Publications by authors named "David Shaffer"

107 Publications

Association of donor hepatitis C virus infection status and risk of BK polyomavirus viremia after kidney transplantation.

Am J Transplant 2021 Oct 6. Epub 2021 Oct 6.

Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.
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http://dx.doi.org/10.1111/ajt.16834DOI Listing
October 2021

Association between ezetimibe usage and hepatitis C RNA levels in uninfected kidney transplant recipients who received hepatitis C infected kidneys.

Clin Transplant 2021 Sep 15:e14485. Epub 2021 Sep 15.

Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, USA.

Kidney transplantation (KT) from hepatitis C virus infected (HCV+) donors to HCV negative recipients achieve excellent graft function but have relatively higher rates of post-KT co-infections presumably due to prolonged HCV viremia in transmission-and-treat approach. Ezetimibe acts as an antagonist of Niemann-Pick C1-Like 1 receptor required for HCV entry and theoretically can reduce HCV viremia. However, no data is available to examine the role of ezetimibe as a bridge therapy between KT surgery and direct acting antiviral (DAA) initiation. A retrospective cohort study including 70 HCV+ to HCV negative KT recipients from Methodist University Hospital and Vanderbilt University Medical Center was performed to determine the association between ezetimibe usage and HCV viremia. Twenty patients received ezetimibe daily while 50 patients did not. Primary outcome of study was mean HCV RNA level at 1-2 weeks post-KT and before initiation of DAA. Median (IQR) viral load (VL) in log copies/ml was one log lower in ezetimibe group versus non-ezetimibe group (4.1 [3.7-5.3] vs. 5.1 [4.4-5.5], P = .01), and highest VL was also lower in ezetimibe group (4.2 [3.7-5.4] vs. 5.4 [4.7-5.9], P = .006). We concluded that ezetimibe bridge therapy might be associated with reduction in HCV VL while waiting for DAA initiation in HCV+ to HCV negative KT recipients.
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http://dx.doi.org/10.1111/ctr.14485DOI Listing
September 2021

Kidney Transplantation From Hepatitis C Viremic Deceased Donors to Aviremic Recipients in a Real-world Setting.

Transplant Direct 2021 Oct 7;7(10):e761. Epub 2021 Sep 7.

Division of Kidney and Pancreas Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN.

Transplantation of hepatitis C viremic (HCV+) deceased donor kidney transplants (DDKT) into aviremic (HCV-) recipients is a strategy to increase organ utilization. However, there are concerns around inferior recipient outcomes due to delayed initiation of direct-acting antiviral (DAA) therapy and sustained HCV replication when implemented outside of a research setting.

Methods: This was a retrospective single-center matched cohort study of DDKT recipients of HCV+ donors (cases) who were matched 1:1 to recipients of HCV- donors (comparators) by age, gender, race, presence of diabetes, kidney donor profile index, and calculated panel-reactive antibody. Data were analyzed using summary statistics, t-tests, and chi-square tests for between-group comparisons, and linear mixed-effects models for longitudinal data.

Results: Each group consisted of 50 recipients with no significant differences in baseline characteristics. The 6-mo longitudinal trajectory of serum creatinine and estimated glomerular filtration rate did not differ between groups. All recipients had similar rates of acute rejection and readmissions (all  > 0.05). One case lost the allograft 151 d posttransplant because of acute rejection, and 1 comparator died on postoperative day 7 from cardiac arrest. HCV+ recipients initiated DAA on average 29 ± 11 d posttransplant. Ninety-eight percent achieved sustained virologic response at 4 and 12 wks with the first course of therapy; 1 patient had persistent HCV infection and was cured with a second course of DAA.

Conclusions: Aviremic recipients of HCV+ DDKT with delayed DAA initiation posttransplant had similar short-term outcomes compared with matched recipient comparators of HCV- donors.
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http://dx.doi.org/10.1097/TXD.0000000000001217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425827PMC
October 2021

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.

Lancet Oncol 2021 07 15;22(7):946-958. Epub 2021 Jun 15.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients.

Methods: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants.

Findings: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia).

Interpretation: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC.

Funding: Eisai and Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00241-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316679PMC
July 2021

Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study.

Clin Cancer Res 2021 Jun 10;27(12):3360-3369. Epub 2021 Feb 10.

Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Purpose: Atezolizumab [anti-programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC.

Patients And Methods: This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments.

Results: All 35 evaluable patients [median age, 68 years (range, 45-83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9-not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34-70); 2-year OS was 35.9% (95% CI: 13-59). Median follow-up was 13.0 months (range, 1.2-28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy.

Conclusions: Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1981DOI Listing
June 2021

Diagnostic Activities and Diagnostic Practices in Medical Education and Teacher Education: An Interdisciplinary Comparison.

