Control of Polarity in Kagome-NiAs Bismuthides.

A 2×2×1 superstructure of the P63/mmc NiAs structure is reported in which kagome nets are stabilized in the octahedral transition metal layers of the compounds Ni0.7Pd0.2Bi, Ni0.6Pt0.4Bi, and Mn0.99Pd0.01Bi. The ordered vacancies that yield the true hexagonal kagome motif lead to filling of trigonal bipyramidal interstitial sites with the transition metal in this family of "kagome-NiAs" type materials. Further ordering of vacancies within these interstitial layers can be compositionally driven to simultaneously yield kagome-connected layers and a net polarization along the c axes in Ni0.9Bi and Ni0.79Pd0.08Bi, which adopt Fmm2 symmetry. The polar and non-polar materials exhibit different electronic transport behaviour, reflecting the tuneability of both structure and properties within the NiAs-type bismuthide materials family.

Barriers to finding psychology postdoctoral training opportunities in intensive care settings.

PURPOSE/OBJECTIVE: U.S. health organizations, including Division 22 of the American Psychological Association, the Society for Critical Care Medicine, and the American Thoracic Society advocate for psychological treatment that improves long-term outcomes in critical illness survivors. However, limited information exists with regard to psychology training opportunities in intensive care settings. We aim to identify and describe (a) existing psychology programs with training in intensive care settings and (b) barriers to finding these training opportunities. RESEARCH METHOD/DESIGN: Using aspects of the Arksey and O'Malley Framework and Preferred Reporting Items for Systematic Review and Meta-Analyses Extension for Scoping Reviews reporting checklist as guides, two independent reviewers searched the Association of Psychology Postdoctoral and Internship Centers (APPIC) Directory and Universal Psychology Postdoctoral Directory (UPPD) to identify programs with training experiences in intensive care settings. RESULTS: Searching the APPIC Directory did not reliably or accurately identify training opportunities in intensive care settings. Thus, only programs identified in the more reliable UPPD search were considered for inclusion. After duplicates were removed, searches using the UPPD yielded 31 programs for review. Of those, 22 programs met inclusion, offering heterogeneous training in intensive care settings. CONCLUSIONS/IMPLICATIONS: These results suggest few opportunities exist for psychology training in intensive care settings and available opportunities are difficult to identify using standard search methods. The identified challenges also emphasize the need for advanced search features for training opportunities within APPIC/UPPD and/or a list of programs offering these training opportunities. Our results highlight the importance of program descriptions that accurately and comprehensively reflect training opportunities-particularly relating to opportunities in intensive care settings. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Human embryonic and fetal biobanking: Establishing the Dutch Fetal Biobank and a framework for standardization.

Recent studies of human embryos and fetuses have advanced our understanding not only of basic biology but also of health and disease, through a combination of detailed three-dimensional (3D) morphology and processes such as gene expression, cellular decision-making and differentiation, and epigenetics during the various phases of human development and growth. Large-scale research initiatives focusing on these topics have been initiated during the last decade, all of which depend on biobanks that provide high-quality images of human embryonic and fetal morphology, as well as on high-quality collections of tissue samples that are obtained and stored appropriately. In this perspective, we describe our experience in establishing the Dutch Fetal Biobank to present the framework and workflow of the biobank, provide a brief discussion of the main legal and ethical aspects involved in establishing a pre-natal tissue bank, and present the preliminary data on the first 329 donated specimens.

Familial multiple discoid fibromas is linked to a locus on chromosome 5 including the FNIP1 gene.

