Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction.

Aims: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. Methods and results: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18–96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33–1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75–1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. Conclusion: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted

Idiosyncratic use of bottom-up and top-down information leads to differences in speech perception flexibility: Converging evidence from ERPs and eye-tracking

Available online 8 October 2021.Listeners generally categorize speech sounds in a gradient manner. However, recent work, using a visual analogue scaling (VAS) task, suggests that some listeners show more categorical performance, leading to less flexible cue integration and poorer recovery from misperceptions (Kapnoula et al., 2017, 2021). We asked how individual differences in speech gradiency can be reconciled with the well-established gradiency in the modal listener, showing how VAS performance relates to both Visual World Paradigm and EEG measures of gradiency. We also investigated three potential sources of these individual differences: inhibitory control; lexical inhibition; and early cue encoding. We used the N1 ERP component to track pre-categorical encoding of Voice Onset Time (VOT). The N1 linearly tracked VOT, reflecting a fundamentally gradient speech perception; however, for less gradient listeners, this linearity was disrupted near the boundary. Thus, while all listeners are gradient, they may show idiosyncratic encoding of specific cues, affecting downstream processing.This project was supported by NIH Grant DC008089 awarded to BM. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 793919, awarded to EK. This work was partially supported by the Basque Government through the BERC 2018-2021 program and by the Spanish State Research Agency through BCBL Severo Ochoa excellence accreditation SEV-2015-0490

Association is not causation: treatment effects cannot be estimated from observational data in heart failure

Aims: Treatment ‘effects’ are often inferred from non-randomized and observational studies. These studies have inherent biases and limitations, which may make therapeutic inferences based on their results unreliable. We compared the conflicting findings of these studies to those of prospective randomized controlled trials (RCTs) in relation to pharmacological treatments for heart failure (HF). Methods and results: We searched Medline and Embase to identify studies of the association between non-randomized drug therapy and all-cause mortality in patients with HF until 31 December 2017. The treatments of interest were: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists (MRAs), statins, and digoxin. We compared the findings of these observational studies with those of relevant RCTs. We identified 92 publications, reporting 94 non-randomized studies, describing 158 estimates of the ‘effect’ of the six treatments of interest on all-cause mortality, i.e. some studies examined more than one treatment and/or HF phenotype. These six treatments had been tested in 25 RCTs. For example, two pivotal RCTs showed that MRAs reduced mortality in patients with HF with reduced ejection fraction. However, only one of 12 non-randomized studies found that MRAs were of benefit, with 10 finding a neutral effect, and one a harmful effect. Conclusion: This comprehensive comparison of studies of non-randomized data with the findings of RCTs in HF shows that it is not possible to make reliable therapeutic inferences from observational associations. While trials undoubtedly leave gaps in evidence and enrol selected participants, they clearly remain the best guide to the treatment of patients

Mental Health Needs & Barriers: Assessment of Latinos in Las Vegas

Research suggests that the prevalence of mental illness in Latinos is not necessarily uncommon and that economic concerns may be an important factor in determining the type of services Latinos are likely to seek (Kouyoumdjian, 2003). For Latinos, mental health disorders such as depression and anxiety have higher rates than the general population but the rate at which Latinos seek treatment is strikingly lower (Barrio, 2008). Observations regarding treatment engagement rates conclude that Latinos also have significantly higher probability of terminating treatments prematurely (Kouyoumdjian, 2003). Aim: to examine the mental health needs and barriers to treatment present in the Latino community of Las Vegas, Nevada

Gradient Activation of Speech Categories Facilitates Listeners’ Recovery From Lexical Garden Paths, But Not Perception of Speech-in-Noise

Published 2021 AprListeners activate speech-sound categories in a gradient way, and this information is maintained and affects activation of items at higher levels of processing (McMurray et al., 2002; Toscano et al., 2010). Recent findings by Kapnoula et al. (2017) suggest that the degree to which listeners maintain within-category information varies across individuals. Here we assessed the consequences of this gradiency for speech perception. To test this, we collected a measure of gradiency for different listeners using the visual analogue scaling (VAS) task used by Kapnoula et al. (2017). We also collected 2 independent measures of performance in speech perception: a visual world paradigm (VWP) task measuring participants’ ability to recover from lexical garden paths (McMurray et al., 2009) and a speech-perception task measuring participants’ perception of isolated words in noise. Our results show that categorization gradiency does not predict participants’ performance in the speech-in-noise task. However, higher gradiency predicted higher likelihood of recovery from temporarily misleading information presented in the VWP task. These results suggest that gradient activation of speech sound categories is helpful when listeners need to reconsider their initial interpretation of the input, making them more efficient in recovering from errors.This project was supported by National Institutes of Health Grant DC008089 awarded to Bob McMurray. This work was partially supported by the Basque Government through the BERC 2018-2021 Program and by the Spanish State Research Agency through BCBL Severo Ochoa excellence accreditation SEV-2015-0490. This project was partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO) through the convocatoria 2016 Subprograma Estatal Ayudas para contratos para la Formación Posdoctoral 2016, Programa Estatal de Promoción del Talento y su Empleabilidad del Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016, reference FJCI-2016-28019 awarded to Efthymia C. Kapnoula. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant 793919, awarded to Efthymia C. Kapnoula

Too much of a good thing: How novelty biases and vocabulary influence known and novel referent selection in 18-month-old children and associative learning models

Identifying the referent of novel words is a complex process that young children do with relative ease. When given multiple objects along with a novel word, children select the most novel item, sometimes retaining the word‐referent link. Prior work is inconsistent, however, on the role of object novelty. Two experiments examine 18‐month‐old children's performance on referent selection and retention with novel and known words. The results reveal a pervasive novelty bias on referent selection with both known and novel names and, across individual children, a negative correlation between attention to novelty and retention of new word‐referent links. A computational model examines possible sources of the bias, suggesting novelty supports in‐the‐moment behavior but not retention. Together, results suggest that when lexical knowledge is weak, attention to novelty drives behavior, but alone does not sustain learning. Importantly, the results demonstrate that word learning may be driven, in part, by low‐level perceptual processes

Dynamic EEG analysis during language comprehension reveals interactive cascades between perceptual processing and sentential expectations

Available online 18 October 2020.Understanding spoken language requires analysis of the rapidly unfolding speech signal at multiple levels: acoustic, phonological, and semantic. However, there is not yet a comprehensive picture of how these levels relate. We recorded electroencephalography (EEG) while listeners (N = 31) heard sentences in which we manipulated acoustic ambiguity (e.g., a bees/peas continuum) and sentential expectations (e.g., Honey is made by bees). EEG was analyzed with a mixed effects model over time to quantify how language processing cascades proceed on a millisecond-by-millisecond basis. Our results indicate: (1) perceptual processing and memory for fine-grained acoustics is preserved in brain activity for up to 900 msec; (2) contextual analysis begins early and is graded with respect to the acoustic signal; and (3) top-down predictions influence perceptual processing in some cases, however, these predictions are available simultaneously with the veridical signal. These mechanistic insights provide a basis for a better understanding of the cortical language network.This work was supported by NIH grant DC008089 awarded to BM. This work was partially supported by the Basque Government through the BERC 2018–2021 program and by the Spanish State Research Agency through BCBL Severo Ochoa excellence accreditation SEV-2015- 0490, as well as by a postdoctoral grant from the Spanish Ministry of Economy and Competitiveness (MINECO; reference FJCI-2016-28019), awarded to EK

Redefining heart failure phenotypes based on ejection fraction

No abstract available