Role of Cyp2c19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

PURPOSE OF REVIEW: Identification of a reliable discriminatory test to accurately stratify patient responses to antiplatelet therapy following coronary revascularization has become increasingly desirable to optimize therapeutic efficacy and safety. RECENT FINDINGS: The expansion of platelet function testing to include genotype assessment has been an evolutionary journey, initially fraught with confounding results. However, more recent and rigorous data analysis suggests that genotype testing- guided, tailored antiplatelet therapy may hold promise in optimizing treatment of patients after coronary intervention. Current evidence increasingly supports the use of genotype guided CYP2C19 testing to better match the post coronary intervention patient with the most efficacious and least risky antiplatelet inhibitor. The risk stratification of poor, intermediate, and good metabolizers of these drugs with such testing promises to yield clinical dividends in terms of morbidity, mortality and cost control, in this growing patient population.

Recent updates on therapeutic targeting of lipoprotein(a) with RNA interference.

PURPOSE OF REVIEW: RNA interference (RNAi)-based therapies that target specific gene products have impacted clinical medicine with 16 FDA approved drugs. RNAi therapy focused on reducing plasma lipoprotein(a) [Lp(a)] levels are under evaluation. RECENT FINDINGS: RNAi-based therapies have made significant progress over the past 2 decades and currently consist of antisense oligonucleotides (ASO) and small interfering RNA (siRNA). Chemical modification of the RNA backbone and conjugation of siRNA enables efficient gene silencing in hepatocytes allowing development of effective cholesterol lowering therapies. Multiple lines of evidence suggest a causative role for Lp(a) in atherosclerotic cardiovascular disease, and recent analyses indicate that Lp(a) is more atherogenic than low density lipoprotein- cholesterol (LDL-C). These findings have led to the 'Lp(a) hypothesis' that lowering Lp(a) may significantly improve cardiovascular outcomes. Four RNAi-based drugs have completed early phase clinical trials demonstrating >80% reduction in plasma Lp(a) levels. Phase 3 clinical trials examining clinical outcomes with these agents are currently underway. SUMMARY: Currently, four RNAi-based drugs have been shown to be effective in significantly lowering plasma Lp(a) levels. Clinical outcome data from phase 3 trials will evaluate the Lp(a) hypothesis.

Bayesian encoding and decoding as distinct perspectives on neural coding.

The Bayesian brain hypothesis is one of the most influential ideas in neuroscience. However, unstated differences in how Bayesian ideas are operationalized make it difficult to draw general conclusions about how Bayesian computations map onto neural circuits. Here, we identify one such unstated difference: some theories ask how neural circuits could recover information about the world from sensory neural activity (Bayesian decoding), whereas others ask how neural circuits could implement inference in an internal model (Bayesian encoding). These two approaches require profoundly different assumptions and lead to different interpretations of empirical data. We contrast them in terms of motivations, empirical support and relationship to neural data. We also use a simple model to argue that encoding and decoding models are complementary rather than competing. Appreciating the distinction between Bayesian encoding and Bayesian decoding will help to organize future work and enable stronger empirical tests about the nature of inference in the brain.

REAFFIRMING THE CORE VALUES OF ACADEMIC CARDIOLOGY.

Academic medical centers are rapidly evolving into academic health systems with expanding clinical activity. These changes coupled with financial pressures due to decreased clinical reimbursements and failure of the NHLBI budget to keep pace with inflation are challenging the ability to succeed in all our missions. New governance structures and financial models may be necessary to success in our research and educational missions.

Sleep apnea and cardiovascular risk.

PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is associated with several cardiovascular risk predictors that have only recently begun to be studied in detail. The strong association between OSA and hypertension, coronary artery disease, congestive heart failure, and sudden cardiac death underscores its significant impact on cardiovascular health. This brief review considers the links between OSA and cardiovascular risk. RECENT FINDINGS: OSA is an important contributor to endothelial dysfunction and damage, while repetitive hypoxia and hypercarbia contribute to autonomic dysfunction and sympathetic stimulation. In turn, these derangements have deleterious hematologic effects, including hypercoagulability and abnormal platelet aggregability, which are important in the pathogenesis of atherothrombotic disease. SUMMARY: The varied deleterious effects of OSA on cardiovascular health stem from a unique 'perfect storm' of hypoxic oxidative stress, autonomic dysregulation, endothelial damage, and inflammation occurring at the microvascular level. Further research may disentangle these multiple etiologic threads and provide a better understanding of the underlying pathophysiological relationship between OSA and cardiovascular disease.

Weak evidence for neural correlates of task-switching in macaque V1.