Previously, we reported a series of families presenting with trichodiscomas, inherited in an autosomal dominant pattern. The phenotype was named familial multiple discoid fibromas (FMDF). The genetic cause of FMDF remained unknown so far. Trichodiscomas are skin lesions previously reported to be part of the same spectrum as the fibrofolliculoma observed in Birt-Hogg-Dubé syndrome (BHD), an inherited disease caused by pathogenic variants in the FLCN gene. Given the clinical and histological differences with BHD and the exclusion of linkage with the FLCN locus, the phenotype was concluded to be distinct from BHD. We performed extensive clinical evaluations and genetic testing in ten families with FMDF. We identified a FNIP1 frameshift variant in nine families and genealogical studies showed common ancestry for eight families. Using whole exome sequencing, we identified six additional rare variants in the haplotype surrounding FNIP1, including a missense variant in the PDGFRB gene that was found to be present in all tested patients with FMDF. Genome-wide linkage analysis showed that the locus on chromosome 5 including FNIP1 was the only region reaching the maximal possible LOD score. We concluded that FMDF is linked to a haplotype on chromosome 5. Additional evaluations in families with FMDF are required to unravel the exact genetic cause underlying the phenotype. When evaluating patients with multiple trichodisomas without a pathogenic variant in the FLCN gene, further genetic testing is warranted and can include analysis of the haplotype on chromosome 5.

Band Structure Engineering of Bi4O4SeCl2 for Thermoelectric Applications.

The mixed anion material Bi4O4SeCl2 has an ultralow thermal conductivity of 0.1 W m-1 K-1 along its stacking axis (c axis) at room temperature, which makes it an ideal candidate for electronic band structure optimization via doping to improve its thermoelectric performance. Here, we design and realize an optimal doping strategy for Bi4O4SeCl2 from first principles and predict an enhancement in the density of states at the Fermi level of the material upon Sn and Ge doping. Experimental work realizes the as-predicted behavior in Bi4-x Sn x O4SeCl2 (x = 0.01) through the precise control of composition. Careful consideration of multiple accessible dopant sites and charge states allows for the effective computational screening of dopants for thermoelectric properties in Bi4O4SeCl2 and may be a suitable route for assessing other candidate materials.

Thoracic aortic aneurysm repair using the elephant trunk technique and associated complications.

The frozen elephant trunk stent has greatly facilitated the repair of elective and emergency arch and proximal descending thoracic aortic aneurysms and dissections. As one of the few tertiary hospitals that routinely inserts and images the floating and frozen elephant trunk grafts, we aim to provide an up-to-date illustration of the contrasting methods of elephant trunk thoracic aortic aneurysm repair through a computed tomography (CT) review and detail the common radiological interpretation pitfalls in addition to the most significant associated complications.

Tunable stiffness enables fast and efficient swimming in fish-like robots.

Fish maintain high swimming efficiencies over a wide range of speeds. A key to this achievement is their flexibility, yet even flexible robotic fish trail real fish in terms of performance. Here, we explore how fish leverage tunable flexibility by using their muscles to modulate the stiffness of their tails to achieve efficient swimming. We derived a model that explains how and why tuning stiffness affects performance. We show that to maximize efficiency, muscle tension should scale with swimming speed squared, offering a simple tuning strategy for fish-like robots. Tuning stiffness can double swimming efficiency at tuna-like frequencies and speeds (0 to 6 hertz; 0 to 2 body lengths per second). Energy savings increase with frequency, suggesting that high-frequency fish-like robots have the most to gain from tuning stiffness.

Low thermal conductivity in a modular inorganic material with bonding anisotropy and mismatch.

The thermal conductivity of crystalline materials cannot be arbitrarily low, as the intrinsic limit depends on the phonon dispersion. We used complementary strategies to suppress the contribution of the longitudinal and transverse phonons to heat transport in layered materials that contain different types of intrinsic chemical interfaces. BiOCl and Bi2O2Se encapsulate these design principles for longitudinal and transverse modes, respectively, and the bulk superlattice material Bi4O4SeCl2 combines these effects by ordering both interface types within its unit cell to reach an extremely low thermal conductivity of 0.1 watts per kelvin per meter at room temperature along its stacking direction. This value comes within a factor of four of the thermal conductivity of air. We demonstrated that chemical control of the spatial arrangement of distinct interfaces can synergically modify vibrational modes to minimize thermal conductivity.

