Impact of belatacept and tacrolimus on cytomegalovirus viral load control and relapse in moderate and high-risk cytomegalovirus serostatus kidney transplant recipients.

BACKGROUND: Belatacept improves long-term graft survival, but control of some primary viral infections may be impaired. We evaluated the impact of belatacept and tacrolimus on cytomegalovirus (CMV) viral control, remission and relapse in CMV high-risk and moderate-risk recipients. METHODS: Using a multistate Markov model, we evaluated viral load state transitions of 173 kidney transplant recipients with at least one episode of viremia within 1 year after transplant: state 1, undetectable/low viral load; state 2, moderate viremia; and state 3, severe viremia. RESULTS: Among high-risk recipients, belatacept-treated recipients exhibited a significantly higher probability of entering moderate viremia (.36; 95% CI = .31, .41) than tacrolimus-treated recipients (.20; 95% CI = .13, .29). The expected number of days in viremic states differed. High-risk belatacept-treated recipients persisted in moderate viremia for significantly longer (128 days, 95% CI = 110, 146) than did tacrolimus-treated recipients (70.0 days, 95% CI = 45.2, 100) and showed a trend of shorter duration in low/undetectable viral load state (172 days, 95% CI = 148, 195) than did tacrolimus-treated recipients (239 days, 95% CI = 195, 277). Moderate-risk recipients showed better viral load control and with no differences by immunosuppression. CONCLUSION: High-risk belatacept-treated recipients showed defects in sustaining viral control relative to tacrolimus-treated recipients. Avoidance of initial use belatacept in high-risk recipients or development of modified management protocols should be considered.

Longitudinal Evaluation of Cytopenias in the Renal Transplant Population.

Cytopenias, a common complication for immunosuppressed patients, are known to be associated with adverse transplant outcomes. However, there is little information on cytopenias in recipients treated with the costimulation blockade agent, belatacept. Methods: We compared cytopenia incidence and manifestations in patients undergoing kidney transplant at Emory University Hospital on tacrolimus and belatacept. To reduce selection bias, the tacrolimus group was narrowed to include only patients eligible for belatacept. Results: Of 1651 patients transplanted between 2009 and 2019, 187 (11%) experienced severe anemia, 309 (19%) experienced leukopenia, and 62 (4%) thrombocytopenia. On multivariable regressions, deceased-donor transplant, cytomegalovirus viremia, and thymoglobulin treatment were associated with risk of developing leukopenia, anemia, and thrombocytopenia. High-risk cytomegalovirus status was also associated with development of leukopenia and anemia. Additionally, azathioprine was associated with development of anemia, and both tacrolimus therapy and Caucasian race were associated with thrombocytopenia. Longitudinal quantifications of hematologic cell lines over the first-year posttransplant were extracted from generalized linear models fit using splines. Only hemoglobin range was significantly different between groups (greater in belatacept patients). Plots of mean cell count for each group suggest an earlier recovery from posttransplant anemia in belatacept patients. Conclusions: Belatacept patients are not at increased risk of cytopenia but may have improved recovery from posttransplant anemia.

CMV high-risk status and posttransplant outcomes in kidney transplant recipients treated with belatacept.

INTRODUCTION: Cytomegalovirus (CMV) remains associated with poor outcomes after kidney transplantation (kTx). The impact of belatacept on CMV infection remains understudied. In this study, we assessed the impact of belatacept on patient and graft survivals. METHODS: CMV seronegative kTx recipients were included. Patient and graft survival were studied using Kaplan-Meier method, log-rank test. Cox models were used to compare outcomes by CMV risk and immunosuppressive regimen. Incidence and persistence of CMV viremia under belatacept vs tacrolimus were compared. RESULTS: Among 308 CMV seronegative recipients, 168 CMV high-risk and 203 belatacept-treated patients were included. High-risk CMV status was associated with lower patient survival and graft survival. Among the CMV high-risk group, patients treated with belatacept presented a higher incidence of CMV viremia, a higher rate of first-line treatment failure and a longer time to virus clearance. They had a nonsignificant trend toward a lower graft survival. CONCLUSION: Belatacept-based maintenance immunosuppression is associated with an increased risk of CMV primary-infection and a prolonged course of viral replication in CMV high-risk patients. Further studies are needed to confirm the nonsignificant trend towards a lower graft survival in CMV high-risk patients treated with belatacept and whether it is explained by the higher risk of CMV reactivation and infection.