A central goal of systems neuroscience is to understand how populations of sensory neurons encode and relay information to the rest of the brain. Three key quantities of interest are 1) how mean neural activity depends on the stimulus (sensitivity), 2) how neural activity (co)varies around the mean (noise correlations), and 3) how predictive these variations are of the subject's behavior (choice probability). Previous empirical work suggests that both choice probability and noise correlations are affected by task training, with decision-related information fed back to sensory areas and aligned to neural sensitivity on a task-by-task basis. We used Utah arrays to record activity from populations of primary visual cortex (V1) neurons from two macaque monkeys that were trained to switch between two coarse orientation-discrimination tasks. Surprisingly, we find no evidence for significant trial-by-trial changes in noise covariance between tasks, nor do we find a consistent relationship between neural sensitivity and choice probability, despite recording from well-tuned task-sensitive neurons, many of which were histologically confirmed to be in supragranular V1, and despite behavioral evidence that the monkeys switched their strategy between tasks. Thus our data at best provide weak support for the hypothesis that trial-by-trial task-switching induces changes to noise correlations and choice probabilities in V1. However, our data agree with a recent finding of a single "choice axis" across tasks. They also raise the intriguing possibility that choice-related signals in early sensory areas are less indicative of task learning per se and instead reflect perceptual learning that occurs in highly overtrained subjects.NEW & NOTEWORTHY Converging evidence suggests that decision processes affect sensory neural activity, and this has informed numerous theories of neural processing. We set out to replicate and extend previous results on decision-related information and noise correlations in V1 of macaque monkeys. However, in our data, we find little evidence for a number of expected effects. Our null results therefore call attention to differences in task training, stimulus design, recording, and analysis techniques between our and prior studies.

An optical atomic clock based on a highly charged ion.

Optical atomic clocks are the most accurate measurement devices ever constructed and have found many applications in fundamental science and technology1-3. The use of highly charged ions (HCI) as a new class of references for highest-accuracy clocks and precision tests of fundamental physics4-11 has long been motivated by their extreme atomic properties and reduced sensitivity to perturbations from external electric and magnetic fields compared with singly charged ions or neutral atoms. Here we present the realization of this new class of clocks, based on an optical magnetic-dipole transition in Ar13+. Its comprehensively evaluated systematic frequency uncertainty of 2.2 × 10-17 is comparable with that of many optical clocks in operation. From clock comparisons, we improve by eight and nine orders of magnitude on the uncertainties for the absolute transition frequency12 and isotope shift (40Ar versus 36Ar) (ref. 13), respectively. These measurements allow us to investigate the largely unexplored quantum electrodynamic (QED) nuclear recoil, presented as part of improved calculations of the isotope shift, which reduce the uncertainty of previous theory14 by a factor of three. This work establishes forbidden optical transitions in HCI as references for cutting-edge optical clocks and future high-sensitivity searches for physics beyond the standard model.

Targeted Therapies in Patients with Pulmonary Arterial Hypertension Due to Congenital Heart Disease.

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disease leading to right heart failure and death if untreated. Medical therapies for PAH have evolved substantially over the last decades and are associated with improvements in functional class, quality of life, and survival. PAH-targeted therapies now consist of multiple inhaled, oral, subcutaneous, and intravenous therapies targeting the phosphodiesterase, guanylate cyclase, endothelin and prostacyclin pathways. Patients with congenital heart disease (CHD) are at high risk of developing PAH and growing evidence exists that PAH-targeted therapy can be beneficial in PAH-CHD. However, the PAH-CHD patient population is challenging to treat due to the heterogeneity and complexity of their cardiac lesions and associated comorbidities. Furthermore, most high-quality randomized placebo-controlled trials investigating the effects of PAH-targeted therapies only included a minority of PAH-CHD patients. Few randomized, controlled trials have investigated the effects of PAH-targeted therapy in pre-specified PAH-CHD populations. Consequently, the results of these clinical trials cannot be extrapolated broadly to the PAH-CHD population. This review summarizes the data from high-quality clinical PAH treatment trials with a specific focus on the PAH-CHD population.

Treatment of Hypertension Among Non-Cardiac Hospitalized Patients.

PURPOSE OF REVIEW: This review provides a contemporary perspective and approach for the treatment of hypertension (HTN) among patients hospitalized for non-cardiac reasons. RECENT FINDINGS: Elevated blood pressure (BP) is a common dilemma encountered by physicians, but guidelines are lacking to assist providers in managing hospitalized patients with elevated BP. Inpatient HTN is common, and management remains challenging given the paucity of data and misperceptions among training and practicing physicians. The outcomes associated with intensifying BP treatment during hospitalization can be harmful, with little to no long-term benefits. Data also suggests that medication intensification at discharge is not associated with improved outpatient BP control. Routine inpatient HTN control in the absence of end-organ damage has not shown to be helpful and may have deleterious effects. Since routine use of intravenous antihypertensives in hospitalized non-cardiac patients has been shown to prolong inpatient stay without benefits, their routine use should be avoided for inpatient HTN control. Future large-scale trials measuring clinical outcomes during prolonged follow-up may help to identify specific circumstances where inpatient HTN control may be beneficial.

