Neurologic impact of atrial fibrillation.

PURPOSE OF REVIEW: Cognitive dysfunction is a complex condition that is becoming increasingly more prevalent. There has been growing acknowledgement that individuals with atrial fibrillation are at an increased risk of cognitive dysfunction beyond the association of age with both disorders. The purpose of this review is to explore the potential underlying mechanisms connecting atrial fibrillation and cognitive dysfunction and to examine the existing evidence for potential treatment options. RECENT FINDINGS: Many mechanisms have been proposed for the association between cognitive dysfunction and atrial fibrillation. These include cerebral infarction (both micro and macro embolic events), cerebral microbleeds including those secondary to therapeutic anticoagulation, an increased inflammatory state, cerebral hypoperfusion, and a genetic predisposition to both diseases. Treatments designed to target each of these mechanisms have led to mixed results and there are no specific interventions that have definitively led to a reduction in the incidence of cognitive dysfunction. SUMMARY: The relationship between cognitive dysfunction and atrial fibrillation remains poorly understood. Standard of care currently focuses on reducing risk factors, managing stroke risk, and maintaining sinus rhythm in appropriately selected patients. Further work needs to be conducted in this area to limit the progression of cognitive dysfunction in patients with atrial fibrillation.

Impact of coronary artery disease on clinical outcomes after TAVR: Insights from the BRAVO-3 randomized trial.

OBJECTIVE: To determine the prognostic impact of coronary artery disease (CAD) in patients randomized to bivalirudin or unfractionated heparin (UFH) during transcatheter aortic valve replacement (TAVR). BACKGROUND: CAD is a common comorbidity among patients undergoing TAVR and studies provide conflicting data on its prognostic impact. METHODS: The Bivalirudin on Aortic Valve Intervention Outcomes-3 (BRAVO-3) randomized trial compared the use of bivalirudin versus UFH in 802 high-surgical risk patients undergoing transfemoral TAVR for severe symptomatic aortic stenosis. Patients were stratified according to the presence or absence of history of CAD as well as periprocedural anticoagulation. The coprimary endpoints were net adverse cardiac events (NACE; a composite of all-cause mortality, myocardial infarction, stroke, or major bleeding) and major Bleeding Academic Research Consortium (BARC) bleeding ≥3b at 30 days postprocedure. RESULTS: Among 801 patients, 437 (54.6%) had history of CAD of whom 223 (51.0%) received bivalirudin. There were no significant differences in NACE (adjusted odds ratio [OR]: 1.04; 95% confidence interval [CI]: 0.69-1.58) or BARC ≥ 3b bleeding (adjusted OR: 0.84; 95% CI: 0.51-1.39) in patients with vs without CAD at 30 days. Among CAD patients, periprocedural use of bivalirudin was associated with similar NACE (OR: 0.80; 95% CI: 0.47-1.35) and BARC ≥ 3b bleeding (OR: 0.64; 95% CI: 0.33-1.25) compared with UFH, irrespective of history of CAD (p-interaction = 0.959 for NACE; p-interaction = 0.479 for major bleeding). CONCLUSION: CAD was not associated with a higher short-term risk of NACE or major bleeding after TAVR. Periprocedural anticoagulation with bivalirudin did not show any advantage over UFH in patients with and without CAD.

Defining Key Features of Complex Coronary Lesions: An Evidence Based Review of Clinical Practice. Part II: Chronic Total Occlusions, Graft Interventions, In-Stent Restenosis, and Antithrombotic Strategies.

Clinicians have long recognized that certain features of coronary artery lesions increase the complexity of intervention. Complex lesions are associated with worse cardiovascular outcomes and a higher risk of subsequent ischemic events. These lesions are categorized by their angiographic features. These features include bifurcation lesions, left main coronary artery disease, calcified lesions, in-stent restenosis, chronic total occlusions and graft interventions. This two-part review aims to highlight the current evidence in the percutaneous management of these lesions. Part two of this review focuses on the indications to treat chronic total occlusions, interventions of failed grafts, tools used to treat in-stent restenosis, as well as antithrombotic strategies.