Front Psychol 2020 20;11:562665. Epub 2020 Oct 20.

Education and Educational Psychology, Department Psychology, LMU University of Munich, Munich, Germany.

In this article, we investigate diagnostic activities and diagnostic practices in medical education and teacher education. Previous studies have tended to focus on comparing knowledge between disciplines, but such an approach is complicated due to the content specificity of knowledge. We compared 142 learners from medical education and 122 learners from teacher education who were asked to (a) diagnose eight simulated cases from their respective discipline in a simulation-based learning environment and (b) write a justificatory report for each simulated case. We coded all justificatory reports regarding four diagnostic activities: , , , and Moreover, using the method of Epistemic Network Analysis, we operationalized diagnostic practices as the relative frequencies of co-occurring diagnostic activities. We found significant differences between learners from medical education and teacher education with respect to both their diagnostic activities and diagnostic practices. Learners from medical education put relatively more emphasis on generating hypotheses and drawing conclusions, therefore applying a more hypothesis-driven approach. By contrast, learners in teacher education had a stronger focus on generating and evaluating evidence, indicating a more data-driven approach. The results may be explained by different epistemic ideals and standards taught in higher education. Further research on the issue of epistemic ideals and standards in diagnosing is needed. Moreover, we recommend that educators think beyond individuals' knowledge and implement measures to systematically teach and increase the awareness of disciplinary standards.
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http://dx.doi.org/10.3389/fpsyg.2020.562665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606905PMC
October 2020

Exploring patient willingness to accept hepatitis C-infected kidneys for transplantation.

BMC Nephrol 2020 11 10;21(1):473. Epub 2020 Nov 10.

Department of General Surgery, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, USA.

Background: As organs infected with Hepatitis C virus (HCV) provide an opportunity to expand the donor pool, the primary aim of this study is to explore patient willingness to accept a kidney from HCV-infected donors compared to other high-risk donors.

Methods: An anonymous, electronic survey was sent to all active kidney transplant waitlist patients at a single large volume transplant center. Patients were asked to respond to three hypothetical organ offers from the following: 1) HCV-infected donor 2) Donor with active intravenous drug use and 3) Donor with longstanding diabetes and hypertension.

Results: The survey was sent to 435 patients of which 125 responded (29% response rate). While 86 out of 125 patients (69%) were willing to accept an HCV-infected kidney, only a minority of respondents were willing to accept a kidney from other high-risk donors. In contrast to other studies, by multivariable logistic regression, age and race were not associated with willingness to accept an HCV-infected kidney.

Conclusions: In this exploratory study, utilization of kidneys from HCV-infected donors to expand the donor pool appears to be an acceptable option to patients.
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http://dx.doi.org/10.1186/s12882-020-02114-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653701PMC
November 2020

The effect of pulsatile pump perfusion on hepatitis C transmission in kidney transplantation: A prospective pilot study.

Clin Transplant 2020 08 16;34(8):e13987. Epub 2020 Jun 16.

Tennessee Donor Services, Dialysis Clinics, Inc., Nashville, TN, USA.

With increasing utilization of hepatitis C (HCV) viremic donor organs, there may be a role for kidney pump perfusion to reduce viral load and prevent HCV transmission. We performed a prospective pilot study of HCV viremic donors; one kidney from each donor pair was pumped with perfusate exchanges and viral load testing at least every 4 hours. Donor, recipient, and transplant characteristics were obtained with clinical outcomes. Linear regression was performed to quantify the association between pump time and perfusate viral load. Six HCV viremic donors for six pairs of aviremic recipients were included. Perfusate of the pumped kidneys showed detectable virus throughout the pump cycles. Although perfusate viral levels decreased with increasing pump times, this was not statistically significant (β = -.48, P = .36). All recipients had detectable HCV RNA postoperatively. The pumped cohort had an insignificantly reduced mean viral load compared to pumped recipients (1352 ± 2006 vs 26 170 ± 61 211, P = .09). Time to initiation of direct-acting antiviral was 32 ± 12 vs 26 ± 7 days (P = .17) and to undetectable levels was 66 ± 27 vs 55 ± 22 days (P = .82) for the pumped and unpumped cohorts, respectively. Pulsatile perfusion alone does not appear adequate to decrease HCV transmission. Future studies will need to explore additional ex vivo interventions to pumping.
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http://dx.doi.org/10.1111/ctr.13987DOI Listing
August 2020

Single molecule magnet behaviour in a square planar S = 1/2 Co(ii) complex and spin-state assignment of multiple relaxation modes.

Chem Commun (Camb) 2020 Jun;56(49):6711-6714

Department of Chemistry, Colorado State University, Fort Collins, CO 80523-1872, USA.

