor graft survival and outcomes. Current DGF definitions based on posttransplant need for dialysis are not standardized and there are no objective methodologies for quantifying DGF severity., Methods: Using Organ Procurement and Transplantation Network data, we examined DGF, and used recipient serum creatinine at discharge as a correlate of renal function and DGF severity (mild: <2.5 mg/dL; severe: ≥2.5 mg/dL). The associations between donor and recipient factors and DGF severity were quantified using logistic regression. We also examined the associations between DGF severity and long-term recipient outcomes, adjusting for potential confounders., Results: A predictive model using donor and recipient factors had a reasonably good ability to discriminate mild (low creatinine) versus severe (high creatinine) DGF (c-statistic of 0.70). In Cox regression, DGF and creatinine at discharge were both independently associated with long-term outcomes, yet their effects differed depending on the outcome (graft function, death-censored graft function, recipient mortality). Our findings suggest that having DGF, but with relatively good renal function (creatinine <2.5) at discharge, may be less deleterious on graft and recipient survival compared with severe, prolonged DGF, which was associated with a decreased median graft survival of ~2.6 y compared with no DGF with low creatinine at discharge., Conclusions: Our novel DGF severity stratification identified unique factors associated with DGF severity, along with DGF's association with long-term graft and patient survival. The adverse cost and outcome implications of severe DGF warrant additional investigation to improve kidney transplantation practice., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Difficulties with emotion regulation affect the majority of youth with attention-deficit/hyperactivity disorder (ADHD) and predict greater functional impairment than ADHD symptoms alone. Deficits in executive functioning are also present for most children with ADHD, and have been linked with emotion regulation difficulties in both clinical and neurotypical populations throughout development. The current study was the first to assess all three core executive functions (working memory, inhibitory control, set shifting) simultaneously in a clinically-diverse sample of children with and without ADHD and common comorbidities and investigate the extent to which they uniquely predict emotion dysregulation. A sample of 151 children ages 8-13 years (M = 10.36, SD = 1.52; 52 girls; 70.2% White/Non-Hispanic) were assessed using a criterion battery of executive functioning tasks, teacher-reported ADHD symptoms, and parent-reported emotion regulation. Results of the bias-corrected, bootstrapped conditional effects path model revealed that better-developed working memory predicted better emotion regulation (β = 0.23) and fewer ADHD symptoms (β = -0.21 to -0.37), that ADHD symptoms (β = -0.18 to -0.20) independently predicted emotion dysregulation, and that working memory exerted indirect effects on emotion regulation through both inattention and hyperactivity/impulsivity (β = 0.04-0.07). Sensitivity analyses indicated that these effects were generally robust to control for age, sex, executive function interrelations, and inclusion/exclusion of children with co-occurring ASD. These findings underscore the importance of working memory (relative to inhibitory control and set shifting) and its relations with ADHD symptoms for understanding children's emotion regulation skills, and may help explain the limited efficacy of first-line ADHD treatments, which do not target working memory, for improving emotion regulation skills., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts., Objective: To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs)., Design, Setting, and Participants: This multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list., Interventions: Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital., Main Outcomes and Measures: The primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft-related severe adverse events within 30 days after transplant., Results: Of 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant., Conclusions and Relevance: This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use., Trial Registration: ClinicalTrials.gov Identifier: NCT02522871.

Objective: The adverse outcomes associated with ADHD are well known, but less is known about the minority of children with ADHD who may be flourishing despite this neurodevelopmental risk. The present multi-informant study is an initial step in this direction with the basic but unanswered question: Are there resilient children with ADHD?, Method: Reliable change analysis of the BASC-3 Resiliency subscale for a clinically evaluated sample of 206 children with and without ADHD (ages 8-13; 81 girls; 66.5% White/Non-Hispanic)., Results: Most children with ADHD are perceived by their parents and teachers as resilient (52.8%-59.2%), with rates that did not differ from the comorbidity-matched Non-ADHD sample., Conclusion: Exploratory analyses highlighted the importance of identifying factors that promote resilience for children with ADHD specifically, such that some child characteristics were promotive (associated with resilience for both groups), some were protective (associated with resilience only for children with ADHD), and some were beneficial only for children without ADHD.