Defining Key Features of Complex Coronary Lesions: An Evidence Based Review of Clinical Practice. Part I: Bifurcations, Left Main Disease, and Calcifications.

Clinicians have long recognized that certain features of coronary artery lesions increase the complexity of intervention. Complex lesions are associated with worse cardiovascular outcomes and a higher risk of subsequent ischemic events. These lesions are categorized by their angiographic features. These features include bifurcation lesions, left main coronary artery disease, calcified lesions, in-stent restenosis, chronic total occlusions and graft interventions. This two-part review aims to highlight the current evidence in the percutaneous management of these lesions. Part one of this review focuses on the best techniques to treat bifurcation lesions, indications for intervention of left main coronary artery disease and additional tools used to treat calcified lesions.

Antiplatelet Therapy in High-Bleeding Risk Patients Undergoing PCI: Walking a Tightrope.

Historically, prevention from ischemic events with dual antiplatelet therapy (DAPT) post percutaneous coronary intervention (PCI) took precedence over protection from bleeding. However, increasing data suggest that major bleeding complications are as detrimental as ischemic events. Awareness about the prognostic impact of bleeding prompted the search for new strategies aimed at maximizing both ischemic and bleeding protection. This is noteworthy because patients at high bleeding risk (HBR) have generally been underrepresented in clinical trials on DAPT and they often are at increased risk of ischemic events as well. The present review discusses the evidence base for new pharmacotherapeutic strategies to decrease bleeding risk without compromising ischemic protection among HBR patients undergoing PCI, including shortening DAPT duration, early aspirin withdrawal, and P2Y 12 inhibitor de-escalation.

Imaging in Percutaneous Coronary Intervention.

Intracoronary imaging (ICI) use during percutaneous coronary intervention (PCI) has been shown to effectively improve cardiovascular outcomes, particularly for high-risk subgroups. However, data from randomized controlled trials are limited and the overall utilization rate of ICI remains variable between different countries and centers. Potential benefits of ICI include identification of appropriate lesions for PCI, improved characterization of lesions, and optimization of stent placement. Currently available modalities of ICI include intravascular ultrasound, optical coherence tomography and near infrared spectroscopy. Within this review, we summarize the contemporary evidence surrounding ICI and discuss its application in clinical practice.

Effective Neutralization of Daratumumab Effects on Pre-Transfusion Testing: a Method Modification.

BACKGROUND: The anti-CD38 antibody daratumumab is a common multiple myeloma treatment. As the erythrocyte's membrane expresses CD38, Daratumumab-treated samples show agglutination in serological pre-transfusion tests, hindering detection of erythrocyte alloantibodies. Dithiothreitol interferes with erythrocyte antigens, affecting investigation of unexpected antibodies. DARAEx®, an anti-CD38 neutralizing agent, overcomes daratumumab-induced effects, without dithiothreitol's interferences. DARAEx® is applied only in Biorad columns. This study aimed to provide a DARAEx® protocol for application with the Grifols platform. METHODS: We introduced a modified DARAEx® protocol (AssutaBB protocol) and performed antibody screenings on samples from nineteen daratumumab-treated patients. RESULTS: The AssutaBB protocol provided antibody screen results for all patients, exactly as established in the default manufacturing protocol. Eleven patients presented natural negative antibody screens; eight presented positive K/E antibodies. CONCLUSIONS: AssutaBB allows the use of the more widespread Grifols platform in daratumumab-treated patients.

Structured networks support sparse traveling waves in rodent somatosensory cortex.

Neurons responding to different whiskers are spatially intermixed in the superficial layer 2/3 (L2/3) of the rodent barrel cortex, where a single whisker deflection activates a sparse, distributed neuronal population that spans multiple cortical columns. How the superficial layer of the rodent barrel cortex is organized to support such distributed sensory representations is not clear. In a computer model, we tested the hypothesis that sensory representations in L2/3 of the rodent barrel cortex are formed by activity propagation horizontally within L2/3 from a site of initial activation. The model explained the observed properties of L2/3 neurons, including the low average response probability in the majority of responding L2/3 neurons, and the existence of a small subset of reliably responding L2/3 neurons. Sparsely propagating traveling waves similar to those observed in L2/3 of the rodent barrel cortex occurred in the model only when a subnetwork of strongly connected neurons was immersed in a much larger network of weakly connected neurons.

