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Purpose: Atypical vowel production contributes to reduced speech intelligibility in children and adults with Down syndrome (DS). This study compares the acoustic data of the corner vowels /i/, /u/, /ae/, and /[open back unrounded vowel]/ from speakers with DS against typically developing/developed (TD) speakers. Method: Measurements of the fundamental frequency (f[subscript o]) and first four formant frequencies (F1-F4) were obtained from single word recordings containing the target vowels from 81 participants with DS (ages 3-54 years) and 293 TD speakers (ages 4-92 years), all native speakers of English. The data were used to construct developmental trajectories and to determine interspeaker and intraspeaker variability. Results: Trajectories for DS differed from TD based on age and sex, but the groups were similar with the striking change in f[subscript o] and F1-F4 frequencies around age 10 years. Findings confirm higher f[subscript o] in DS, and vowel-specific differences between DS and TD in F1 and F2 frequencies, but not F3 and F4. The measure of F2 differences of front-versus-back vowels was more sensitive of compression than reduced vowel space area/centralization across age and sex. Low vowels had more pronounced F2 compression as related to reduced speech intelligibility. Intraspeaker variability was significantly greater for DS than TD for nearly all frequency values across age. Discussion: Vowel production differences between DS and TD are age- and sex-specific, which helps explain contradictory results in previous studies. Increased intraspeaker variability across age in DS confirms the presence of a persisting motor speech disorder. Atypical vowel production in DS is common and related to dysmorphology, delayed development, and disordered motor control.

BackgroundPatients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable effects on pathways related to myocardial structure and function and therefore could impact subsequent heart failure events. The effect of apabetalone on heart failure events after an ACS is not currently known.MethodsThe phase 3 BETonMACE trial was a double-blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecified secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied.ResultsPatients (age 62 years, 74.4% males, 90% high-intensity statin use, LDL-C 70.3 mg/dL, HDL-C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal finding of a lower rate of first hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38-0.94], P = 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27-0.83], P = 0.01) and the combination of cardiovascular death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI 0.53-0.98], P = 0.04).ConclusionApabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to define the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS.

Background and objectivesCKD and type 2 diabetes mellitus interact to increase the risk of major adverse cardiovascular events (i.e., cardiovascular death, nonfatal myocardial infarction, or stroke) and congestive heart failure. A maladaptive epigenetic response may be a cardiovascular risk driver and amenable to modification with apabetalone, a selective modulator of the bromodomain and extraterminal domain transcription system. We examined this question in a prespecified analysis of BETonMACE, a phase 3 trial.Design, setting, participants, & measurementsBETonMACE was an event-driven, randomized, double-blind, placebo-controlled trial comparing effects of apabetalone versus placebo on major adverse cardiovascular events and heart failure hospitalizations in 2425 participants with type 2 diabetes and a recent acute coronary syndrome, including 288 participants with CKD with eGFR

Abstract Background and Aims Patients with type 2 diabetes (T2D) and acute coronary syndrome (ACS) are at high risk for recurrent cardiovascular (CV) events, particularly in the presence of chronic kidney disease (CKD). Apabetalone (APB) is a novel inhibitor of bromodomain and extraterminal (BET) proteins. Its cardiovascular efficacy and safety were evaluated in a phase 3 trial, BETonMACE. Method BETonMACE was a randomized, double-blind, comparison of effects of ABP or placebo (PBO) on major adverse CV events (MACE) defined as CV-death, non-fatal myocardial infarct or stroke, in 2425 pts with T2D and recent ACS. Here we report MACE plus CHF hospitalization in subjects with or without CKD Stage 3. Results Baseline characteristics: median age 62 years, 25.6% female, 87.6% white, 90% high intensity statin use, mean LDL-C 70.3 and HDL-C 33.3 mg/dl, median HbA1c 7.3%, and 11% with CKD Stage 3. Overall in the trial, MACE plus CHF hospitalization occurred in 139 (11.5%) patients with ABP and 173 (14.3%) with PBO (HR 0.78, 95% CI 0.63-0.98). In the subgroup with CKD, MACE plus CHF hospitalization occurred in 16 (12.9%) on APB and 41 (25%) on PBO (HR 0.48, 95% CI 0.26-0.89). In the subgroup without CKD, MACE plus CHF hospitalization occurred in 123 (11.3%) and 132 (12.7%) with APB or PBO, respectively (HR 0.89, 95% CI 0.70-1. Conclusion Patients with T2D, ACS, and Stage 3 CKD have a very high risk of subsequent MACE plus CHF hospitalization. The BET protein inhibitor ABP may reduce this risk.

ImportanceBromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Apabetalone is a selective bromodomain and extraterminal protein inhibitor targeting bromodomain 2 and is hypothesized to have potentially favorable effects on pathways related to atherothrombosis. Pooled phase 2 data suggest favorable effects on clinical outcomes.ObjectiveTo test whether apabetalone significantly reduces major adverse cardiovascular events.Design, setting, and participantsA randomized, double-blind, placebo-controlled trial, conducted at 190 sites in 13 countries. Patients with an acute coronary syndrome in the preceding 7 to 90 days, type 2 diabetes, and low high-density lipoprotein cholesterol levels were eligible for enrollment, which started November 11, 2015, and ended July 4, 2018, with end of follow-up on July 3, 2019.InterventionsPatients were randomized (1:1) to receive apabetalone, 100 mg orally twice daily (n = 1215), or matching placebo (n = 1210) in addition to standard care.Main outcomes and measuresThe primary outcome was a composite of time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke.ResultsAmong 2425 patients who were randomized (mean age, 62 years; 618 women [25.6%]), 2320 (95.7%) had full ascertainment of the primary outcome. During a median follow-up of 26.5 months, 274 primary end points occurred: 125 (10.3%) in apabetalone-treated patients and 149 (12.4%) in placebo-treated patients (hazard ratio, 0.82 [95% CI, 0.65-1.04]; P = .11). More patients allocated to apabetalone than placebo discontinued study drug (114 [9.4%] vs 69 [5.7%]) for reasons including elevations of liver enzyme levels (35 [2.9%] vs 11 [0.9%]).Conclusions and relevanceAmong patients with recent acute coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, the selective bromodomain and extraterminal protein inhibitor apabetalone added to standard therapy did not significantly reduce the risk of major adverse cardiovascular events.Trial registrationClinicalTrials.gov Identifier: NCT02586155.

A randomized, double-blind trial was conducted to determine efficacy of torcetrapib, a potent cholesteryl ester transfer protein inhibitor to reduce major cardiovascular events. The trial was terminated prematurely as it increased risk of death and cardiac events in patients receiving torcetrapib.

Background: Postcancer work limitations may affect a substantial proportion of patients and contribute to the "financial toxicity" of cancer treatment. The degree and nature of work limitations and employment outcomes are poorly understood for cancer patients, particularly in the immediate period of transition after active treatment. We prospectively examined employment, work ability, and work limitations during and after treatment. Methods: A total of 120 patients receiving curative therapy who were employed prior to their cancer diagnosis and who intended to work during or after end of treatment (EOT) completed surveys at baseline (pretreatment), EOT, and 3, 6, and 12 months after EOT. Surveys included measures of employment, work ability, and work limitations. Descriptive statistics (frequencies, percentages, means with standard deviations) were calculated. Results: A total of 111 participants completed the baseline survey. On average, participants were 48 years of age and were mostly white (95%) and female (82%) with a diagnosis of breast cancer (69%). Full‐time employment decreased during therapy (from 88% to 50%) and returned to near prediagnosis levels by 12‐month follow‐up (78%). Work‐related productivity loss due to health was high during treatment. Conclusions: This study is the first to report the effects of curative intent cancer therapy on employment, work ability, and work limitations both during and after treatment. Perceived work ability was generally high overall 12 months after EOT, although a minority reported persistent difficulty. A prospective analysis of factors (eg, job type, education, symptoms) most associated with work limitations is underway to assist in identifying at‐risk patients. Adjuvant therapy for cancer can have a negative effect on a patient's ability to work, but the degree of work limitation due to cancer treatment has not been captured prospectively in a longitudinal fashion. This prospective study of patients with cancer receiving adjuvant chemotherapy who worked during cancer treatment reveals that most patients eventually returned to the same level of work that they had performed before treatment. [ABSTRACT FROM AUTHOR]

Objective To compare rates of retinal detachment ( RD) postphacoemulsification in American Bichon Frises with and without prophylactic retinopexy. Procedures Medical records of 54 Bichon Frises undergoing phacoemulsification with or without prophylactic retinopexy between 2003 and 2013 in one or both eyes were reviewed from five Midwestern university veterinary teaching hospitals. Inclusion criteria were preoperative ERG, at least 6 months of follow-up postphacoemulsification, and the absence of preexisting RD as determined by ophthalmic examination and/or ultrasound. Statistical analyses were performed using chi-squared test, and Wilcoxon rank-sum tests and Wilson confidence intervals with the P-value <0.05 were considered significant. Results Phacoemulsification was performed without retinopexy in 79 eyes (42 dogs, non- PR group) and with prophylactic retinopexy in 23 eyes (12 dogs, PR group). Incidence of diabetes mellitus was 10/42 and 3/12 in the non- PR and the PR groups, respectively ( P = 0.93). Intraocular lens implantation was performed in 40/42 non- PR dogs and 11/12 PR dogs ( P = 0.63, 73/79 vs. 21/23 eyes). At final re-examination, RD occurred in 4/79 eyes without retinopexy, compared to 0/23 RD in the retinopexy group. There was no statistically significant difference in RD rates between the two groups ( P = 0.27). Conclusions These data provide no statistical evidence to support prophylactic retinopexy in Bichon Frises. Due to the low rate of retinal detachment following phacoemulsification without prophylactic retinopexy, the procedure appears to offer limited benefit to offset cost, procedural risk, and risk of extended or repeated anesthesia in Bichon Frises. [ABSTRACT FROM AUTHOR]