Abstract
Aims
Patients with pulmonary hypertension (PHT) are often excluded from surgical therapies for tricuspid regurgitation (TR). Transcatheter tricuspid valve repair (TTVR) with the MitraClip™ ...technique is a novel treatment option for these patients. We aimed to assess the role of PHT in severe TR and its implications for TTVR.
Methods and results
A total of 243 patients underwent TTVR at two centres. One hundred twenty-one patients were grouped as iPHT+ invasive systolic pulmonary artery pressures (PAPs) ≥50 mmHg. Patients were similarly stratified according to echocardiographic PAPs (ePHT). The occurrence of the combined clinical endpoint (death, heart failure hospitalization, and reintervention) was investigated during a follow-up of 330 (interquartile range 175–402) days. iPHT+ patients were at higher preoperative risk (P < 0.01), had more severe symptoms (P = 0.01), higher N-terminal pro-B-type natriuretic peptide levels (P < 0.01), more impaired right ventricular (RV) function (P < 0.01), and afterload corrected RV function (P < 0.01). Procedural TTVR success was similar in iPHT+ and iPHT− patients (84 vs. 84%, P = 0.99). The echocardiographic diagnostic accuracy to detect iPHT was only 55%. During follow-up, 35% of patients reached the combined clinical endpoint. The discordant diagnosis of iPHT+/ePHT− carried the highest risk for the combined clinical endpoint HR 3.76 (CI 2.25–6.37), P < 0.01, while iPHT+/ePHT+ patients had a similar survival-free time from the combined endpoint compared to iPHT− patients (P = 0.48). In patients with isolated tricuspid procedure (n = 131) a discordant iPHT+/ePHT− diagnosis and an impaired afterload corrected RV function (P < 0.01 for both) were independent predictors for the occurrence of the combined endpoint.
Conclusion
The discordant echocardiographic and invasive diagnosis of PHT in severe TR predicts outcomes after TTVR.
OBJECTIVE: The objective of this study was to assess the risk of acute pancreatitis in patients with type 2 diabetes compared with that in patients without diabetes. We also examined the risk of ...biliary disease (defined as occurrence of cholelithiasis, acute cholecystitis, or cholecystectomy), which is a major cause of pancreatitis. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using a large, geographically diverse U.S. health care claims database. Eligible patients (greater-than-or-equal18 years) were enrolled for at least 12 continuous months (1999-2005), with no incident events of pancreatitis or biliary disease during that 1 year baseline period. ICD-9 codes and prescription data were used to identify patients with type 2 diabetes; ICD-9 codes were also used to identify cases of pancreatitis and biliary disease. Overall, 337,067 patients with type 2 diabetes were matched on age and sex with 337,067 patients without diabetes. Incidence rates of disease and 95% CI were calculated per 100,000 person-years of exposure. RESULTS: The type 2 diabetic cohort had a 2.83-fold (95% CI 2.61-3.06) greater risk of pancreatitis and 1.91-fold (1.84-1.99) greater risk of biliary disease compared with the nondiabetic cohort. Relative to patients of corresponding age without diabetes, younger type 2 diabetic patients had the highest risk of pancreatitis (<45 years: incidence rate ratio IRR 5.26 95% CI 4.31-6.42; greater-than-or-equal45 years: 2.44 2.23-2.66). CONCLUSIONS: These data suggest that patients with type 2 diabetes may have an increased risk of acute pancreatitis and biliary disease.