We report the first example of field-induced single molecule magnet (SMM) behaviour in a square-planar S = 1/2 Co(ii) pincer complex [(PNNNP)CoBr]Br (2). The related five-coordinate complexes [(PCNCP)CoBr2] (1) and [(PONOP)CoBr2] (3) also exhibit SMM properties. Partial spin crossover displayed by 3 allows for assignment of distinct relaxation modes to each spin state.
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http://dx.doi.org/10.1039/d0cc01854fDOI Listing
June 2020

Evaluating how residents talk and what it means for surgical performance in the simulation lab.

Am J Surg 2020 07 8;220(1):37-43. Epub 2020 Feb 8.

University of Wisconsin-Madison, Department of Surgery, School of Medicine and Public Health, 600 Highland Ave, Madison, WI, 53792, USA.

Background: This paper explores a method for assessing intraoperative performance by modeling how surgeons integrate skills and knowledge through discourse.

Methods: Senior residents (N = 11) were recorded while performing a simulated laparoscopic ventral hernia (LVH) repair. Audio transcripts were coded for five discourse elements related to knowledge, skills, and operative independence. Epistemic network analysis was used to model the ordered integration of the five discourse elements.

Results: Participants with poorer hernia repair outcomes had stronger connections between the discourse elements operative planning and asking for information or advice (Operative planning), while participants with better hernia repair outcomes had stronger connections between the discourse elements giving assistant instructions and identifying errors (Operative management): (p = .006; Cohen's d = 2.79).

Conclusion: Participants with better hernia repair outcomes engaged in more operative management communication during the simulated procedure. This ability to integrate multiple operative steps and verbally communicate them significantly correlated with better operative outcomes.
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http://dx.doi.org/10.1016/j.amjsurg.2020.02.016DOI Listing
July 2020

A phase 2, randomized trial evaluating the combination of dalantercept plus axitinib in patients with advanced clear cell renal cell carcinoma.

Cancer 2019 07 5;125(14):2400-2408. Epub 2019 Apr 5.

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Background: In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC).

Methods: In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate.

Results: Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group.

Conclusions: Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.
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http://dx.doi.org/10.1002/cncr.32061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602847PMC
July 2019

Teaching practicing surgeons what not to do: An analysis of instruction fluidity during a simulation-based continuing medical education course.

Surgery 2019 06 12;165(6):1082-1087. Epub 2019 Mar 12.

University of Wisconsin-Madison, School of Medicine and Public Health, Department of Surgery, Madison, WI.

Background: Interest is growing in simulation-based continuing medical education courses for practicing surgeons. However, little research has explored the instruction employed during these courses. This study examines instruction practices used during an annual simulation-based continuing medical education course.

Methods: Audio-video data were collected from surgeon instructors (n = 12) who taught a simulated laparoscopic hernia repair continuing medical education course across 2 years. Surgeon learners (n = 58) were grouped by their self-reported laparoscopic and hernia repair experience. Instructors' transcribed dialogue was automatically coded for 5 types of responses to the following questions: anecdotes, confirming, correcting, guidance, and what not to do. Differences in these responses were measured against the progress of the simulations and across learners with different experience levels. Postcourse interviews with instructors were conducted for additional qualitative validation.

Results: Performing t tests of instructor responses revealed that they were significantly more likely to answer in forms coded as anecdotes when responding to relative experts and in forms coded as what not to do when responding to novices. Linear regressions of each code against normalized progressions of each simulation revealed a significant relationship between progression through a simulation and frequency of the what not to do code for less-experienced learners. Postcourse interviews revealed that instructors continuously assess participants throughout a session and modify their teaching strategies.

Conclusion: Instructors significantly modified the focus of their teaching as a function both of their learners' self-reported experience levels, their assessment of learner needs, and learner progression through the training sessions.
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http://dx.doi.org/10.1016/j.surg.2019.01.016DOI Listing
June 2019

A2 to B Kidney Transplantation in the Post-Kidney Allocation System Era: A 3-year Experience with Anti-A Titers, Outcomes, and Cost.

J Am Coll Surg 2019 04 30;228(4):635-641. Epub 2019 Jan 30.

Division of Kidney and Pancreas Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN.

Background: The new kidney allocation systems (KAS) instituted December 2014 permitted A2 to B deceased donor kidney transplantation (DDKTx) to improve access and reduce disparities in wait time for minorities. A recent United Network for Organ Sharing (UNOS) analysis, however, indicated only 4.5% of B candidates were registered for A2 kidneys. Cited barriers to A2 to B DDKTx include titer thresholds, patient eligibility, and increased costs. There are little published data on post-transplantation anti-A titers or outcomes of A2 to B DDKTx since this allocation change.

Study Design: We conducted a retrospective, single center, cohort analysis of 29 consecutive A2 to B and 50 B to B DDKTx from December 2014 to December 2017. Pre- and postoperative anti-A titers were monitored prospectively. Outcomes included post-transplant anti-A titers, patient and graft survival, renal function, and hospital costs.

