Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling.

RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD-mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between ß2 and ß3 of the N-lobe of the kinase, which is in close proximity to the ATP-binding pocket. Through characterization of a new series of ATP pocket-binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2-XIAP interaction, and of cellular and in vivoNOD2 signaling. Our study exemplifies how targeting of the ATP-binding pocket in RIPK2 can be exploited to interfere with the RIPK2-XIAP interaction for modulation of NOD signaling.

Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3.

Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains.

Child diet and health outcomes of the simple suppers program: a 10-week, 2-group quasi-experimental family meals trial.

BACKGROUND: Racial minority children, particularly from low-income households, are at risk for obesity. Family meals have a protective effect on child nutritional health. However, the current evidence is limited in racial and socioeconomic diversity. The objective of this study was to evaluate the impact of a family meals intervention, Simple Suppers, on improvements in diet and health outcomes from baseline (T0) to post-intervention (T1) in intervention compared to waitlist control participants, and determine retention of change in outcomes among intervention participants at 10-week follow-up (T2). METHODS: Simple Suppers was a 10-week family meals intervention implemented as a 2-group quasi-experimental trial. Ten 90-min lessons were delivered weekly. Data were collected at T0 and T1, and from intervention participants at T2. Participants were racially diverse 4-10 year-old children from low-income households. Setting was a faith-based community center. Main outcomes were daily servings of fruit, vegetables, and sugar-sweetened beverages and diet quality; z-scores for body mass index (BMI), waist circumference, systolic and diastolic blood pressure (BP); weight status categories; food preparation skills; and family meals (frequency of dinner, breakfast, TV viewing during meals, meals in dining area). Generalized linear mixed models (GLMMs) and mixed-effects ordinal regression models were used to assess intervention impact (T0:T1). Paired t-tests examined retention of change among intervention participants (T1:T2). RESULTS: One hundred forty children enrolled and 126 completed T1 (90% retention); 71 of 87 intervention participants completed T2(79% retention). Mean (SD) age was 6.9(1.9) yr, 62% female, 60% Black, and 42% low-income. Intervention vs waitlist controls had higher food preparation skills (p < 0.001) and lower TV viewing during meals (p = 0.04) at T1.There were no group differences in dietary intake or quality or z-scores for BMI, waist circumference, or BP, however intervention versus waitlist controls experienced a greater change toward healthy weight (p = 0.04) At T2, intervention participants demonstrated a retention of improved food preparation skills. CONCLUSIONS: Simple Suppers led to improvements in children's weight status, food preparation skills, and TV viewing during meals, but not diet or z-scores for BMI, waist circumference, or BP. Future research should examine the preventive effects of healthy family mealtime routines in children at greatest risk for obesity. TRIAL REGISTRATION: NCT02923050; Simple Suppers Scale-up (S3); Retrospectively registered on Oct 2016; First participant enrolled on Jan 2015.

Design, Synthesis and Characterization of Covalent KDM5 Inhibitors.

Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub-family. The covalent binding to the targeted proteins was confirmed by MS and time-dependent inhibition. Additional competition assays show that compounds were non 2-OG competitive. Target engagement and ChIP-seq analysis showed that the compounds inhibited the KDM5 members in cells at nano- to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites.

Assessment and management of diarrhea following VEGF receptor TKI treatment in patients with ovarian cancer.

Angiogenesis is a proven clinical target for the treatment of advanced epithelial ovarian cancer. Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) offer patients potential new treatment regimens as they can be given as monotherapy, in combination with poly(ADP-ribose) polymerase (PARP) inhibitors, or with and following cytotoxic chemotherapy. If VEGFR-TKIs are licensed for use in ovarian cancer, patients will require prompt and effective management of adverse events, including diarrhea, to optimize compliance and benefit. As diarrhea is one of the most prevalent toxicities of this class of drug, it is important to consider the potential causes, be they disease related (bowel obstruction), treatment related (VEGFR-TKI-related or infective/neutropenic septic diarrhea when patients are receiving cytotoxic chemotherapy combined with VEGFR inhibitor treatment), or incurred through diet. Here, we provide an overview of the possible mechanisms responsible for VEGFR-TKI-induced diarrhea. We review potential interventions that can help in the management of diarrhea induced by VEGFR-TKIs, when used in combination or as single agents, and we provide a diarrhea treatment algorithm to serve as a clinical reference point for the management of diarrhea in patients with ovarian cancer treated with a VEGFR-TKI in combination with chemotherapy or PARP inhibitors, or as monotherapy.