Effect of the ASCENT Intervention to Increase Knowledge of Kidney Allocation Policy Changes Among Dialysis Providers.

INTRODUCTION: The Allocation System Changes for Equity in Kidney Transplantation (ASCENT) trial was a cluster-randomized pragmatic, effectiveness-implementation study designed to test whether a multicomponent educational intervention targeting leadership, clinic staff, and patients in dialysis facilities improved knowledge and awareness of the 2014 Kidney Allocation System (KAS) change. METHODS: Participants included 690 dialysis facility medical directors, nephrologists, social workers, and other staff within 655 US dialysis facilities, with 51% (n = 334) in the intervention group and 49% (n = 321) in the control group. Intervention activities included a webinar targeting medical directors and facility staff, an approximately 10-minute educational video targeting dialysis staff, an approximately 10-minute educational video targeting patients, and a facility-specific audit and feedback report of transplant performance. The control group received a standard United Network for Organ Sharing brochure. Provider knowledge was a secondary outcome of the ASCENT trial and the primary outcome of this study; knowledge was assessed as a cumulative score on a 5-point Likert scale (higher score = greater knowledge). Intention-to-treat analysis was used. RESULTS: At baseline, nonintervention providers had a higher mean knowledge score (mean ± SD, 2.45 ± 1.43) than intervention providers (mean ± SD, 2.31 ± 1.46). After 3 months, the average knowledge score was slightly higher in the intervention (mean ± SD, 3.14 ± 1.28) versus nonintervention providers (mean ± SD, 3.07 ± 1.24), and the estimated mean difference in knowledge scores between the groups at follow-up minus the mean difference at baseline was 0.25 (95% confidence interval [CI], 0.11-0.48; P = 0.039). The effect size (0.41) was low to moderate. CONCLUSION: Dialysis facility provider education could help extend the impact of a national policy change in organ allocation.

Are Female Applicants Disadvantaged in National Institutes of Health Peer Review? Combining Algorithmic Text Mining and Qualitative Methods to Detect Evaluative Differences in R01 Reviewers' Critiques.

BACKGROUND: Women are less successful than men in renewing R01 grants from the National Institutes of Health. Continuing to probe text mining as a tool to identify gender bias in peer review, we used algorithmic text mining and qualitative analysis to examine a sample of critiques from men's and women's R01 renewal applications previously analyzed by counting and comparing word categories. METHODS: We analyzed 241 critiques from 79 Summary Statements for 51 R01 renewals awarded to 45 investigators (64% male, 89% white, 80% PhD) at the University of Wisconsin-Madison between 2010 and 2014. We used latent Dirichlet allocation to discover evaluative "topics" (i.e., words that co-occur with high probability). We then qualitatively examined the context in which evaluative words occurred for male and female investigators. We also examined sex differences in assigned scores controlling for investigator productivity. RESULTS: Text analysis results showed that male investigators were described as "leaders" and "pioneers" in their "fields," with "highly innovative" and "highly significant research." By comparison, female investigators were characterized as having "expertise" and working in "excellent" environments. Applications from men received significantly better priority, approach, and significance scores, which could not be accounted for by differences in productivity. CONCLUSIONS: Results confirm our previous analyses suggesting that gender stereotypes operate in R01 grant peer review. Reviewers may more easily view male than female investigators as scientific leaders with significant and innovative research, and score their applications more competitively. Such implicit bias may contribute to sex differences in award rates for R01 renewals.

Analysis of National Institutes of Health R01 Application Critiques, Impact, and Criteria Scores: Does the Sex of the Principal Investigator Make a Difference?