Results: African Americans comprised 72% of the A2 to B and 60% of the B to B group. There was no difference in mean wait time (58.8 vs 70.8 months). Paired tests indicated that anti-A IgG titers in A2 to B DDKTx were increased at discharge (p = 0.001) and at 4 weeks (p = 0.037). There were no significant differences in patient or graft survival, serum creatinine (SCr), or estimated glomerular filtration rate (eGFR), but the trajectories of SCr and eGFR differed between groups over the follow-up period. A2 to B had significantly higher mean transplant total hospital costs ($114,638 vs $91,697, p < 0.001) and hospital costs net organ acquisition costs ($42,356 vs $20,983, p < 0.001).

Conclusions: Initial experience under KAS shows comparable outcomes for A2 to B vs B to B DDKTx. Anti-A titers increased significantly post-transplantation, but did not adversely affect outcomes. Hospital costs were significantly higher with A2 to B DDKTx. Transplant programs, regulators, and payors will need to weigh improved access for minorities with increased costs.
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http://dx.doi.org/10.1016/j.jamcollsurg.2018.12.023DOI Listing
April 2019

Quantifying the Qualitative with Epistemic Network Analysis: A Human Factors Case Study of Task-Allocation Communication in a Primary Care Team.

IISE Trans Healthc Syst Eng 2018 29;8(1):72-82. Epub 2018 Jan 29.

Wisconsin Center for Education Research, University of Wisconsin - Madison, Madison, Wisconsin, USA.

Health care is fundamentally about people, and therefore, engineering approaches for studying healthcare systems must consider the perspective, concepts and methods offered by the human factors and ergonomics (HFE) discipline. HFE analysis is often qualitative to provide in-depth description of work systems and processes. To deepen our understanding of care processes, we propose the next level of analysis, i.e. quantification of qualitative data. Here, we describe epistemic network analysis (ENA) as a novel method to quantify qualitative data and present a case study applying ENA to assess communication in a primary care team. One high-performing primary care team consisting of a physician, nurse, medical assistant and unit clerk was observed for 15 hours. We analyzed task-allocation communications and identified the sender, receiver, synchronicity and acceptance. We used logistic regression and ENA to evaluate sender, receiver and synchronicity impact on task acceptance. The physician and unit clerk were most successful allocating tasks. Future work should consider the role of synchronous, interruptive communication as potentially useful in time-critical tasks and further investigate the role of the unit clerk. HFE researchers should consider ENA as a tool to expand and deepen their understanding of care processes by quantifying qualitative data.
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http://dx.doi.org/10.1080/24725579.2017.1418769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201247PMC
January 2018

O-O Radical Coupling: From Detailed Mechanistic Understanding to Enhanced Water Oxidation Catalysis.

Inorg Chem 2018 Sep 30;57(17):10533-10542. Epub 2018 Apr 30.

Chemistry Division , Brookhaven National Laboratory , Upton , New York 11973 , United States.

A deeper mechanistic understanding of the key O-O bond formation step of water oxidation by the [Ru(bda)(L)] (bdaH = 2,2'-bipyridine-6,6'-dicarboxylic acid; L is a pyridine or isoquinoline derivative) family of catalysts is reached through harmonious experimental and computational studies of two series of modified catalysts with systematic variations in the axial ligands. The introduction of halogen and electron-donating substituents in [Ru(bda)(4-X-py)] and [Ru(bda)(6-X-isq)] (X is H, Cl, Br, and I for the pyridine series and H, F, Cl, Br, and OMe for the isoquinoline series) enhances the noncovalent interactions between the axial ligands in the transition state for the bimolecular O-O coupling, resulting in a lower activation barrier and faster catalysis. From detailed transition state calculations in combination with experimental kinetic studies, we find that the main contributor to the free energy of activation is entropy due to the highly organized transition states, which is contrary to other reports. Previous work has considered only the electronic influence of the substituents, suggesting electron-withdrawing groups accelerate catalysis, but we show that a balance between polarizability and favorable π-π interactions is the key, leading to rationally devised improvements. Our calculations predict the catalysts with the lowest Δ G for the O-O coupling step to be [Ru(bda)(4-I-py)] and [Ru(bda)(6,7-(OMe)-isq)] for the pyridine and isoquinoline families, respectively. Our experimental results corroborate these predictions: the turnover frequency for [Ru(bda)(4-I-py)] (330 s) is a 10-fold enhancement with respect to that of [Ru(bda)(py)], and the turnover frequency for [Ru(bda)(6-OMe-isq)] reaches 1270 s, two times faster than [Ru(bda)(isq)].
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http://dx.doi.org/10.1021/acs.inorgchem.8b00329DOI Listing
September 2018

Using epistemic network analysis to identify targets for educational interventions in trauma team communication.