Background Safety of biologics is important when treating patients with psoriasis. Objective We sought to determine the safety of ixekizumab in psoriasis. Methods Integrated safety data are presented ...from a 12-week induction period, a 12- to 60-week maintenance period, and from all ixekizumab-treated patients from 7 clinical trials. Exposure-adjusted incidence rates (IRs) per 100 patient-years are reported. Results Overall, 4209 patients received ixekizumab (total exposure: 6480 patient-years). During the induction period, the IRs of patients experiencing 1 or more treatment-emergent adverse event (AE) were 251 and 236 among ixekizumab- and etanercept-treated patients, respectively, and for serious AEs was 8.3 in both groups. During maintenance, for ixekizumab, the IRs of treatment-emergent AEs and serious AEs were 100.4 and 7.8, respectively. Among all ixekizumab-treated patients from 7 trials, the IR of Candida infections was 2.5. The IRs of treatment-emergent AEs of special interest (including serious infections, malignancies, major adverse cardiovascular events) were comparable for ixekizumab and etanercept during the induction period. Limitations Additional long-term data are required. Conclusion Ixekizumab had an acceptable safety profile with no unexpected safety findings during ixekizumab maintenance in psoriasis.
On a daily basis, humans interact with a vast range of objects and tools. A class of tasks, which can pose a serious challenge to our motor skills, are those that involve manipulating objects with ...internal degrees of freedom, such as when folding laundry or using a lasso. Here, we use the framework of optimal feedback control to make predictions of how humans should interact with such objects. We confirm the predictions experimentally in a two-dimensional object manipulation task, in which subjects learned to control six different objects with complex dynamics. We show that the non-intuitive behavior observed when controlling objects with internal degrees of freedom can be accounted for by a simple cost function representing a trade-off between effort and accuracy. In addition to using a simple linear, point-mass optimal control model, we also used an optimal control model, which considers the non-linear dynamics of the human arm. We find that the more realistic optimal control model captures aspects of the data that cannot be accounted for by the linear model or other previous theories of motor control. The results suggest that our everyday interactions with objects can be understood by optimality principles and advocate the use of more realistic optimal control models for the study of human motor neuroscience.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To assess the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in a double-blind phase III trial enrolling patients with active psoriatic arthritis (PsA).
...Patients naive to biologic therapy with active PsA were randomised to subcutaneous injections of placebo (N=106), adalimumab 40 mg once every 2 weeks (active reference; N=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (N=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (N=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 24.
Significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%) (p≤0.001; non-responder imputation method). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and there was significantly less progression of structural damage at week 24 (p≤0.01). Clearance of plaque psoriasis was greater with ixekizumab than placebo (p≤0.001). Efficacy results with adalimumab, the active reference arm, showed significant improvements versus placebo. Treatment-emergent adverse events were more frequent with ixekizumab (65.7-66.4%) and adalimumab (64.4%) than placebo (47.2%) (p<0.05).
In biologic-naive patients with active PsA, ixekizumab treatment resulted in improvements in disease activity and physical function, as well as in the inhibition of structural damage progression. Overall, adverse events were more frequent in all active groups compared with placebo.
NCT01695239; EudraCT2011-002326-49; Results.
Expected utility models are often used as a normative baseline for human performance in motor tasks. However, this baseline ignores computational costs that are incurred when searching for the ...optimal strategy. In contrast, bounded rational decision-theory provides a normative baseline that takes computational effort into account, as it describes optimal behavior of an agent with limited information-processing capacity to change a prior motor strategy (before information-processing) into a posterior strategy (after information-processing). Here, we devised a pointing task where subjects had restricted reaction and movement time. In particular, we manipulated the permissible reaction time as a proxy for the amount of computation allowed for planning the movements. Moreover, we tested three different distributions over the target locations to induce different prior strategies that would influence the amount of required information-processing. We found that movement endpoint precision generally decreases with limited planning time and that non-uniform prior probabilities allow for more precise movements toward high-probability targets. Considering these constraints in a bounded rational decision model, we found that subjects were generally close to bounded optimal. We conclude that bounded rational decision theory may be a promising normative framework to analyze human sensorimotor performance.