PURPOSE: Prior text analysis of R01 critiques suggested that female applicants may be disadvantaged in National Institutes of Health (NIH) peer review, particularly for renewals. NIH altered its review format in 2009. The authors examined R01 critiques and scoring in the new format for differences due to principal investigator (PI) sex. METHOD: The authors analyzed 739 critiques-268 from 88 unfunded and 471 from 153 funded applications for grants awarded to 125 PIs (76 males, 49 females) at the University of Wisconsin-Madison between 2010 and 2014. The authors used seven word categories for text analysis: ability, achievement, agentic, negative evaluation, positive evaluation, research, and standout adjectives. The authors used regression models to compare priority and criteria scores, and results from text analysis for differences due to PI sex and whether the application was for a new (Type 1) or renewal (Type 2) R01. RESULTS: Approach scores predicted priority scores for all PIs' applications (P < .001), but scores and critiques differed significantly for male and female PIs' Type 2 applications. Reviewers assigned significantly worse priority, approach, and significance scores to female than male PIs' Type 2 applications, despite using standout adjectives (e.g., "outstanding," "excellent") and making references to ability in more critiques (P < .05 for all comparisons). CONCLUSIONS: The authors' analyses suggest that subtle gender bias may continue to operate in the post-2009 NIH review format in ways that could lead reviewers to implicitly hold male and female applicants to different standards of evaluation, particularly for R01 renewals.

A quantitative linguistic analysis of National Institutes of Health R01 application critiques from investigators at one institution.

PURPOSE: Career advancement in academic medicine often hinges on the ability to garner research funds. The National Institutes of Health's (NIH's) R01 award is the "gold standard" of an independent research program. Studies show inconsistencies in R01 reviewers' scoring and in award outcomes for certain applicant groups. Consistent with the NIH recommendation to examine potential bias in R01 peer review, the authors performed a text analysis of R01 reviewers' critiques. METHOD: The authors collected 454 critiques (262 from 91 unfunded and 192 from 67 funded applications) from 67 of 76 (88%) R01 investigators at the University of Wisconsin-Madison with initially unfunded applications subsequently funded between December 2007 and May 2009. To analyze critiques, the authors developed positive and negative grant application evaluation word categories and selected five existing categories relevant to grant review. They analyzed results with linear mixed-effects models for differences due to applicant and application characteristics. RESULTS: Critiques of funded applications contained more positive descriptors and superlatives and fewer negative evaluation words than critiques of unfunded applications. Experienced investigators' critiques contained more references to competence. Critiques showed differences due to applicant sex despite similar application scores or funding outcomes: more praise for applications from female investigators, greater reference to competence/ability for funded applications from female experienced investigators, and more negative evaluation words for applications from male investigators (all P<.05). CONCLUSIONS: Results suggest that text analysis is a promising tool for assessing consistency in R01 reviewers' judgments, and gender stereotypes may operate in R01 review.

The effect of an intervention to break the gender bias habit for faculty at one institution: a cluster randomized, controlled trial.

PURPOSE: Despite sincere commitment to egalitarian, meritocratic principles, subtle gender bias persists, constraining women's opportunities for academic advancement. The authors implemented a pair-matched, single-blind, cluster randomized, controlled study of a gender-bias-habit-changing intervention at a large public university. METHOD: Participants were faculty in 92 departments or divisions at the University of Wisconsin-Madison. Between September 2010 and March 2012, experimental departments were offered a gender-bias-habit-changing intervention as a 2.5-hour workshop. Surveys measured gender bias awareness; motivation, self-efficacy, and outcome expectations to reduce bias; and gender equity action. A timed word categorization task measured implicit gender/leadership bias. Faculty completed a work-life survey before and after all experimental departments received the intervention. Control departments were offered workshops after data were collected. RESULTS: Linear mixed-effects models showed significantly greater changes post intervention for faculty in experimental versus control departments on several outcome measures, including self-efficacy to engage in gender-equity-promoting behaviors (P = .013). When ≥ 25% of a department's faculty attended the workshop (26 of 46 departments), significant increases in self-reported action to promote gender equity occurred at three months (P = .007). Post intervention, faculty in experimental departments expressed greater perceptions of fit (P = .024), valuing of their research (P = .019), and comfort in raising personal and professional conflicts (P = .025). CONCLUSIONS: An intervention that facilitates intentional behavioral change can help faculty break the gender bias habit and change department climate in ways that should support the career advancement of women in academic medicine, science, and engineering.