Surgery 2018 04 15;163(4):938-943. Epub 2018 Feb 15.

Department of Surgery, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA. Electronic address:

Background: Epistemic Network Analysis (ENA) is a technique for modeling and comparing the structure of connections between elements in coded data. We hypothesized that connections among team discourse elements as modeled by ENA would predict the quality of team performance in trauma simulation.

Methods: The Modified Non-technical Skills Scale for Trauma (T-NOTECHS) was used to score a simulation-based trauma team resuscitation. Sixteen teams of 5 trainees participated. Dialogue was coded using Verbal Response Modes (VRM), a speech classification system. ENA was used to model the connections between VRM codes. ENA models of teams with lesser T-NOTECHS scores (n = 9, mean = 16.98, standard deviation [SD] = 1.45) were compared with models of teams with greater T-NOTECHS scores (n = 7, mean = 21.02, SD = 1.09).

Results: Teams had different patterns of connections among VRM speech form codes with regard to connections among questions and edifications (meanHIGH = 0.115, meanLOW = -0.089; t = 2.21; P = .046, Cohen d = 1.021). Greater-scoring groups had stronger connections between stating information and providing acknowledgments, confirmation, or advising. Lesser-scoring groups had a stronger connection between asking questions and stating information. Discourse data suggest that this pattern reflected increased uncertainty. Lesser-scoring groups also had stronger connections from edifications to disclosures (revealing thoughts, feelings, and intentions) and interpretations (explaining, judging, and evaluating the behavior of others).

Conclusion: ENA is a novel and valid method to assess communication among trauma teams. Differences in communication among higher- and lower-performing teams appear to result from the ways teams use questions. ENA allowed us to identify targets for improvement related to the use of questions and stating information by team members.
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http://dx.doi.org/10.1016/j.surg.2017.11.009DOI Listing
April 2018

Increasing kidney donor profile index sequence does not adversely affect medium-term health-related quality of life after kidney transplantation.

Clin Transplant 2018 Apr 30;32(4):e13212. Epub 2018 Mar 30.

Department of Surgery, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: The United Network for Organ Sharing system allocates deceased donor kidneys based on the kidney donor profile index (KDPI), stratified as sequences (A ≤ 20%, B > 20-<35%, C ≥ 35-≤85%, and D > 85%), with increasing KDPI associated with decreased graft survival. While health-related quality of life (HRQOL) may improve after transplantation, the effect of donor kidney quality, reflected by KDPI sequence, on post-transplant HRQOL has not been reported.

Methods: Health-related quality of life was measured using the eight scales and physical and mental component summaries (PCS, MCS) of the SF-36 Health Survey. Multivariable mixed effects models that adjusted for age, gender, rejection, and previous transplant and analysis of variance methods tested the effects of time and KDPI sequence on post-transplant HRQOL.

Results: A total of 141 waitlisted adults and 505 recipients (>1700 observations) were included. Pretransplant PCS and MCS averaged, respectively, slightly below and within general population norms (GPN; 40-60). At 31 ± 26 months post-transplant, average PCS (41 ± 11) and MCS (51 ± 11), overall and within each KDPI sequence, were within GPN. KDPI sequence was not related to post-transplant HRQOL (P > .134) or its trajectory (interaction P > .163).

Conclusion: Increasing KDPI does not adversely affect the medium-term values and trajectories of HRQOL after kidney transplantation. This may reassure patients and centers when considering using high KDPI kidneys.
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http://dx.doi.org/10.1111/ctr.13212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933873PMC
April 2018

The hands and head of a surgeon: Modeling operative competency with multimodal epistemic network analysis.

Am J Surg 2018 11 2;216(5):835-840. Epub 2017 Dec 2.

University of Wisconsin-Madison, School of Medicine and Public Health, Department of Surgery, 600 Highland Avenue, Madison, WI 53792, USA. Electronic address:

Background: This paper explores a method for assessing intraoperative performance by modeling how surgeons integrate psychomotor, procedural, and cognitive skills to manage errors.

Methods: Audio-video data were collected from general surgery residents (N = 45) performing a simulated laparoscopic ventral hernia repair. Errors were identified using a standard checklist, and speech was coded for elements related to error recognition and management. Epistemic network analysis (ENA) was used to model the integration of error management skills.

Results: There was no correlation between number or type of errors committed and operative outcome. However, ENA models showed significant differences in the integration of error management skills between high-performing and low-performing residents.

Conclusion: These results suggest that error checklists and surgeons' speech can be used to model the integration of psychomotor, procedural, and cognitive aspects of intraoperative performance. Moreover, ENA can identify and quantify this integration, providing insight on performance gaps in both individuals and populations.
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http://dx.doi.org/10.1016/j.amjsurg.2017.11.027DOI Listing
November 2018

Why saying what you mean matters: An analysis of trauma team communication.