Background and Objectives: Subclinical acute rejection is associated with poor outcomes in kidney transplant recipients. As an alternative to surveillance biopsies, noninvasive screening has been established with a blood gene expression profile. Donor-derived cellfree DNA (cfDNA) has been used to detect rejection in patients with allograft dysfunction but not tested extensively in stable patients. We hypothesized that we could complement noninvasive diagnostic performance for subclinical rejection by combining a donor-derived cfDNA and a gene expression profile assay., Design, Setting, Participants, & Measurements: We performed a post hoc analysis of simultaneous blood gene expression profile and donor-derived cfDNA assays in 428 samples paired with surveillance biopsies from 208 subjects enrolled in an observational clinical trial (Clinical Trials in Organ Transplantation-08). Assay results were analyzed as binary variables, and then, their continuous scores were combined using logistic regression. The performance of each assay alone and in combination was compared., Results: For diagnosing subclinical rejection, the gene expression profile demonstrated a negative predictive value of 82%, a positive predictive value of 47%, a balanced accuracy of 64%, and an area under the receiver operating curve of 0.75. The donor-derived cfDNA assay showed similar negative predictive value (84%), positive predictive value (56%), balanced accuracy (68%), and area under the receiver operating curve (0.72). When both assays were negative, negative predictive value increased to 88%. When both assays were positive, positive predictive value increased to 81%. Combining assays using multivariable logistic regression, area under the receiver operating curve was 0.81, significantly higher than the gene expression profile ( P <0.001) or donor-derived cfDNA alone ( P =0.006). Notably, when cases were separated on the basis of rejection type, the gene expression profile was significantly better at detecting cellular rejection (area under the receiver operating curve, 0.80 versus 0.62; P =0.001), whereas the donor-derived cfDNA was significantly better at detecting antibody-mediated rejection (area under the receiver operating curve, 0.84 versus 0.71; P =0.003)., Conclusions: A combination of blood-based biomarkers can improve detection and provide less invasive monitoring for subclinical rejection. In this study, the gene expression profile detected more cellular rejection, whereas donor-derived cfDNA detected more antibody-mediated rejection., (Copyright © 2021 by the American Society of Nephrology.)

Yttrium-90 (Y-90) radioembolization for the treatment of hepatocellular carcinoma can present safety challenges when transplanting recently treated Y-90 patients. To reduce surgeons' contact with radioactive tissue and remain within occupational dose limits, current guidelines recommend delaying transplants at least 14 days, if possible. We wanted to determine the level of radiation exposure to the transplant surgeon when explanting an irradiated liver before the recommended decay period. An ex-vivo radiation exposure analysis was conducted on the explanted liver of a patient who received Y-90 therapy 46 h prior to orthotopic liver transplant. To estimate exposure to the surgeon's hands, radiation dosimeter rings were placed inside three different surgical glove configurations and exposed to the explanted liver. Estimated radiation doses corrected for Y-90 decay were calculated. Radiation safety gloves performed best, with an average radiation exposure rate of 5.36 mSV h -1 in the static hand position, an 83% reduction in exposure over controls with no glove (31.31 mSv h -1 ). Interestingly, non-radiation safety gloves also demonstrated reduced exposure rates, well below occupational regulation limits. Handling of Y-90 radiated organs within the immediate post-treatment period can be done safely and does not exceed federal occupational dose limits if appropriate gloves and necessary precautions are exercised., (© 2021 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Background: Focal segmental glomerulosclerosis (FSGS) is a common recurrent glomerulopathy associated with graft loss and patient survival after kidney transplantation (KT). However, its natural history, clinical predictors, and treatment response are still poorly understood. Steroid withdrawal regimens in KT have been associated with improvements in cardiovascular risk and patient outcomes. The Scripps Center for Organ Transplantation (SCOT) uses a rapid low-dose steroid withdrawal immunosuppression (IS) protocol for KT maintenance., Methods: We assessed the impact of our protocol on FSGS disease recurrence over a 10-y period to reassess our steroid and IS protocols and to evaluate if our patient outcomes