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Atrial fibrillation (AF) is common in patients with transthyretin cardiac amyloidosis (ATTR-CA). The optimal strategy to prevent strokes in patients with ATTR-CA and AF is unknown. To compare outcomes in patients with ATTR-CA and AF treated with warfarin versus novel oral anticoagulants (NOACs). This study was a retrospective analysis of patients with ATTR-CA stratified by presence or absence of AF and anticoagulation therapy. The primary outcome included a time to event analysis for the combined outcomes of stroke, transient ischaemic attack (TIA), major bleed, or death. Of 290 patients, 217 patients (74.8%) had AF. Of those with AF (n = 217), 78 (35.9%) patients received warfarin compared with 116 (53.5%) patients who received NOACs. There were 17 thrombotic events, all in those diagnosed with AF compared with none in the patients without AF (p =.01). Over a mean follow-up of 2.4 years (range 0.1–12) there was no difference in primary outcome between those with AF treated with warfarin compared with NOACs (p =.35). Patient with ATTR-CA and AF are at increased risk for stroke compared to patients with ATTR-CA and without AF. Thrombotic events and major bleeds did not differ between those who received warfarin and NOACs. [ABSTRACT FROM AUTHOR]

Aims: Advances in diagnostic imaging have increased the recognition of coexisting transthyretin cardiac amyloidosis (ATTR‐CA) and severe aortic stenosis (AS), with a reported prevalence between 8–16%. In this prospective study, we aimed to evaluate the implications of ATTR‐CA on outcomes after transcatheter aortic valve replacement (TAVR). Methods and results: At two academic centres, we screened patients with severe AS undergoing TAVR for ATTR‐CA. Using Kaplan–Meier analysis, we compared survival free from death and a combined endpoint of death and first heart failure hospitalization between patients with and without ATTR‐CA. Cox proportional‐hazards models were used to determine the association of ATTR‐CA with these endpoints. The rate of heart failure hospitalization was compared amongst those with and without ATTR‐CA. Overall, 204 patients (83 years, 65% male, Society of Thoracic Surgeons score 6.6%, 72% New York Heart Association class III/IV) were included, 27 (13%) with ATTR‐CA. Over a median follow‐up of 2.04 years, there was no difference in mortality (log rank, P = 0.99) or the combined endpoint (log rank, P = 0.79) between patients with and without ATTR‐CA. In Cox proportional‐hazards models, the presence of ATTR‐CA was not associated with death. However, patients with ATTR‐CA had increased rates of heart failure hospitalization at 1 year (0.372 vs. 0.114 events/person‐year, P < 0.004) and 3 years (0.199 vs. 0.111 events/person‐year, P = 0.087) following TAVR. Conclusion: In moderate‐risk patients with severe AS undergoing TAVR, there was a 13% prevalence of ATTR‐CA, which did not affect mortality. The observed increase in heart failure hospitalization following TAVR in those with ATTR‐CA suggests the consequences of the underlying infiltrative myopathy. [ABSTRACT FROM AUTHOR]

Light‐chain (AL) cardiac amyloidosis (CA) has a worse prognosis than transthyretin (ATTR) CA. In this single‐center study, we compared post‐heart transplant (OHT, orthotopic heart transplantation) survival for AL and ATTR amyloidosis, hypothesizing that these differences would persist post‐OHT. Thirty‐nine patients with CA (AL, n = 18; ATTR, n = 21) and 1023 non‐amyloidosis subjects undergoing OHT were included. Cox proportional hazards modeling was used to evaluate the impact of amyloid subtype and era (early era: from 2001 to 2007; late era: from 2008 to 2018) on survival post‐OHT. Survival for non‐amyloid patients was greater than ATTR (P =.034) and AL (P <.001) patients in the early era. One, 3‐, and 5‐year survival rates were higher for ATTR patients than AL patients in the early era (100% vs 75%, 67% vs 50%, and 67% vs 33%, respectively, for ATTR and AL patients). Survival in the non‐amyloid cohort was 87% at 1 year, 81% at 3 years, and 76% at 5 years post‐OHT. In the late era, AL and ATTR patients had unadjusted 1‐year, 3‐year, and 5‐year survival rates of 100%, which was comparable to non‐amyloid patients (90% vs 84% vs 81%). Overall, these findings demonstrate that in the current era, differences in post‐OHT survival for AL compared to ATTR are diminishing; OHT outcomes for selected patients with CA do not differ from non‐amyloidosis patients. [ABSTRACT FROM AUTHOR]

Background: Patients with transthyretin (TTR) cardiac amyloidosis demonstrate cardiac cachexia with progression of their cardiomyopathy, which is characterised by malnutrition and a heightened inflammatory state. How best to measure this condition is less well characterised. We investigated differences in survival among patients with ATTR cardiac amyloidosis by nutritional status as defined by modified BMI (mBMI) and by inflammatory state as defined by serum uric acid. Methods and results: This study was a retrospective analysis of patients diagnosed with ATTR cardiac amyloidosis at a single tertiary medical centre. Baseline characteristics were compared by nutritional status as measured by mBMI and by inflammatory state as measured by serum uric acid. Kaplan-Meier survival analyses were used to compare nutritional status and inflammatory status for the composite outcome of death. Cox proportional hazards modelling was used to assess predictors of death in this cohort. Three hundred patients (mean age 75 ± 11) years, 84.3% male) were included. Those with low mBMI (<1185 kg/m2 g/L) had shorter time to death (5.4 vs. 6.8 years, log rank p =.045) and those with elevated serum uric acid (>8.8 mg/dL) had shorter time to death (4.9 vs. 7.7 years, log rank p <.0001). Those with both low mBMI and elevated serum uric acid had the shortest time to death (4.3 years, log rank p =.005). In this cohort, mBMI was not a univariate predictor of death though there was a trend towards significance (HR 0.92, per 100 kg/m2 g/L, 95% CI 0.828–1.016, p =.099). Serum uric acid was a univariate predictor of death (HR 1.27 per 1 mg/dL, 95% CI 1.114–1.455, p <.001). In multivariate Cox analysis, this association remained significant (HR 1.31 per 1 mg/dL increase, 95% CI 1.096–1.560, p =.003) as well as in a separate stepwise model controlling for potential confounders including daily diuretic use, uric acid lowering therapy, and renal dysfunction. Conclusions: Both nutritional status as measured by mBMI and inflammation as measured by serum uric acid are associated with survival in patients with TTR cardiac amyloidosis however only serum uric acid is an independent predictor of death. [ABSTRACT FROM AUTHOR]