Early impact of the ICD-10-CM transition on selected health outcomes in 13 electronic health care databases in the United States.

PURPOSE: To describe the consistency in the frequency of 5 health outcomes across the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and Tenth Revision, Clinical Modification (ICD-10-CM) eras in the US. METHODS: We examined the incidence of 3 acute conditions (acute myocardial infarction [AMI], angioedema, ischemic stroke) and the prevalence of 2 chronic conditions (diabetes, hypertension) during the final 5 years of the ICD-9-CM era (January 2010-September 2015) and the first 15 months of the ICD-10-CM era (October 2015-December 2016) in 13 electronic health care databases in the Sentinel System. For each health outcome reviewed during the ICD-10-CM era, we evaluated 4 definitions, including published algorithms derived from other countries, as well as simple-forward, simple-backward, and forward-backward mapping using the General Equivalence Mappings. For acute conditions, we also compared the incidence between April to December 2014 and April to December 2016. RESULTS: The analyses included data from approximately 172 million health plan members. While the incidence or prevalence of AMI and hypertension performed similarly across the 2 eras, the other 3 outcomes did not demonstrate consistent trends for some or all the ICD-10-CM definitions assessed. CONCLUSIONS: When using data from both the ICD-9-CM and ICD-10-CM eras, or when using results from ICD-10-CM data to compare to results from ICD-9-CM data, researchers should test multiple ICD-10-CM outcome definitions as part of sensitivity analysis. Ongoing assessment of the impact of ICD-10-CM transition on identification of health outcomes in US electronic health care databases should occur as more data accrue.

Assessing the impact of the new ICD-10-CM coding system on pharmacoepidemiologic studies-An application to the known association between angiotensin-converting enzyme inhibitors and angioedema.

PURPOSE: To replicate the well-established association between angiotensin-converting enzyme inhibitors versus beta blockers and angioedema in the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) era. METHODS: We conducted a retrospective, inception cohort study in a large insurance database formatted to the Sentinel Common Data Model. We defined study periods spanning the ICD-9-CM era only, ICD-10-CM era only, and ICD-9-CM and ICD-10-CM era and conducted simple-forward mapping (SFM), simple-backward mapping (SBM), and forward-backward mapping (FBM) referencing the General Equivalence Mappings to translate the outcome (angioedema) and covariates from ICD-9-CM to ICD-10-CM. We performed propensity score (PS)-matched and PS-stratified Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In the ICD-9-CM and ICD-10-CM eras spanning April 1 to September 30 of 2015 and 2016, there were 152 017 and 145 232 angiotensin-converting enzyme inhibitor initiators and 115 073 and 116 652 beta-blocker initiators, respectively. The PS-matched HR was 4.19 (95% CI, 2.82-6.23) in the ICD-9-CM era, 4.37 (2.92-6.52) in the ICD-10-CM era using SFM, and 4.64 (3.05-7.07) in the ICD-10-CM era using SBM and FBM. The PS-matched HRs from the mixed ICD-9-CM and ICD-10-CM eras ranged from 3.91 (2.69-5.68) to 4.35 (3.33-5.70). CONCLUSION: The adjusted HRs across different diagnostic coding eras and the use of SFM versus SBM and FBM produced numerically different but clinically similar results. Additional investigations as ICD-10-CM data accumulate are warranted.

Prospective surveillance pilot of rivaroxaban safety within the US Food and Drug Administration Sentinel System.

PURPOSE: The US Food and Drug Administration's Sentinel system developed tools for sequential surveillance. METHODS: In patients with non-valvular atrial fibrillation, we sequentially compared outcomes for new users of rivaroxaban versus warfarin, employing propensity score matching and Cox regression. A total of 36 173 rivaroxaban and 79 520 warfarin initiators were variable-ratio matched within 2 monitoring periods. RESULTS: Statistically significant signals were observed for ischemic stroke (IS) (first period) and intracranial hemorrhage (ICH) (second period) favoring rivaroxaban, and gastrointestinal bleeding (GIB) (second period) favoring warfarin. In follow-up analyses using primary position diagnoses from inpatient encounters for increased definition specificity, the hazard ratios (HR) for rivaroxaban vs warfarin new users were 0.61 (0.47, 0.79) for IS, 1.47 (1.29, 1.67) for GIB, and 0.71 (0.50, 1.01) for ICH. For GIB, the HR varied by age: <66 HR = 0.88 (0.60, 1.30) and 66+ HR = 1.49 (1.30, 1.71). CONCLUSIONS: This study demonstrates the capability of Sentinel to conduct prospective safety monitoring and raises no new concerns about rivaroxaban safety.

Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.

Methods and design of a 10-week multi-component family meals intervention: a two group quasi-experimental effectiveness trial.

BACKGROUND: Given the ongoing childhood obesity public health crisis and potential protective effect of family meals, there is need for additional family meals research, specifically experimental studies with expanded health outcomes that focus on the at-risk populations in highest need of intervention. Future research, specifically intervention work, would also benefit from an expansion of the target age range to include younger children, who are laying the foundation of their eating patterns and capable of participating in family meal preparations. The purpose of this paper is to address this research gap by presenting the objectives and research methods of a 10-week multi-component family meals intervention study aimed at eliciting positive changes in child diet and weight status. METHODS: This will be a group quasi-experimental trial with staggered cohort design. Data will be collected via direct measure and questionnaires at baseline, intervention completion (or waiting period for controls), and 10-weeks post-intervention. Setting will be faith-based community center. Participants will be 60 underserved families with at least 1, 4-10 year old child will be recruited and enrolled in the intervention (n = 30) or waitlist control group (n = 30). The intervention (Simple Suppers) is a 10-week family meals program designed for underserved families from racial/ethnic diverse backgrounds. The 10, 90-min program lessons will be delivered weekly over the dinner hour. Session components include: a) interactive group discussion of strategies to overcome family meal barriers, plus weekly goal setting for caregivers; b) engagement in age-appropriate food preparation activities for children; and c) group family meal for caregivers and children. Main outcome measures are change in: child diet quality; child standardized body mass index; and frequency of family meals. Regression models will be used to compare response variables results of intervention to control group, controlling for confounders. Analyses will account for clustering by family and cohort. Significance will be set at p < 0.05. DISCUSSION: This is the first experimentally designed family meals intervention that targets underserved families with elementary school age children and includes an examination of health outcomes beyond weight status. Results will provide researchers and practitioners with insight on evidence-based programming to aid in childhood obesity prevention. TRIAL REGISTRATION: NCT02923050 . Registered 03 October 2016. Retrospectively registered.

Combined hydrogels that switch human pluripotent stem cells from self-renewal to differentiation.

The ability of materials to define the architecture and microenvironment experienced by cells provides new opportunities to direct the fate of human pluripotent stem cells (HPSCs) [Robinton DA, Daley GQ (2012) Nature 481(7381):295-305]. However, the conditions required for self-renewal vs. differentiation of HPSCs are different, and a single system that efficiently achieves both outcomes is not available [Giobbe GG, et al. (2012) Biotechnol Bioeng 109(12):3119-3132]. We have addressed this dual need by developing a hydrogel-based material that uses ionic de-cross-linking to remove a self-renewal permissive hydrogel (alginate) and switch to a differentiation-permissive microenvironment (collagen). Adjusting the timing of this switch can preferentially steer the HPSC differentiation to mimic lineage commitment during gastrulation to ectoderm (early switch) or mesoderm/endoderm (late switch). As an exemplar differentiated cell type, we showed that directing early lineage specification using this single system can promote cardiogenesis with increased gene expression in high-density cell populations. This work will facilitate regenerative medicine by allowing in situ HPSC expansion to be coupled with early lineage specification within defined tissue geometries.

Discovery of a PCAF Bromodomain Chemical Probe.

The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.

Vowel identification by cochlear implant users: Contributions of duration cues and dynamic spectral cues.

A recent study from our laboratory assessed vowel identification in cochlear implant (CI) users, using full /dVd/ syllables and partial (center- and edges-only) syllables with duration cues neutralized [Donaldson, Rogers, Cardenas, Russell, and Hanna (2013). J. Acoust. Soc. Am. 134, 3021-3028]. CI users' poorer performance for partial syllables as compared to full syllables, and for edges-only syllables as compared to center-only syllables, led to the hypotheses (1) that CI users may rely strongly on vowel duration cues; and (2) that CI users have more limited access to dynamic spectral cues than steady-state spectral cues. The present study tested those hypotheses. Ten CI users and ten young normal hearing (YNH) listeners heard full /dVd/ syllables and modified (center- and edges-only) syllables in which vowel duration cues were either preserved or eliminated. The presence of duration cues significantly improved vowel identification scores in four CI users, suggesting a strong reliance on duration cues. Duration effects were absent for the other CI users and the YNH listeners. On average, CI users and YNH listeners demonstrated similar performance for center-only stimuli and edges-only stimuli having the same total duration of vowel information. However, three CI users demonstrated significantly poorer performance for the edges-only stimuli, indicating apparent deficits of dynamic spectral processing.

LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.

The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.

Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains.

Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (Kd = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets.

A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-π interaction.

The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation-π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.

Unexpected Noncovalent Off-Target Activity of Clinical BTK Inhibitors Leads to Discovery of a Dual NUDT5/14 Antagonist.

Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead. Further investigation of the prototypical BTK inhibitor ibrutinib also revealed potent inhibition of the largely unstudied NUDIX hydrolase family member NUDT14. By exploring structure-activity relationships (SARs) around the core scaffold, we identify a potent, noncovalent, and cell-active dual NUDT5/14 inhibitor. Cocrystallization experiments yielded new insights into the NUDT14 hydrolase active site architecture and inhibitor binding, thus providing a basis for future chemical probe design.

Specialized early treatment for persons with disorders of consciousness: program components and outcomes.

OBJECTIVES: To describe a specialized early treatment program for persons with disorders of consciousness (DOC) that includes family education; to identify rates of secondary conditions, imaging used, and selected interventions; and to evaluate outcomes. DESIGN: A single-center, retrospective, pre-post design using electronic medical record data. SETTING: A Commission on Accreditation of Rehabilitation Facilities-accredited, long-term acute care hospital that provides acute medical and inpatient rehabilitation levels of care for people with catastrophic injuries. PARTICIPANTS: Persons (N=210) aged 14 to 69 years with DOC of primarily traumatic etiology admitted at a mean ± SD of 41.0 ± 27.2 days postinjury; 2% were in coma, 41% were in the vegetative state, and 57% were in the minimally conscious state. INTERVENTIONS: An acute medical level of care with ≥90 minutes of daily interdisciplinary rehabilitation and didactic and hands-on caretaking education for families. MAIN OUTCOME MEASURES: Coma Recovery Scale-Revised, Modified Ashworth Scale, and discharge disposition. RESULTS: Program admission medical acuity included dysautonomia (15%), airway modifications (79%), infections (eg, pneumonia, 16%; urinary tract infection, 14%; blood, 11%), deep vein thrombosis (17%), pressure ulcers (14%), and marked hypertonia (30% in each limb). There were 168 program interruptions (ie, 139 surgeries, 29 nonsurgical intensive care unit transfers). Mean length of stay ± SD was 39.1 ± 29.4 days (range, 6-204d). Patients showed improved consciousness and respiratory function and reduced presence or severity of pressure ulcers and upper extremity hypertonia. At discharge, 54% showed sufficient emergence from a minimally conscious state to transition to mainstream inpatient rehabilitation, and 29% did not emerge but were discharged home to family with ongoing programmatic support; only 13% did not emerge and were institutionalized. CONCLUSIONS: Persons with DOC resulting primarily from a traumatic etiology who receive specialized early treatment that includes acute medical care and ≥90 minutes of daily rehabilitation are likely to show improved consciousness and body function; more than half may transition to mainstream inpatient rehabilitation. Families who receive comprehensive education and hands-on training with ongoing follow-up support may be twice as likely to provide care for medically stable persons with DOC in their homes versus nursing facility placement.

Vowel identification by cochlear implant users: contributions of static and dynamic spectral cues.

Previous research has shown that normal hearing listeners can identify vowels in syllables on the basis of either quasi-static or dynamic spectral cues; however, it is not known how well cochlear implant (CI) users with current-generation devices can make use of these cues. The present study assessed vowel identification in adult CI users and a comparison group of young normal hearing (YNH) listeners. Stimuli were naturally spoken /dVd/ syllables and modified syllables that retained only quasi-static spectral cues from an 80-ms segment of the vowel center ("C80" stimuli) or dynamic spectral cues from two 20-ms segments of the vowel edges ("E20" stimuli). YNH listeners exhibited near-perfect performance for the unmodified (99.8%) and C80 (92.9%) stimuli and maintained good performance for the E20 stimuli (70.2%). CI users exhibited poorer average performance than YNH listeners for the Full stimuli (72.3%) and proportionally larger reductions in performance for the C80 stimuli (41.8%) and E20 stimuli (29.0%). Findings suggest that CI users have difficulty identifying vowels on the basis of spectral cues in the absence of duration cues, and have limited access to brief dynamic spectral cues. Error analyses suggest that CI users may rely strongly on vowel duration cues when those cues are available.