diverge from published data. We compared 4 groups: steroids always, steroid free, steroid switch on, and steroid weaned off. We used IS and induction-matched retrospective data from United Network for Organ Sharing (UNOS) to investigate patient and graft survival for FSGS at SCOT., Results: Our analysis results differ from earlier studies showing that FSGS was associated with a higher risk of graft loss, perhaps because of selection of a UNOS data set filtered to match the SCOT IS protocol for making direct comparisons. Overall outcomes of graft failure and recipient death did not differ between SCOT patients and steroid-free transplant patient data from the UNOS data for FSGS. SCOT recurrence rate for FSGS was 7.5%, which was lower than in most published single-center studies., Conclusions: Based on our results, we believe that it is safe to continue the steroid avoidance protocols at SCOT and the steroid-free protocol may not be detrimental when the adverse effects and toxicities associated with steroid use are considered., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Irritability is an impairing problem in children with ASD that may be associated with other behavioral and emotional concerns. The Affective Reactivity Index (ARI) is a parent-rated measure of irritability widely used in children with mood disorders, however, its utility in children with ASD remains unclear. In this study, we examined ARI parent ratings in children with ASD and contributions of parent-rated anxiety and noncompliance to irritability measured by the ARI. Participants included 81 children with ASD, aged 8-16 years. Results suggest that both anxiety and noncompliance contribute to irritability, but that anxiety only contributes to irritability in the absence of noncompliance. Further, the ARI is likely to be a useful measure of irritability in children with ASD.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR =  1.03 1.68 2.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF =  1.45 2.09 3.02 ; PFNC =  1.67 2.40 3.46 ; PCC =  1.48 2.24 3.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR =  1.34 1.62 1.95 ) than CLDKT (aHR =  1.96 2.29 2.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Although interest in the role of donor-specific antibodies (DSAs) in kidney transplant rejection, graft survival, and histopathological outcomes is increasing, their impact on steroid avoidance or minimization in renal transplant populations is poorly understood. Primary outcomes of graft survival, rejection, and histopathological findings were assessed in 188 patients who received transplants between 2012 and 2015 at the Scripps Center for Organ Transplantation, which follows a steroid avoidance protocol. Analyses were performed using data from the United Network for Organ Sharing. Cohorts included kidney transplant recipients with de novo DSAs (dnDSAs; n = 27), preformed DSAs (pfDSAs; n = 15), and no DSAs (nDSAs; n = 146). Median time to dnDSA development (classes I and II) was shorter (102 days) than in previous studies. Rejection of any type was associated with DSAs to class I HLA (P < .05) and class II HLA (P < .01) but not with graft loss. Although mean fluorescence intensity (MFI) independently showed no association with rejection, an MFI >5000 showed a trend toward more antibody-mediated rejection (P < .06), though graft loss was not independently associated. Banff chronic allograft nephropathy scores and a modified chronic injury score were increased in the dnDSA cohort at 6 months, but not at 2 years (P < .001 and P < .08, respectively). Our data suggest that dnDSAs and pfDSAs impact short-term rejection rates but do not negatively impact graft survival or histopathological outcomes at 2 years. Periodic protocol post-transplant DSA monitoring may preemptively identify patients who develop dnDSAs who are at a higher risk for rejection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Transplant candidates can be listed at multiple transplant centers to increase the probability of receiving an organ. We evaluated the association between multilisting (ML) status and access to a deceased donor kidney transplant (DDKT) to determine if ML provides a long-term advantage regarding wait-list mortality and recipient outcomes., Materials and Methods: Candidates between January 2010 and October 2017 were identified as either singly or multiply listed using Organ Procurement and Transplantation Network data and cohorts before and after implementation of the Kidney Allocation System (KAS). Cross-sectional logistic regression was used to assess relationships between candidate factors and ML prevalence (5.4%)., Results: Factors associated with ML pre-KAS included having blood type B (reference, type O; odds ratio [OR], 1.20; P < .001), having private insurance (OR, 1.5; P < .001), wait time (OR, 1.28; P < .001), and increasing calculated panel-reactive antibody (cPRA) (reference, cPRA 0-100; OR for cPRA 80-98, 2.83; OR for cPRA 99, 3.47; OR for cPRA 100, 5.18; P < .001). Transplant rates were double for multilisted vs singly listed recipients (adjusted hazard ratio [aHR], 2.16; P < .001). Extra-donor service area ML candidates received transplants 2.5 years quicker than single-listing (SL) candidates, conferring a 42% wait-list advantage. Recipient death (aHR, 0.94; P = .122) and graft failure (aHR, 0.91; P = .006) rates were also lower for ML recipients., Conclusions: In the KAS era, ML continues to increase the likelihood of receiving a DDKT and lower the incidence of wait-list mortality, and it confers a survival advantages over SL., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose of Review: Organ transplantation research has led to the discovery of several interesting individual mechanistic pathways, molecules and potential drug targets but there are still no comprehensive studies that have addressed how these varied mechanisms work in unison to regulate the posttransplant immune response that drives kidney rejection and dysfunction., Recent Findings: Systems biology is a rapidly expanding field that aims to integrate existing knowledge of molecular concepts and large-scale genomic and clinical datasets into networks that can be used in cutting edge computational models to define disease mechanisms in a holistic manner. Systems biology approaches have brought a paradigm shift from a reductionist view of biology to a wider agnostic assessment of disease from several lines of evidence. Although the complex nature of the posttransplant immune response makes it difficult to pinpoint mechanisms, systems biology is enabling discovery of unknown biological interactions using the cumulative power of genomic data sets, clinical data and endpoints, and improved computational methods for the systematic deconvolution of this response., Summary: An integrative systems biology approach that leverages genomic data from varied technologies, such as DNA sequencing, copy number variation, RNA sequencing, and methylation profiles along with long-term clinical follow-up data has the potential to define a framework that can be mined to provide novel insights for developing therapeutic interventions in organ transplantation., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown., Methods: We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes., Results: After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates., Conclusions: Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors declare no funding or conflicts of interest.

The human microbiome encompasses a variety of microorganisms that change dynamically and are in close contact with the body. The microbiome influences health and homeostasis, as well as the immune system, and any significant change in this equilibrium (dysbiosis) triggers both acute and chronic health conditions. Microbiome research has surged, in part, due to advanced sequencing technologies enabling rapid, accurate, and cost-effective identification of the microbiome. A major prerequisite for stool sample collection to study the gut microbiome in longitudinal prospective studies requires standardized protocols that can be easily replicated. However, there are still significant bottlenecks to stool specimen collection that contribute to low patient retention rates in microbiome studies. These barriers are further exacerbated in solid organ transplant recipients where diarrhea is estimated to occur in up to half the patient population. We sought to test two relatively easy sample collection methods (fecal swab and wipes) and compare them to the more cumbersome "gold" standard collection method (scoop) using two different sequencing technologies (16S ribosomal RNA sequencing and shotgun metagenomics). Our comparison of the collection methods shows that both the swabs and the wipes are comparable to the scoop method in terms of bacterial abundance and diversity. The swabs, however, were closer in representation to the scoop and were easier to collect and process compared to the wipes. Potential contamination of the swab and the wipe samples by abundant skin commensals was low in our analysis. Comparison of the two sequencing technologies showed that they were complementary, and that 16S sequencing provided enough coverage to detect and differentiate between bacterial species identified in the collected samples. Our pilot study demonstrates that alternative collection methods for stool sampling are a viable option in clinical applications, such as organ transplant studies. The use of these methods may result in better patient retention recruitment rates in serial microbiome studies.

