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"Hoffman, James E"
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Natural history and progression of transthyretin amyloid cardiomyopathy: insights from ATTR‐ACT
Aims Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a progressive, fatal disorder that remains underdiagnosed. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) was the first large clinical trial to include both wild‐type (ATTRwt) and hereditary (ATTRv) patients. A description of the natural history of ATTR‐CM, utilizing data from placebo‐treated patients in ATTR‐ACT, will provide a greater understanding of presentation and progression of ATTR‐CM and may aid in disease awareness, earlier diagnosis and treatment monitoring. Methods and results Changes in clinical endpoints (mortality, cardiovascular [CV]‐related hospitalizations, 6‐min walk test [6MWT] distance and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ‐OS] score) from baseline to Month 30 in the 177 patients (134 ATTRwt, 43 ATTRv) who received placebo in ATTR‐ACT were assessed. ATTRwt patients tended to have less severe disease at baseline. Over the duration of ATTR‐ACT, there were 76 (42.9%) all‐cause deaths, and 107 (60.5%) patients had a CV‐related hospitalization. There was a lower proportion of all‐cause deaths in ATTRwt (49, 36.6%) than ATTRv (27, 62.8%). There was a similar, steady decline in mean (SD) 6MWT distance from baseline to Month 30 in ATTRwt (93.9 [93.7] m) and ATTRv (89.1 [107.2] m) patients. The decline in mean (SD) KCCQ‐OS score was less severe in ATTRwt (13.8 [20.7]) than ATTRv (21.0 [26.4]) patients. Conclusions Patients with ATTR‐CM experience a severe, progressive disease. In ATTR‐ACT, placebo‐treated patients with ATTRv, compared with ATTRwt, had more severe disease at baseline, and their disease progressed more rapidly as shown by mortality, hospitalizations and quality of life over time.
Journal Article
Emotion-induced blindness reflects competition at early and late processing stages: An ERP study
Emotion-induced blindness (EIB) refers to impaired awareness of items appearing soon after an
irrelevant
,
emotionally arousing
stimulus. Superficially, EIB appears to be similar to the attentional blink (AB), a failure to report a target that closely follows another
relevant target
. Previous studies of AB using event-related potentials suggest that the AB results from interference with selection (N2 component) and consolidation (P3b component) of the second target into working memory. The present study applied a similar analysis to EIB and, similarly, found that an irrelevant emotional distractor suppressed the N2 and P3b components associated with the following target at short lags. Emotional distractors also elicited a positive deflection that appeared to be similar to the P
D
component, which has been associated with attempts to suppress salient, irrelevant distractors (Kiss, Grubert, Petersen, & Eimer,
2012
; Sawaki, Geng, & Luck,
2012
; Sawaki & Luck,
2010
). These results suggest that irrelevant emotional pictures gain access to working memory, even when observers are attempting to ignore them and, like the AB, prevent access of a closely following target.
Journal Article
The role of visual attention in multiple object tracking: Evidence from ERPs
We examined the role of visual attention in the multiple object tracking (MOT) task by measuring the amplitude of the N1 component of the event-related potential to probe flashes presented on targets, distractors, or empty background areas. We found evidence that visual attention enhances targets and suppresses distractors (Experiments 1 and 3). However, we also found that when tracking load was light (two targets and two distractors), accurate tracking could be carried out without any apparent contribution from the visual attention system (Experiment 2). Our results suggest that attentional selection during MOT is flexibly determined by task demands, as well as tracking load, and that visual attention may not always be necessary for accurate tracking.
Journal Article
The N400 component reflecting semantic and repetition priming of visual scenes is suppressed during the attentional blink
In the attentional blink paradigm, participants attempt to identify two targets appearing in a rapidly presented stream of distractors. Report accuracy is typically high for the first target (T1) while identification of the second target (T2) is impaired when it follows within about 200–400 ms of T1. An important question is whether T2 is processed to a semantic level even when participants are unaware of its identity. We examined this issue in three studies that used natural scenes as stimuli and the N400 component of the event-related potential (ERP) as a measure of semantic priming. In the first experiment, the prime (e.g., a doghouse in a yard) was presented at the beginning of the trial and a test picture that was related (e.g., a dog standing in the kitchen) or unrelated (e.g., a coffee mug on a table) appeared as T2. In the second experiment, the prime was presented as T2 and the test picture appeared at the end of the picture sequence. In both experiments, we found robust semantic priming when participants were aware of the identity of the blinked picture and an absence of priming when they were unaware. In Experiment
3
, we used identity priming to assess whether earlier representations preceding semantics were preserved, and again found that priming critically depended on awareness of the prime’s identity. These results suggest that semantic priming in scenes, as measured with the N400, is a higher-level process that critically depends on attention and awareness.
Journal Article
Safety and Efficacy of Traditional Heart Failure Therapies in Patients With Cardiac Amyloidosis and Heart Failure
Randomized controlled trials have demonstrated mortality benefits for several medication classes in patients with heart failure (HF), especially with reduced ejection fraction (EF). However, the benefit of these traditional HF therapies in patients with HF from cardiac amyloidosis is unclear. our study aimed to evaluate the safety and efficacy of traditional HF therapies in patients with cardiac amyloidosis and HF with reduced EF or HF with mid-range EF (HFmrEF). We conducted a single-center retrospective study. Patients were included if they were diagnosed with cardiac amyloidosis and HF with reduced EF or HF with mid-range EF between January 2012 and 2022. The primary outcomes of interest were medication use patterns (for β blockers [BB], angiotensin-converting enzyme inhibitors [ACEI], angiotensin receptor blockers [ARBs], angiotensin receptor neprilysin inhibitors [ARNI], and mineralocorticoid receptor antagonists [MRAs]); potential medication side effects (symptomatic bradycardia, fatigue, hypotension, lightheadedness, and syncope); hospitalization; and death. The associations of BB, ACEI/ARB/ARNI, and MRA use with clinical outcomes were evaluated using Kaplan-Meier and Cox proportional hazards regression. A total of 82 patients met study criteria. At time of cardiac amyloidosis diagnosis, 63.4% were on a BB, 51.2% were on an ACEI/ARB/ARNI, and 43.9% were on an MRA. At last follow-up, 51.2% were on a BB, 35.4% were on an ACEI/ARB/ARNI, and 43.9% were on an MRA. There were no statistically significant differences in rates of potential medication side effects in patients on the medication class compared with those who were not. There was no association with hospitalization or mortality for baseline or follow-up BB, ACEI/ARB/ARNI, or MRA use. In conclusion, BBs, ACEI/ARB/ARNIs, and MRAs may be safely used in this population. However, their use does not appear to improve mortality or hospitalization.
Journal Article
Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens
Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.
Journal Article