Task-induced neural covariability as a signature of approximate Bayesian learning and inference.

Perception is often characterized computationally as an inference process in which uncertain or ambiguous sensory inputs are combined with prior expectations. Although behavioral studies have shown that observers can change their prior expectations in the context of a task, robust neural signatures of task-specific priors have been elusive. Here, we analytically derive such signatures under the general assumption that the responses of sensory neurons encode posterior beliefs that combine sensory inputs with task-specific expectations. Specifically, we derive predictions for the task-dependence of correlated neural variability and decision-related signals in sensory neurons. The qualitative aspects of our results are parameter-free and specific to the statistics of each task. The predictions for correlated variability also differ from predictions of classic feedforward models of sensory processing and are therefore a strong test of theories of hierarchical Bayesian inference in the brain. Importantly, we find that Bayesian learning predicts an increase in so-called "differential correlations" as the observer's internal model learns the stimulus distribution, and the observer's behavioral performance improves. This stands in contrast to classic feedforward encoding/decoding models of sensory processing, since such correlations are fundamentally information-limiting. We find support for our predictions in data from existing neurophysiological studies across a variety of tasks and brain areas. Finally, we show in simulation how measurements of sensory neural responses can reveal information about a subject's internal beliefs about the task. Taken together, our results reinterpret task-dependent sources of neural covariability as signatures of Bayesian inference and provide new insights into their cause and their function.

Pre-excitation Due to Fascicular-Ventricular Pathway: An Electrocardiographic Diagnosis: A Case Report.

A 79-year-old Caucasian male was referred to cardiology clinic because the electrocardiogram showed premature atrial complexes and pre-excitation (delta waves) thought to be consistent with Wolff-Parkinson-White (WPW) syndrome. He did not report symptoms of palpitations or syncope. Careful analysis of the electrocardiogram revealed a fascicular-ventricular pathway (FVP) responsible for pre-excitation. Differentiating FVP from WPW syndrome is essential as the risk profile is different with each. Electrocardiographic observations that could help identify the presence of an FVP and its diagnostic, prognostic, and therapeutic implications are presented.

A confirmation bias in perceptual decision-making due to hierarchical approximate inference.

Making good decisions requires updating beliefs according to new evidence. This is a dynamical process that is prone to biases: in some cases, beliefs become entrenched and resistant to new evidence (leading to primacy effects), while in other cases, beliefs fade over time and rely primarily on later evidence (leading to recency effects). How and why either type of bias dominates in a given context is an important open question. Here, we study this question in classic perceptual decision-making tasks, where, puzzlingly, previous empirical studies differ in the kinds of biases they observe, ranging from primacy to recency, despite seemingly equivalent tasks. We present a new model, based on hierarchical approximate inference and derived from normative principles, that not only explains both primacy and recency effects in existing studies, but also predicts how the type of bias should depend on the statistics of stimuli in a given task. We verify this prediction in a novel visual discrimination task with human observers, finding that each observer's temporal bias changed as the result of changing the key stimulus statistics identified by our model. The key dynamic that leads to a primacy bias in our model is an overweighting of new sensory information that agrees with the observer's existing belief-a type of 'confirmation bias'. By fitting an extended drift-diffusion model to our data we rule out an alternative explanation for primacy effects due to bounded integration. Taken together, our results resolve a major discrepancy among existing perceptual decision-making studies, and suggest that a key source of bias in human decision-making is approximate hierarchical inference.

Gamut of cardiac manifestations and complications of COVID-19: a contemporary review.

COVID-19 has posed an extraordinary burden on health and the economy worldwide. Patients with cardiovascular diseases are more likely to have severe illness due to COVID-19 and are at increased risk for complications and mortality. We performed a narrative literature review to assess the burden of COVID-19 and cardiovascular morbidity and mortality. Myocardial injury has been reported in 20%-30% of patients hospitalized due to COVID-19 and is associated with a worse prognosis and high mortality (~50%-60%). Proposed mechanisms of myocardial injury include inflammation within the myocardium (due to direct viral infection or cytokine storm), endotheliitis, coronary vasculitis, myocarditis, demand ischemia, plaque destabilization and right ventricular failure. The right ventricle is particularly vulnerable to injury and failure in COVID-19-infected patients, given the hypoxic pulmonary vasoconstriction, pulmonary microthrombi or pulmonary embolism. Echocardiography is an effective and accessible tool to evaluate left and right ventricular functions and risk stratify patients with COVID-19 infection. Cardiac MRI has detected and characterized myocardial injury, with changes compatible with other inflammatory cardiomyopathies. The long-term consequences of these inflammatory changes are unknown, but accumulating data will provide insight regarding the longitudinal impact of COVID-19 infection on cardiovascular morbidity and mortality.