Co-occurring anxiety is common in children with autism spectrum disorder (ASD). However, inconsistencies across parent and child reports of anxiety may complicate the assessment of anxiety in this population. The present study examined parent and child anxiety ratings in children with ASD with and without anxiety disorders and tested the association between parent-child anxiety rating discrepancy and ASD symptom severity. Participants included children aged 8-16 years in three diagnostic groups: ASD with co-occurring anxiety disorders (ASD + Anxiety; n = 34), ASD without co-occurring anxiety disorders (ASD; n = 18), and typically developing healthy controls (TD; n = 50). Parents and children completed ratings of child anxiety using the Multidimensional Anxiety Rating Scale. Patterns of parent and child anxiety ratings differed among the three groups, with parent ratings exceeding child ratings only in the ASD + Anxiety group. Parents reported higher levels of child anxiety in the ASD + Anxiety versus ASD group, whereas children reported comparable levels of anxiety in the two groups. Among children with ASD, ASD symptom severity was positively associated with the degree to which parent ratings exceeded child ratings. Results suggest that children with ASD and co-occurring anxiety disorders endorse some anxiety symptoms but may underreport overall levels of anxiety. In addition, ASD symptom severity might increase discrepancies in parent-child anxiety ratings. These findings suggest a unique and valuable role of child anxiety ratings and suggest that both parent and child anxiety ratings should be considered in light of children's ASD symptom severity and used to guide further assessment. Autism Res 2020, 13: 93-103. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Children with autism spectrum disorder (ASD) commonly experience anxiety; yet, their perceptions of their anxiety might differ from their parents' perceptions. This study found that, while children with ASD and anxiety disorders acknowledge some anxiety, their parents report them as having higher levels of anxiety. Also, child and parent perceptions of anxiety may differ more for children with more severe ASD symptoms. How these findings may guide research and clinical practice is discussed., (© 2019 International Society for Autism Research, Wiley Periodicals, Inc.)

Children with autism spectrum disorder (ASD) are reported to have greater levels of anger rumination than typically developing children. This study examined anger rumination in children with ASD in comparison to children with disruptive behavior disorder without ASD. We also tested if anger rumination is associated with aggression and the core ASD symptoms of restricted and repetitive behaviors (RRBs). This study included three groups of children aged 8-16 years: 63 had ASD (ASD group), 79 had disruptive behavior disorder (DB group), and 40 healthy controls (HC). ASD and DB groups showed greater anger rumination relative to the HC group. Anger rumination was associated with RRBs in children with ASD, suggesting the link to core ASD symptoms.

TruGraf v1 is a laboratory-developed DNA microarray-based gene expression blood test to enable proactive noninvasive serial assessment of kidney transplant recipients with stable renal function. It has been previously validated in patients identified as Transplant eXcellence (TX: stable serum creatinine, normal biopsy results, indicative of immune quiescence), and not-TX (renal dysfunction and/or rejection on biopsy results). TruGraf v1 is intended for use in subjects with stable renal function to measure the immune status as an alternative to invasive, expensive, and risky surveillance biopsies., Materials and Methods: In this study, simultaneous blood tests and clinical assessments were performed in 192 patients from 7 transplant centers to evaluate TruGraf v1. The molecular testing laboratory was blinded to renal function and biopsy results., Results: Overall, TruGraf v1 accuracy (concordance between TruGraf v1 result and clinical and/or histologic assessment) was 74% (142/192), and a result of TX was accurate in 116 of 125 (93%). The negative predictive value for TruGraf v1 was 90%, with a sensitivity 74% and specificity of 73%. Results did not significantly differ in patients with a biopsy-confirmed diagnosis vs those without a biopsy., Conclusions: TruGraf v1 can potentially support a clinical decision enabling unnecessary surveillance biopsies with high confidence, making it an invaluable addition to the transplant physician's tool kit for managing patients. TruGraf v1 testing can potentially avoid painful and risky invasive biopsies, reduce health care costs, and enable frequent assessment of patients with stable renal function to confirm the presence of immune quiescence in the peripheral blood., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: TruGraf v1 is a well-validated DNA microarray-based test that analyzes blood gene expression profiles as an indicator of immune status in kidney transplant recipients with stable renal function., Methods: In this study, investigators assessed clinical utility of the TruGraf test in patient management. In a retrospective study, simultaneous blood tests and clinical assessments were performed in 192 patients at 7 transplant centers, and in a prospective observational study they were performed in 45 subjects at 5 transplant centers., Results: When queried regarding whether or not the TruGraf test result impacted their decision regarding patient management, in 168 of 192 (87.5%) cases the investigator responded affirmatively. The prospective study indicated that TruGraf results supported physicians' decisions on patient management 87% (39/45) of the time, and in 93% of cases physicians indicated that they would use serial TruGraf testing