Efficiency Correction Is Required for Accurate Quantitative PCR Analysis and Reporting.

BACKGROUND: Quantitative PCR (qPCR) aims to measure the DNA or RNA concentration in diagnostic and biological samples based on the quantification cycle (Cq) value observed in the amplification curves. Results of qPCR experiments are regularly calculated as if all assays are 100% efficient or reported as just Cq, ΔCq, or ΔΔCq values. CONTENTS: When the reaction shows specific amplification, it should be deemed to be positive, regardless of the observed Cq. Because the Cq is highly dependent on amplification efficiency that can vary among targets and samples, accurate calculation of the target quantity and relative gene expression requires that the actual amplification efficiency be taken into account in the analysis and reports. PCR efficiency is frequently derived from standard curves, but this approach is affected by dilution errors and hampered by properties of the standard and the diluent. These factors affect accurate quantification of clinical and biological samples used in diagnostic applications and collected in challenging conditions. PCR efficiencies determined from individual amplification curves avoid these confounders. To obtain unbiased efficiency-corrected results, we recommend absolute quantification with a single undiluted calibrator with a known target concentration and efficiency values derived from the amplification curves of the calibrator and the unknown samples. SUMMARY: For meaningful diagnostics or biological interpretation, the reported results of qPCR experiments should be efficiency corrected. To avoid ambiguity, the Minimal Information for Publications on Quantitative Real-Time PCR Experiments (MIQE) guidelines checklist should be extended to require the methods that were used (1) to determine the PCR efficiency and (2) to calculate the reported target quantity and relative gene expression value.

ATLAS trial of adjuvant axitinib in patients with renal cell carcinoma: subgroup analyses with focus on axitinib dosing and racial groups.

BACKGROUND: The ATLAS trial, investigating adjuvant axitinib versus placebo in renal cell carcinoma (RCC), was stopped for futility at a preplanned interim analysis. We report subgroup outcome analyses by ethnicity, time on treatment, dose modification and toxicity. PATIENTS AND METHODS: Patient demographics, baseline characteristics, treatment duration and exposure and safety were analysed for Asian versus non-Asian patients treated with axitinib versus placebo. Disease-free survival (DFS) was analysed by ethnicity, treatment duration (≥1 versus <1 year), dose modification and adverse event (AE) grade. RESULTS: No DFS benefit was observed for Asian {hazard ratio (HR) 0.883 [95% confidence interval (CI) 0.638-1.220]} or non-Asian [HR 0.828 (95% CI 0.490-1.400)] patients treated with axitinib or placebo. Fewer Asian versus non-Asian patients were in the highest-risk group in axitinib (51.9% versus 72.3%) or placebo (51.5% versus 66.0%) arm. Highest-risk patients in both subgroups had no DFS benefit with either treatment. More axitinib-treated Asian versus non-Asian patients had dose reductions due to AEs (58.8% versus 46.0%; P = 0.028). Asian patients experienced more nasopharyngitis but less fatigue or asthenia than non-Asians. Among Asian patients, proteinuria, hypothyroidism, nasopharyngitis, and hypertension were more common in Japanese patients than Korean patients and more common in Korean patients than Chinese patients. Patients receiving axitinib >1 year versus ≤1 year did not have different DFS: HR 0.572 (95% CI 0.247-1.327); P = 0.1874. Compared with patients on stable axitinib dose, DFS was longer in patients with dose reduction [HR 0.458 (95% CI 0.305-0.687); P = 0.0001], whereas DFS was not different in those with dose escalation [HR 1.936 (95% CI 0.937-3.997); P = 0.0685]. DFS was not different in patients experiencing grade ≥2 versus <2 AEs within 6 months of initiating axitinib: HR 0.885 (95% CI 0.419-1.869); P = 0.7488. CONCLUSIONS: Asian versus non-Asian subgroup analysis revealed differences in AE experience and drug exposure. There were no DFS differences based on ethnicity or treatment duration, but axitinib dose reduction led to longer DFS.