Am J Surg 2018 Feb 8;215(2):250-254. Epub 2017 Nov 8.

Department of Surgery, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.

Background: We hypothesized that team communication with unmatched grammatical form and communicative intent (mixed mode communication) would correlate with worse trauma teamwork.

Methods: Interdisciplinary trauma simulations were conducted. Team performance was rated using the TEAM tool. Team communication was coded for grammatical form and communicative intent. The rate of mixed mode communication (MMC) was calculated. MMC rates were compared to overall TEAM scores. Statements with advisement intent (attempts to guide behavior) and edification intent (objective information) were specifically examined. The rates of MMC with advisement intent (aMMC) and edification intent (eMMC) were also compared to TEAM scores.

Results: TEAM scores did not correlate with MMC or eMMC. However, aMMC rates negatively correlated with total TEAM scores (r = -0.556, p = 0.025) and with the TEAM task management component scores (r = -0.513, p = 0.042).

Conclusions: Trauma teams with lower rates of mixed mode communication with advisement intent had better non-technical skills as measured by TEAM.
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http://dx.doi.org/10.1016/j.amjsurg.2017.11.008DOI Listing
February 2018

Telemedicine-Enabled Clinical Trial of Metformin in Patients With Prostate Cancer.

JCO Clin Cancer Inform 2017 11;1:1-10

Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.

Purpose: Clinical trials are critical to informing cancer care but often are hampered by slow accrual and lack of generalizability because of poor geographic accessibility. We tested the feasibility of replacing onsite study visits with telemedicine visits in a prospective clinical trial.

Methods: Castration-naïve patients with prostate cancer and a rising serum prostate-specific antigen after definitive local therapy were eligible. Patients were required to have a single onsite visit for enrollment. Study treatment consisted of oral metformin 850 mg daily for 1 month followed by 850 mg twice daily for 5 months. Telehealth video visits (televisits) were conducted monthly by using a Health Insurance Portability and Accountability Act-compliant smartphone application. The primary objective was to determine the feasibility of telemedicine-enabled study visits. Secondary objectives were defining safety, anticancer activity, quality of life, and patient satisfaction.

Results: Fifteen patients with a median age of 68 years (range, 57 to 83 years) and median one-way driving time to the study center of 71 minutes (range, 12 to 147 minutes) were enrolled. The patients completed 84 eligible televisits (completion rate, 100%; 95% CI, 0.80 to 1). Diarrhea was the most common adverse event but was limited to grade 1 in severity; a single patient experienced grade ≥ 3 adverse events. Seven patients (46.7%; 95% CI, 24.8% to 69.9%) had a ≤ 20% increase in prostate-specific antigen relative to baseline. Patients agreed or strongly agreed that they would participate in a telemedicine-enabled clinical trial in the future.

Conclusion: To our knowledge, this interventional oncology clinical trial is the first to be conducted through telemedicine. Telemedicine-enabled trials are feasible and may overcome geographic barriers to trial participation. Metformin was generally well tolerated but associated with modest anticancer activity.
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http://dx.doi.org/10.1200/CCI.17.00044DOI Listing
November 2017

Lability and Basicity of Bipyridine-Carboxylate-Phosphonate Ligand Accelerate Single-Site Water Oxidation by Ruthenium-Based Molecular Catalysts.

J Am Chem Soc 2017 11 23;139(43):15347-15355. Epub 2017 Oct 23.

Chemistry Division, Brookhaven National Laboratory , Upton, New York 11973-5000, United States.

A critical step in creating an artificial photosynthesis system for energy storage is designing catalysts that can thrive in an assembled device. Single-site catalysts have an advantage over bimolecular catalysts because they remain effective when immobilized. Hybrid water oxidation catalysts described here, combining the features of single-site bis-phosphonate catalysts and fast bimolecular bis-carboxylate catalysts, have reached turnover frequencies over 100 s, faster than both related catalysts under identical conditions. The new [(bpHc)Ru(L)] (bpHcH = 2,2'-bipyridine-6-phosphonic acid-6'-carboxylic acid, L = 4-picoline or isoquinoline) catalysts proceed through a single-site water nucleophilic attack pathway. The pendant phosphonate base mediates O-O bond formation via intramolecular atom-proton transfer with a calculated barrier of only 9.1 kcal/mol. Additionally, the labile carboxylate group allows water to bind early in the catalytic cycle, allowing intramolecular proton-coupled electron transfer to lower the potentials for oxidation steps and catalysis. That a single-site catalyst can be this fast lends credence to the possibility that the oxygen evolving complex adopts a similar mechanism.
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http://dx.doi.org/10.1021/jacs.7b06096DOI Listing
November 2017

Lability and Basicity of Bipyridine-Carboxylate-Phosphonate Ligand Accelerate Single-Site Water Oxidation by Ruthenium-Based Molecular Catalysts.