in future patient management. A total of 21 of 39 (54%) reported results confirmed their decision that no intervention was needed, and 17 of 39 (44%) reported that results specifically informed them that a decision not to perform a surveillance biopsy was correct., Conclusions: TruGraf is the first and only noninvasive test to be evaluated for clinical utility in determining rejection status of patients with stable renal function and shows promise of providing support for clinical decisions to avoid unnecessary surveillance biopsies with a high degree of confidence. TruGraf is an invaluable addition to the transplant physician's tool kit for managing patient health by avoiding painful and invasive biopsies, reducing health care costs, and enabling frequent assessment of patients with stable renal function to confirm immune quiescence., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Thirty percent of kidney transplant recipients are readmitted in the first month posttransplantation. Those with donor-specific antibody requiring desensitization and incompatible live donor kidney transplantation (ILDKT) constitute a unique subpopulation that might be at higher readmission risk. Drawing on a 22-center cohort, 379 ILDKTs with Medicare primary insurance were matched to compatible transplant-matched controls and to waitlist-only matched controls on panel reactive antibody, age, blood group, renal replacement time, prior kidney transplantation, race, gender, diabetes, and transplant date/waitlisting date. Readmission risk was determined using multilevel, mixed-effects Poisson regression. In the first month, ILDKTs had a 1.28-fold higher readmission risk than compatible controls (95% confidence interval [CI] 1.13-1.46; P < .001). Risk peaked at 6-12 months (relative risk [RR] 1.67, 95% CI 1.49-1.87; P < .001), attenuating by 24-36 months (RR 1.24, 95% CI 1.10-1.40; P < .001). ILDKTs had a 5.86-fold higher readmission risk (95% CI 4.96-6.92; P < .001) in the first month compared to waitlist-only controls. At 12-24 (RR 0.85, 95% CI 0.77-0.95; P = .002) and 24-36 months (RR 0.74, 95% CI 0.66-0.84; P < .001), ILDKTs had a lower risk than waitlist-only controls. These findings of ILDKTs having a higher readmission risk than compatible controls, but a lower readmission risk after the first year than waitlist-only controls should be considered in regulatory/payment schemas and planning clinical care., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Global Kidney Exchange (GKE) offers an opportunity to expand living renal transplantation internationally to patients without financial means. These international pairs are entered into a US kidney exchange program that provides long-term financial support in an effort to identify opportunities for suitable exchanges for both these international pairs and US citizens., Objective: While the promise of GKE is significant, it has been met with ethical criticism since its inception in 2015. This paper aims to demonstrate the selection process and provide >3 yr of follow-up on the first GKE donor and recipient from the Philippines., Design, Setting, and Participants: The first GKE transplant occurred with a young Filipino husband and wife who were immunologically compatible, but lacked the financial means to continue hemodialysis or undergo a kidney transplant in their home country. The pair was enrolled in the Alliance for Paired Donation matching system, several alternative kidney exchanges were identified, and the pair subsequently underwent renal transplantation and donation in the USA financed by philanthropy. The resulting nonsimultaneous extended altruistic chain provided transplantation for the Filipino husband and 11 US patients., Outcome Measurements and Statistical Analysis: The Filipino donor and recipient were followed by transplant professionals in both the Philippines and the USA. Follow-up data were maintained as required by the Organ Procurement and Transplantation Network in the USA., Results and Limitations: The Filipino donor has normal blood pressure and renal function, and the Filipino recipient is doing well 3.5 yr after their donation and transplantation., Conclusions: While criticisms of GKE highlight concerns for possible exploitation of financially disadvantaged groups, these results demonstrate that these concerns did not come to fruition, and the outcome experienced by the GKE donor and recipient (and other US participants) was successful., Patient Summary: The first Filipino Global Kidney Exchange (GKE) donor-recipient pair continues to be followed by both US and Filipino transplant centers. Both are in good health, support the GKE program, and advocate for its expansion., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Incompatible living donor kidney transplantation (ILDKT) has been established as an effective option for end-stage renal disease patients with willing but HLA-incompatible living donors, reducing mortality and improving quality of life. Depending on antibody titer, ILDKT can require highly resource-intensive procedures, including intravenous immunoglobulin, plasma exchange, and/or cell-depleting antibody treatment, as well as protocol biopsies and donor-specific antibody testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT (n = 926) with varying antibody titers to matched compatible transplants (n = 2762) performed between 2002 and 2011. Data were assembled from a national cohort study of ILDKT and a unique data set linking hospital cost accounting data and Medicare claims. ILDKT was more expensive than matched compatible transplantation, ranging from 20% higher adjusted costs for positive on Luminex assay but negative flow cytometric crossmatch, 26% higher for positive flow cytometric crossmatch but negative cytotoxic crossmatch, and 39% higher for positive