A randomized phase IIa study of quantified bone scan response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 dichloride alone or in combination with abiraterone acetate/prednisone or enzalutamide.

BACKGROUND: In metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide). PATIENTS AND METHODS: This randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR. RESULTS: Overall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline. CONCLUSIONS: Technetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.

One Site, Two Cations, Three Environments: s2 and s0 Electronic Configurations Generate Pb-Free Relaxor Behavior in a Perovskite Oxide.

The piezoelectric devices widespread in society use noncentrosymmetric Pb-based oxides because of their outstanding functional properties. The highest figures of merit reported are for perovskites based on the parent Pb(Mg1/3Nb2/3)O3 (PMN), which is a relaxor: a centrosymmetric material with local symmetry breaking that enables functional properties, which resemble those of a noncentrosymmetric material. We present the Pb-free relaxor (K1/2Bi1/2)(Mg1/3Nb2/3)O3 (KBMN), where the thermal and (di)electric behavior emerges from the discrete structural roles of the s0 K+ and s2 Bi3+ cations occupying the same A site in the perovskite structure, as revealed by diffraction methods. This opens a distinctive route to Pb-free piezoelectrics based on relaxor parents, which we demonstrate in a solid solution of KBMN with the Pb-free ferroelectric (K1/2Bi1/2)TiO3, where the structure and function evolve together, revealing a morphotropic phase boundary, as seen in PMN-derived systems. The detailed multiple-length-scale understanding of the functional behavior of KBMN suggests that precise chemical manipulation of the more diverse local displacements in the Pb-free relaxor will enhance performance.

Drug-Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side-Chain Lipophilicity.

Large macrocyclic peptides can achieve surprisingly high membrane permeability, although the properties that govern permeability in this chemical space are only beginning to come into focus. We generated two libraries of cyclic decapeptides with stable cross-ß conformations, and found that peptoid substitutions within the ß-turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing ß-strands led to "chameleonic" species that were rigid in nonpolar media but highly flexible in water. Both rigid and chameleonic compounds showed high permeability over a wide lipophilicity range, with peak permeabilities differing significantly depending on scaffold rigidity. Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides, and that scaffold rigidity can be used to tune optimal lipophilicity.

Risk Factors for Suicide in a National Sample of Veterans With Multiple Sclerosis.

OBJECTIVES: To examine risk factors in the year before suicide in a national sample of United States veterans with multiple sclerosis (MS), as well as means of suicide and receipt of mental health services prior to death. DESIGN: Case control study. Individuals in the Veterans Affairs MS National Data Repository were linked to the National Death Index Plus to obtain death records, including specific causes of death. Participants were veterans with MS who died by suicide and randomly selected nonsuicide MS controls (5 per participant) who were alive at the time of the index suicide. Mental health disorders and medical comorbidities were identified in the year before death for suicides and during the identical time period for controls. SETTING: Veterans Health Administration. PARTICIPANTS: Veterans (N=426) who received treatment for MS in the United States Veterans Health Administration between 1999 and 2011. There were 71 deaths by suicide and 355 randomly selected controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Suicide. RESULTS: Results from the adjusted multivariable model suggest that the following factors were associated with an increased risk for suicide: male sex (odds ratio [OR], 3.60; 95% confidence interval [CI], 1.35-9.42), depression (OR, 1.82; 95% CI, 1.03-3.23), and alcohol use disorder (OR, 3.10; 95% CI, 1.38-6.96). Half (50.7%) had a mental health appointment in the year before suicide. The primary means of suicide was by firearm (62.0%). CONCLUSIONS: Routine assessment of suicide risk in individuals with MS is warranted, particularly for those with recent history of depression or alcohol use disorder.

Clinical outcomes in men of diverse ethnic backgrounds with metastatic castration-resistant prostate cancer.

BACKGROUND: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen. PATIENTS AND METHODS: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors. RESULTS: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively. CONCLUSIONS: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.