J Am Chem Soc 2017 11 23;139(43):15347-15355. Epub 2017 Oct 23.

Chemistry Division, Brookhaven National Laboratory , Upton, New York 11973-5000, United States.

A critical step in creating an artificial photosynthesis system for energy storage is designing catalysts that can thrive in an assembled device. Single-site catalysts have an advantage over bimolecular catalysts because they remain effective when immobilized. Hybrid water oxidation catalysts described here, combining the features of single-site bis-phosphonate catalysts and fast bimolecular bis-carboxylate catalysts, have reached turnover frequencies over 100 s, faster than both related catalysts under identical conditions. The new [(bpHc)Ru(L)] (bpHcH = 2,2'-bipyridine-6-phosphonic acid-6'-carboxylic acid, L = 4-picoline or isoquinoline) catalysts proceed through a single-site water nucleophilic attack pathway. The pendant phosphonate base mediates O-O bond formation via intramolecular atom-proton transfer with a calculated barrier of only 9.1 kcal/mol. Additionally, the labile carboxylate group allows water to bind early in the catalytic cycle, allowing intramolecular proton-coupled electron transfer to lower the potentials for oxidation steps and catalysis. That a single-site catalyst can be this fast lends credence to the possibility that the oxygen evolving complex adopts a similar mechanism.
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http://dx.doi.org/10.1021/jacs.7b06096DOI Listing
November 2017

O-O bond formation in ruthenium-catalyzed water oxidation: single-site nucleophilic attack vs. O-O radical coupling.

Chem Soc Rev 2017 Oct;46(20):6170-6193

Chemistry Division, Brookhaven National Laboratory, Upton, NY 11973-5000, USA.

In this review we discuss at the mechanistic level the different steps involved in water oxidation catalysis with ruthenium-based molecular catalysts. We have chosen to focus on ruthenium-based catalysts to provide a more coherent discussion and because of the availability of detailed mechanistic studies for these systems but many of the aspects presented in this review are applicable to other systems as well. The water oxidation cycle has been divided in four major steps: water oxidative activation, O-O bond formation, oxidative activation of peroxide intermediates, and O evolution. A significant portion of the review is dedicated to the O-O bond formation step as the key step in water oxidation catalysis. The two main pathways to accomplish this step, single-site water nucleophilic attack and O-O radical coupling, are discussed in detail and compared in terms of their potential use in photoelectrochemical cells for solar fuels generation.
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http://dx.doi.org/10.1039/c7cs00542cDOI Listing
October 2017

A Cost Comparison for Telehealth Utilization in the Kidney Transplant Waitlist Evaluation Process.

Transplantation 2018 02;102(2):279-283

Renal Transplant, U.S. Department of Veterans Affairs Hospital, Tennessee Valley, Nashville, TN.

Background: There have been limited publications on telehealth utilization in transplantation with no prior reports of telehealth-related costs for pretransplant evaluations. The aim of this study is to compare costs throughout the evaluation process for those patients assessed initially by telehealth with those seen in-person.

Methods: All patients approved for kidney transplant waitlist evaluation at our center from March 2013 thru May 2016 with decisions were included in this study. Patients approved for evaluation were scheduled for either an initial telehealth or in-person visit, partly based on patient factors. Clinically related and travel-related costs were calculated. Time estimates for patient time needed to complete visit, time from application approval to initial visit, and time from application approval to decision were obtained. Comparisons were made using t tests.

Results: Thirty-nine months were included for 302 patients. All categories of clinically or travel-related costs were significantly less for the telehealth cohort (P < 0.0001). Total mean cost per patient was US $656.11 versus US $1108.91 for the cohort initially evaluated by telehealth versus in-person (P < 0.001). The time needed to complete an evaluation (1.7 vs 2.4 days, P < 0.001) and the time to initial evaluation (51.4 vs 87.9.0 days, P < 0.001) were significantly less in the telehealth cohort. The cohort seen by telehealth was older with increased comorbidities (<0.001).

Conclusions: As telemedicine applications continue to proliferate, we present our experience with telehealth for initial kidney transplant waitlist evaluations with associated reductions in cost and time which may also improve access to transplantation.
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http://dx.doi.org/10.1097/TP.0000000000001903DOI Listing
February 2018

Implementation of telehealth is associated with improved timeliness to kidney transplant waitlist evaluation.

J Telemed Telecare 2018 Aug 26;24(7):485-491. Epub 2017 Jun 26.