One application of positron emission tomography (PET), a nuclear imaging technique, in neuroscience involves in vivo estimation of the density of various proteins (often, neuroreceptors) in the brain. PET scanning begins with the injection of a radiolabeled tracer that binds preferentially to the target protein; tracer molecules are then continuously delivered to the brain via the bloodstream. By detecting the radioactive decay of the tracer over time, dynamic PET data are constructed to reflect the concentration of the target protein in the brain at each time. The fundamental problem in the analysis of dynamic PET data involves estimating the impulse response function (IRF), which is necessary for describing the binding behavior of the injected radiotracer. Virtually all existing methods have three common aspects: summarizing the entire IRF with a single scalar measure; modeling each subject separately; and the imposition of parametric restrictions on the IRF. In contrast, we propose a functional data analytic approach that regards each subject's IRF as the basic analysis unit, models multiple subjects simultaneously, and estimates the IRF nonparametrically. We pose our model as a linear mixed effect model in which population level fixed effects and subject-specific random effects are expanded using a B-spline basis. Shrinkage and roughness penalties are incorporated in the model to enforce identifiability and smoothness of the estimated curves, respectively, while monotonicity and nonnegativity constraints impose biological information on estimates. We illustrate this approach by applying it to clinical PET data with subjects belonging to three diagnosic groups. We explore differences among groups by means of pointwise confidence intervals of the estimated mean curves based on bootstrap samples. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

Objective: Patients with chronic stroke have been shown to have failure to release interhemispheric inhibition (IHI) from the intact to the damaged hemisphere before movement execution (premovement IHI). This inhibitory imbalance was found to correlate with poor motor performance in the chronic stage after stroke and has since become a target for therapeutic interventions. The logic of this approach, however, implies that abnormal premovement IHI is causal to poor behavioral outcome and should therefore be present early after stroke when motor impairment is at its worst. To test this idea, in a longitudinal study, we investigated interhemispheric interactions by tracking patients' premovement IHI for one year following stroke.Methods: We assessed premovement IHI and motor behavior five times over a 1-year period after ischemic stroke in 22 patients and 11 healthy participants.Results: We found that premovement IHI was normal during the acute/subacute period and only became abnormal at the chronic stage; specifically, release of IHI in movement preparation worsened as motor behavior improved. In addition, premovement IHI did not correlate with behavioral measures cross-sectionally, whereas the longitudinal emergence of abnormal premovement IHI from the acute to the chronic stage was inversely correlated with recovery of finger individuation.Interpretation: These results suggest that interhemispheric imbalance is not a cause of poor motor recovery, but instead might be the consequence of underlying recovery processes. These findings call into question the rehabilitation strategy of attempting to rebalance interhemispheric interactions in order to improve motor recovery after stroke. Ann Neurol 2019;85:502-513. [ABSTRACT FROM AUTHOR]

Summary: We introduce a novel method for separating amplitude and phase variability in exponential family functional data. Our method alternates between two steps: the first uses generalized functional principal components analysis to calculate template functions, and the second estimates smooth warping functions that map observed curves to templates. Existing approaches to registration have primarily focused on continuous functional observations, and the few approaches for discrete functional data require a pre‐smoothing step; these methods are frequently computationally intensive. In contrast, we focus on the likelihood of the observed data and avoid the need for preprocessing, and we implement both steps of our algorithm in a computationally efficient way. Our motivation comes from the Baltimore Longitudinal Study on Aging, in which accelerometer data provides valuable insights into the timing of sedentary behavior. We analyze binary functional data with observations each minute over 24 hours for 592 participants, where values represent activity and inactivity. Diurnal patterns of activity are obscured due to misalignment in the original data but are clear after curves are aligned. Simulations designed to mimic the application indicate that the proposed methods outperform competing approaches in terms of estimation accuracy and computational efficiency. Code for our method and simulations is publicly available. [ABSTRACT FROM AUTHOR]

We propose a novel method for estimating population-level and subject-specific effects of covariates on the variability of functional data. We extend the functional principal components analysis framework by modeling the variance of principal component scores as a function of covariates and subject-specific random effects. In a setting where principal components are largely invariant across subjects and covariate values, modeling the variance of these scores provides a flexible and interpretable way to explore factors that affect the variability of functional data. Our work is motivated by a novel dataset from an experiment assessing upper extremity motor control, and quantifies the reduction in movement variability associated with skill learning. The proposed methods can be applied broadly to understand movement variability, in settings that include motor learning, impairment due to injury or disease, and recovery. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]