Modular Design via Multiple Anion Chemistry of the High Mobility van der Waals Semiconductor Bi4O4SeCl2.

Making new van der Waals materials with electronic or magnetic functionality is a chemical design challenge for the development of two-dimensional nanoelectronic and energy conversion devices. We present the synthesis and properties of the van der Waals material Bi4O4SeCl2, which is a 1:1 superlattice of the structural units present in the van der Waals insulator BiOCl and the three-dimensionally connected semiconductor Bi2O2Se. The presence of three anions gives the new structure both the bridging selenide anion sites that connect pairs of Bi2O2 layers in Bi2O2Se and the terminal chloride sites that produce the van der Waals gap in BiOCl. This retains the electronic properties of Bi2O2Se while reducing the dimensionality of the bonding network connecting the Bi2O2Se units to allow exfoliation of Bi4O4SeCl2 to 1.4 nm height. The superlattice structure is stabilized by the configurational entropy of anion disorder across the terminal and bridging sites. The reduction in connective dimensionality with retention of electronic functionality stems from the expanded anion compositional diversity.

A PCA-Based Framework for Determining Remotely Sensed Geological Surface Orientations and Their Statistical Quality.

The orientations of planar rock layers are fundamental to our understanding of structural geology and stratigraphy. Remote sensing platforms including satellites, unmanned aerial vehicles, and Light Detection and Ranging scanners are increasingly used to build three-dimensional models of structural features on Earth and other planets. Remotely gathered orientation measurements are straightforward to calculate but subject to uncertainty inherited from input data, differences in viewing geometry, and the plane-fitting process, complicating geological interpretation. Here, we improve upon the present state of the art by developing a generalized means for computing and reporting errors in strike-dip measurements from remotely sensed data. We outline a general framework for representing the error space of uncertain orientations in Cartesian and spherical coordinates and develop a principal component analysis (PCA) regression method, which captures statistical errors independent of viewing geometry and input data structure. We also introduce graphical techniques to visualize the uniqueness and quality of orientation measurements and a process to increase statistical power by jointly fitting bedding planes under the assumption of parallel stratigraphy. These new techniques are validated by comparison of field-gathered orientation measurements with those derived from minimally processed satellite imagery of the San Rafael Swell, Utah, and unmanned aerial vehicle imagery from the Naukluft Mountains, Namibia. We provide software packages supporting planar fitting and visualization of error distributions. This method increases the precision and comparability of structural measurements gathered using a new generation of remote sensing techniques.

Removal of artifact bias from qPCR results using DNA melting curve analysis.

Quantitative PCR (qPCR) allows the precise measurement of DNA concentrations and is generally considered to be straightforward and trouble free. However, analyses using validated Sybr Green I-based assays regularly amplify both the correct product and an artifact. Amplification of more than 1 product can be recognized when melting curve analysis is performed after the qPCR. Currently, such reactions need to be excluded from further analysis because the quantification result is considered meaningless. However, when the fraction of the fluorescence associated with the correct product can be determined, the quantitative result of the qPCR analysis can be corrected. The main assumptions of this correction model are: 1) the melting peak of the correct product can be identified, 2) the PCR efficiencies of all amplified products are similar, 3) the relative size of the melting peaks reflects the relative concentrations of the products, and 4) the relative concentrations do not change as the reaction reaches plateau. These assumptions were validated in a series of model experiments. The results show that the quantitative results can be corrected. Implementation of a correction for the presence of artifact amplification in the analysis of qPCR data leads to more reliable quantitative results in qPCR experiments.-Ruijter, J. M., Ruiz-Villalba, A., van den Hoff, A. J. J., Gunst, Q. D., Wittwer, C. T., van den Hoff, M. J. B. Removal of artifact bias from qPCR results using DNA melting curve analysis.

Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.

BACKGROUND: Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045. PATIENTS AND METHODS: Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR. RESULTS: A total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy. CONCLUSIONS: Long-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02256436.