cytotoxic crossmatch (p < 0.0001 for all). ILDKT was associated with longer median length of stay (12.9 vs. 7.8 days), higher Medicare payments ($91 330 vs. $63 782 p < 0.0001), and greater outlier payments. In conclusion, ILDKT increases the cost of and payments for kidney transplantation., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Transplantation of liver grafts from donation after cardiac death (DCD) is limited. To identify barriers of DCD liver utilization, all active US liver transplant centers (n = 138) were surveyed, and the responses were compared with the United Network for Organ Sharing (UNOS) data. In total, 74 (54%) centers responded, and diversity in attitudes was observed, with many not using organ and/or recipient prognostic variables defined in prior studies and UNOS data analysis. Most centers (74%) believed lack of a system allowing a timely retransplant is a barrier to utilization. UNOS data demonstrated worse 1- and 5-year patient survival (PS) and graft survival (GS) in DCD (PS, 86% and 64%; GS, 82% and 59%, respectively) versus donation after brain death (DBD) recipients (PS, 90% and 71%; GS, 88% and 69%, respectively). Donor alanine aminotransferase (ALT), recipient Model for End-Stage Liver Disease (MELD), and cold ischemia time (CIT) significantly impacted DCD outcomes to a greater extent than DBD outcomes. At 3 years, relisting and retransplant rates were 7.9% and 4.6% higher in DCD recipients. To optimize outcome, our data support the use of DCD liver grafts with CIT <6-8 hours in patients with MELD ≤ 20. In conclusion, standardization of donor and recipient criteria, defining the impact of ischemic cholangiopathy, addressing donor hospital policies, and developing a strategy for timely retransplant may help to expand the use of these organs. Liver Transplantation 23 1372-1383 2017 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

Organ shortage is the major limitation to kidney transplantation in the developed world. Conversely, millions of patients in the developing world with end-stage renal disease die because they cannot afford renal replacement therapy-even when willing living kidney donors exist. This juxtaposition between countries with funds but no available kidneys and those with available kidneys but no funds prompts us to propose an exchange program using each nation's unique assets. Our proposal leverages the cost savings achieved through earlier transplantation over dialysis to fund the cost of kidney exchange between developed-world patient-donor pairs with immunological barriers and developing-world patient-donor pairs with financial barriers. By making developed-world health care available to impoverished patients in the developing world, we replace unethical transplant tourism with global kidney exchange-a modality equally benefitting rich and poor. We report the 1-year experience of an initial Filipino pair, whose recipient was transplanted in the United states with an American donor's kidney at no cost to him. The Filipino donor donated to an American in the United States through a kidney exchange chain. Follow-up care and medications in the Philippines were supported by funds from the United States. We show that the logistical obstacles in this approach, although considerable, are surmountable., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

This article is a review of the salient points and a future prospective based on the 2014 Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) liver donation and transplantation data report recently published by the American Journal of Transplantation. Emphasis of our commentary and interpretation is placed on data relating to waitlist dynamics, organ utilization rates, the impact of recent advances in the treatment of hepatitis C, and the increases in end-stage renal disease among liver transplant candidates. Finally, we share our vision on potential areas of innovation that are likely to significantly improve the field of liver transplantation in the near future., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual&#95;reports/current/509a&#95;ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear., Methods: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study., Results: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded., Conclusions: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Background: While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival remains poor. Immunotherapy may improve outcomes, especially as adjuvant to local therapies. Gene-mediated cytotoxic immunotherapy (GMCI) generates a systemic anti-tumor response through local delivery of an adenoviral vector expressing the HSV-tk gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug. GMCI has demonstrated synergy with standard of care (SOC) in other tumor types. This is the first application in pancreatic cancer., Methods: Four dose levels (3 × 10(10) to 1 × 10(12) vector particles) were evaluated as adjuvant to surgery for resectable disease (Arm A) or to 5-FU chemoradiation for locally advanced disease (Arm B). Each patient received two cycles of AdV-tk + prodrug., Results: Twenty-four patients completed therapy, 12 per arm, with no dose-limiting toxicities. All Arm A patients were explored, eight were resected, one was locally advanced and three had distant metastases. CD8(+) T cell infiltration increased an average of 22-fold (range sixfold to 75-fold) compared with baseline (p = 0.0021). PD-L1 expression increased in 5/7 samples analyzed. One node-positive resected patient is alive >66 months without recurrence. Arm B RECIST response rate was 25 % with a median OS of 12 months and 1-year survival of 50 %. Patient-reported quality of life showed no evidence of deterioration., Conclusions: AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer.