Long-term molecular dynamics simulations are used to compare the single particle dipole reorientation time, the diffusion constant, the viscosity, and the frequency-dependent dielectric constant of ...the coarse-grained big multipole water (BMW) model to two common atomistic three-point water models, SPC/E and TIP3P. In particular, the agreement between the calculated viscosity of BMW and the experimental viscosity of water is satisfactory. We also discuss contradictory values for the static dielectric properties reported in the literature. Employing molecular hydrodynamics, we show that the viscosity can be computed from single particle dynamics, circumventing the slow convergence of the standard approaches. Furthermore, our data indicate that the Kivelson relation connecting single particle and collective reorientation time holds true for all systems investigated. Since simulations with coarse-grained force fields often employ extremely large time steps, we also investigate the influence of time step on dynamical properties. We observe a systematic acceleration of system dynamics when increasing the time step. Carefully monitoring energy/temperature conservation is found to be a sufficient criterion for the reliable calculation of dynamical properties. By contrast, recommended criteria based on the ratio of fluctuations of total vs. kinetic energy are not sensitive enough.
Structure learning in action Braun, Daniel A.; Mehring, Carsten; Wolpert, Daniel M.
Behavioural brain research,
01/2010, Letnik:
206, Številka:
2
Journal Article
Recenzirano
Odprti dostop
‘Learning to learn’ phenomena have been widely investigated in cognition, perception and more recently also in action. During concept learning tasks, for example, it has been suggested that ...characteristic features are abstracted from a set of examples with the consequence that learning of similar tasks is facilitated—a process termed ‘learning to learn’. From a computational point of view such an extraction of invariants can be regarded as learning of an underlying structure. Here we review the evidence for structure learning as a ‘learning to learn’ mechanism, especially in sensorimotor control where the motor system has to adapt to variable environments. We review studies demonstrating that common features of variable environments are extracted during sensorimotor learning and exploited for efficient adaptation in novel tasks. We conclude that structure learning plays a fundamental role in skill learning and may underlie the unsurpassed flexibility and adaptability of the motor system.
Traditional pain assessment approaches ranging from self-reporting methods, to observational scales, rely on the ability of an individual to accurately assess and successfully report observed or ...experienced pain episodes. Automatic pain assessment tools are therefore more than desirable in cases where this specific ability is negatively affected by various psycho-physiological dispositions, as well as distinct physical traits such as in the case of professional athletes, who usually have a higher pain tolerance as regular individuals. Hence, several approaches have been proposed during the past decades for the implementation of an autonomous and effective pain assessment system. These approaches range from more conventional supervised and semi-supervised learning techniques applied on a set of carefully hand-designed feature representations, to deep neural networks applied on preprocessed signals. Some of the most prominent advantages of deep neural networks are the ability to automatically learn relevant features, as well as the inherent adaptability of trained deep neural networks to related inference tasks. Yet, some significant drawbacks such as requiring large amounts of data to train deep models and over-fitting remain. Both of these problems are especially relevant in pain intensity assessment, where labeled data is scarce and generalization is of utmost importance. In the following work we address these shortcomings by introducing several novel multi-modal deep learning approaches (characterized by specific supervised, as well as self-supervised learning techniques) for the assessment of pain intensity based on measurable bio-physiological data. While the proposed supervised deep learning approach is able to attain state-of-the-art inference performances, our self-supervised approach is able to significantly improve the data efficiency of the proposed architecture by automatically generating physiological data and simultaneously performing a fine-tuning of the architecture, which has been previously trained on a significantly smaller amount of data.
We define common thermodynamic concepts purely within the framework of general Markov chains and derive Jarzynski's equality and Crooks' fluctuation theorem in this setup. In particular, we regard ...the discrete-time case, which leads to an asymmetry in the definition of work that appears in the usual formulation of Crooks' fluctuation theorem. We show how this asymmetry can be avoided with an additional condition regarding the energy protocol. The general formulation in terms of Markov chains allows transferring the results to other application areas outside of physics. Here, we discuss how this framework can be applied in the context of decision-making. This involves the definition of the relevant quantities, the assumptions that need to be made for the different fluctuation theorems to hold, as well as the consideration of discrete trajectories instead of the continuous trajectories, which are relevant in physics.
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