Optical clock comparison for Lorentz symmetry testing.

Questioning basic assumptions about the structure of space and time has greatly enhanced our understanding of nature. State-of-the-art atomic clocks1-3 make it possible to precisely test fundamental symmetry properties of spacetime and search for physics beyond the standard model at low energies of just a few electronvolts4. Modern tests of Einstein's theory of relativity try to measure so-far-undetected violations of Lorentz symmetry5; accurately comparing the frequencies of optical clocks is a promising route to further improving such tests6. Here we experimentally demonstrate agreement between two single-ion optical clocks at the 10-18 level, directly validating their uncertainty budgets, over a six-month comparison period. The ytterbium ions of the two clocks are confined in separate ion traps with quantization axes aligned along non-parallel directions. Hypothetical Lorentz symmetry violations5-7 would lead to periodic modulations of the frequency offset as the Earth rotates and orbits the Sun. From the absence of such modulations at the 10-19 level we deduce stringent limits of the order of 10-21 on Lorentz symmetry violation parameters for electrons, improving previous limits8-10 by two orders of magnitude. Such levels of precision will be essential for low-energy tests of future quantum gravity theories describing dynamics at the Planck scale4, which are expected to predict the magnitude of residual symmetry violations.

The Role of Percutaneous Coronary Intervention in the Treatment of Chronic Total Occlusions: Rationale and Review of the Literature.

BACKGROUND: Chronic total occlusion (CTO) of a coronary artery is defined as an occluded segment with no antegrade flow and a known or estimated duration of at least 12 weeks. OBJECTIVE: We considered the current literature describing the indications and clinical outcomes for denovo CTO- percutaneous coronary intervention (PCI), and discuss the role of CTO-PCI and future directions for this procedure. METHODS: Databases (PubMed, the Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL were searched and relevant studies of CTO-PCI were selected for review. RESULTS: The prevalence of coronary artery CTO's has been reported to be ~ 20% among patients undergoing diagnostic coronary angiography for suspected coronary artery disease. Revascularization of any CTO can be technically challenging and a time-consuming procedure with relatively low success rates and may be associated with a higher incidence of complications, particularly at non-specialized centers. However, with an increase in experience and technological advances, several centers are now reporting success rates above 80% for these lesions. There is marked variability among studies in reporting outcomes for CTO-PCI with some reporting potential mortality benefit, better quality of life and improved cardiac function parameters. Anecdotally, properly selected patients who undergo a successful CTO-PCI most often have profound relief of ischemic symptoms. Intuitively, it makes sense to revascularize an occluded coronary artery with the goal of improving cardiovascular function and patient quality of life. CONCLUSION: CTO-PCI is a rapidly expanding specialized procedure in interventional cardiology and is reasonable or indicated if the occluded vessel is responsible for symptoms or in selected patients with silent ischemia in whom there is a large amount of myocardium at risk and PCI is likely to be successful.

Laser-controlled adaptive optics for beam quality improvements in a multi-pass thin-disk amplifier.

We devise a laser-controlled adaptive optical element that operates intracavity under high-intensity radiation. This element substitutes a conventional mechanically deformable mirror and is free of critical heat-sensitive components and electronics. The deformation mechanism is based on the projection of a continuous-wave control laser onto a specially designed mirror. Mounted to a water-cooled heat sink, the mirror can handle laser radiation beyond 3 MW/cm2. The properties of the adaptive optical element, including the maximum correctable wavefront pitch of 800 nm, are discussed. The successful implementation in a multi-pass thin-disk amplifier is presented. An improvement of the beam quality by a factor of three is achieved. We identify measures to enhance the performance of the adaptive optics towards efficient operation in a high-power laser system.

Autobalanced Ramsey Spectroscopy.

We devise a perturbation-immune version of Ramsey's method of separated oscillatory fields. Spectroscopy of an atomic clock transition without compromising the clock's accuracy is accomplished by actively balancing the spectroscopic responses from phase-congruent Ramsey probe cycles of unequal durations. Our simple and universal approach eliminates a wide variety of interrogation-induced line shifts often encountered in high precision spectroscopy, among them, in particular, light shifts, phase chirps, and transient Zeeman shifts. We experimentally demonstrate autobalanced Ramsey spectroscopy on the light shift prone ^{171}Yb^{+} electric octupole optical clock transition and show that interrogation defects are not turned into clock errors. This opens up frequency accuracy perspectives below the 10^{-18} level for the Yb^{+} system and for other types of optical clocks.