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15-2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71-6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28-3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98-7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

There are no minimally invasive diagnostic metrics for acute kidney transplant rejection (AR), especially in the setting of the common confounding diagnosis, acute dysfunction with no rejection (ADNR). Thus, though kidney transplant biopsies remain the gold standard, they are invasive, have substantial risks, sampling error issues and significant costs and are not suitable for serial monitoring. Global gene expression profiles of 148 peripheral blood samples from transplant patients with excellent function and normal histology (TX; n = 46), AR (n = 63) and ADNR (n = 39), from two independent cohorts were analyzed with DNA microarrays. We applied a new normalization tool, frozen robust multi-array analysis, particularly suitable for clinical diagnostics, multiple prediction tools to discover, refine and validate robust molecular classifiers and we tested a novel one-by-one analysis strategy to model the real clinical application of this test. Multiple three-way classifier tools identified 200 highest value probesets with sensitivity, specificity, positive predictive value, negative predictive value and area under the curve for the validation cohort ranging from 82% to 100%, 76% to 95%, 76% to 95%, 79% to 100%, 84% to 100% and 0.817 to 0.968, respectively. We conclude that peripheral blood gene expression profiling can be used as a minimally invasive tool to accurately reveal TX, AR and ADNR in the setting of acute kidney transplant dysfunction., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Solid organ transplantation is encumbered by an increasing number of waitlisted patients unrequited by the current organ supply. Preclinical models suggest that advances in deceased donor management and treatment can increase the quantity and quality of organs available for transplantation. However, the science of donor intervention and the execution of high quality, prospective, multi-center, randomized-controlled trials are restricted by a myriad of logistical challenges mired in regulatory and ethical ambiguity. By highlighting the obstacles to conducting research in deceased donors, this report endeavors to stimulate the creation of a multi-disciplinary framework to facilitate the design, implementation and supervision of innovative trials that increase the quantity and/or quality of deceased donor organs., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The most common cause of kidney transplant failure is the poorly characterized histopathologic entity interstitial fibrosis and tubular atrophy (IFTA). There are no known unifying mechanisms, no effective therapy, and no proven preventive strategies. Possible mechanisms include chronic immune rejection, inflammation, drug toxicity, and chronic kidney injury from secondary factors. To gain further mechanistic insight, we conducted a large-scale proteogenomic study of kidney transplant biopsies with IFTA of varying severity. We acquired proteomic data using tandem mass spectrometry with subsequent quantification, analysis of differential protein expression, validation, and functional annotations to known molecular networks. We performed genome-wide expression profiling in parallel. More than 1400 proteins with unique expression profiles traced the progression from normal transplant biopsies to biopsies with mild to moderate and severe disease. Multiple sets of proteins were mapped to different functional pathways, many increasing with histologic severity, including immune responses, inflammatory cell activation, and apoptosis consistent with the chronic rejection hypothesis. Two examples include the extensive population of the alternative rather than the classical complement pathway, previously not appreciated for IFTA, and a comprehensive control network for the actin cytoskeleton and cell signaling of the acute-phase response. In summary, this proteomic effort using kidney tissue contributes mechanistic insight into several biologic processes associated with IFTA.