1 Renal Transplant, US Department of Veterans Affairs Hospital, Tennessee Valley, Nashville, TN, USA.

Introduction The United States Department of Veterans Affairs (VA) National Transplant Program has made efforts to improve access by introducing Web-based referrals and telehealth. The aims of this study were to describe the programmatic implementation and evaluate the effectiveness of new technology on the timeliness to kidney transplant evaluation at a VA medical centre. Methods Between 1 January 2009 and 31 May 2016, 835 patients were approved for evaluation. Monthly data were summarized as: number of applications, median days to evaluation, and median percentage of evaluations that occurred within 30 days. Temporal trends were analysed using non-parametric comparisons of medians between three eras: Pre Web-based submission, Web-based submission, and Web-based submission with videoconference (VC) telehealth. Results The number of applications did not vary between eras ( p = 0.353). The median time to evaluation and the median percentage of patients with appointments within 30 days improved significantly in the Web-based submission with VC era when compared with the Web-based and Pre Web-based eras (37 vs. 260 and 116 days, respectively, p < 0.001; 100% vs. 8% and 0%, respectively, p < 0.001). Discussion We have been able to markedly improve the timeliness to kidney transplant waitlist evaluation with the addition of telehealth.
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http://dx.doi.org/10.1177/1357633X17715526DOI Listing
August 2018

Cisplatin Therapy Does Not Worsen Renal Function in Severe Antenatal Bartter Syndrome.

Case Rep Nephrol Dial 2017 May-Aug;7(2):49-54. Epub 2017 May 8.

cGenitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

A 30-year-old man with severe antenatal Bartter syndrome, diagnosed and treated in infancy, developed testicular carcinoma. Despite the known renal complications of cisplatin, this drug was used for his chemotherapy because of its superior antineoplastic effect. Nonsteroidal anti-inflammatory drug administration was continued during cisplatin therapy. Despite an increase in his oral potassium requirement, renal function was maintained following completion of chemotherapy. In spite of its significant associated nephrotoxicity, cisplatin can be used in patients with severe antenatal Bartter syndrome if required for therapy of malignancy.
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http://dx.doi.org/10.1159/000475838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465520PMC
May 2017

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

Lancet 2017 01 8;389(10064):67-76. Epub 2016 Dec 8.

Genentech, South San Francisco, CA, USA.

Background: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.

Methods: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652.

Findings: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.

Interpretation: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.

Funding: F Hoffmann-La Roche, Genentech.
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http://dx.doi.org/10.1016/S0140-6736(16)32455-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568632PMC
January 2017

Teaching health care workers to adopt a systems perspective for improved control and prevention of health care-associated infections.

Am J Infect Control 2016 11 14;44(11):1360-1364. Epub 2016 Jul 14.

Department of Medicine, Division of Infectious Disease, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI; William S. Middleton Memorial Veterans Hospital, Madison, WI. Electronic address:

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http://dx.doi.org/10.1016/j.ajic.2016.04.211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055227PMC
November 2016

Manipulating the Rate-Limiting Step in Water Oxidation Catalysis by Ruthenium Bipyridine-Dicarboxylate Complexes.

Inorg Chem 2016 Nov 1;55(22):12024-12035. Epub 2016 Nov 1.

Department of Natural Sciences, Baruch College, The City University of New York , New York, New York 10010, United States.

In order to gain a deeper mechanistic understanding of water oxidation by [(bda)Ru(L)] catalysts (bdaH = [2,2'-bipyridine]-6,6'-dicarboxylic acid; L = pyridine-type ligand), a series of modified catalysts with one and two trifluoromethyl groups in the 4 position of the bda ligand was synthesized and studied using stopped-flow kinetics. The additional -CF groups increased the oxidation potentials for the catalysts and enhanced the rate of electrocatalytic water oxidation at low pH. Stopped-flow measurements of cerium(IV)-driven water oxidation at pH 1 revealed two distinct kinetic regimes depending on catalyst concentration. At relatively high catalyst concentration (ca. ≥10 M), the rate-determining step (RDS) was a proton-coupled oxidation of the catalyst by cerium(IV) with direct kinetic isotope effects (KIE > 1). At low catalyst concentration (ca. ≤10 M), the RDS was a bimolecular step with k/k ≈ 0.8. The results support a catalytic mechanism involving coupling of two catalyst molecules. The rate constants for both RDSs were determined for all six catalysts studied. The presence of -CF groups had inverse effects on the two steps, with the oxidation step being fastest for the unsubstituted complexes and the bimolecular step being faster for the most electron-deficient complexes. Though the axial ligands studied here did not significantly affect the oxidation potentials of the catalysts, the nature of the ligand was found to be important not only in the bimolecular step but also in facilitating electron transfer from the metal center to the sacrificial oxidant.
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http://dx.doi.org/10.1021/acs.inorgchem.6b02193DOI Listing
November 2016
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