Stent selection among patients with chronic kidney disease: Results from the NCDR CathPCI Registry.

OBJECTIVES: This study sought to define contemporary rates of drug eluting stent (DES) usage in patients with chronic kidney disease (CKD). BACKGROUND: Among patients with CKD undergoing percutaneous coronary interventions (PCIs), outcomes are superior for those who receive DES compared to those who receive bare metal stents (BMSs). However, perceived barriers may limit the use of DES in this population. METHODS: All adult PCI cases from the NCDR CathPCI Registry involving coronary stent placement between July 1, 2009 and December 31, 2015 were analyzed. The rate of DES usage was then compared among four groups, stratified by CKD stage (I/II, III, IV, and V). Subgroup analysis was conducted based on PCI status and indication. Cases were linked to Medicare claims data to assess 1-year mortality. RESULTS: A total of 3,650,333 PCI cases met criteria for analysis. DES usage significantly declined as renal function worsened (83.0%, 79.9%, 75.6%, and 75.6%, respectively, in the four CKD stages; p < .001). DES usage was universally lower across the four groups in the setting of ST-Elevation Myocardial Infarction (STEMI) (70.6%, 66.5%, 58.7%, 58.0%; p < .001) and higher in the setting of elective PCI (87.6%, 84.9%, 82.3%, 77.9%; p < .0001). DES was associated with improved 1-year survival, and usage increased over time across each group. CONCLUSIONS: DESs are underutilized in patients with advanced renal dysfunction. Although DES usage has increased over time, variation still exists between patients with normal renal function and those with CKD.

Retrieving Decadal Climate Change from Satellite Radiance Observations-A 100-year CO2 Doubling OSSE Demonstration.

Preparing for climate change depends on the observation and prediction of decadal trends of the environmental variables, which have a direct impact on the sustainability of resources affecting the quality of life on our planet. The NASA Climate Absolute Radiance and Refractivity Observatory (CLARREO) mission is proposed to provide climate quality benchmark spectral radiance observations for the purpose of determining the decadal trends of climate variables, and validating and improving the long-range climate model forecasts needed to prepare for the changing climate of the Earth. The CLARREO will serve as an in-orbit, absolute, radiometric standard for the cross-calibration of hyperspectral radiance spectra observed by the international system of polar operational satellite sounding sensors. Here, we demonstrate that the resulting accurately cross-calibrated polar satellite global infrared spectral radiance trends (e.g., from the Metop IASI instrument considered here) can be interpreted in terms of temperature and water vapor profile trends. This demonstration is performed using atmospheric state data generated for a 100-year period from 2000-2099, produced by a numerical climate model prediction that was forced by the doubling of the global average atmospheric CO2 over the 100-year period. The vertical profiles and spatial distribution of temperature decadal trends were successfully diagnosed by applying a linear regression profile retrieval algorithm to the simulated hyperspectral radiance spectra for the 100-year period. These results indicate that it is possible to detect decadal trends in atmospheric climate variables from high accuracy all-sky satellite infrared radiance spectra using the linear regression retrieval technique.

Rapid Disinhibition by Adjustment of PV Intrinsic Excitability during Whisker Map Plasticity in Mouse S1.

Rapid plasticity of layer (L) 2/3 inhibitory circuits is an early step in sensory cortical map plasticity, but its cellular basis is unclear. We show that, in mice of either sex, 1 d whisker deprivation drives the rapid loss of L4-evoked feedforward inhibition and more modest loss of feedforward excitation in L2/3 pyramidal (PYR) cells, increasing the excitation-inhibition conductance ratio. Rapid disinhibition was due to reduced L4-evoked spiking by L2/3 parvalbumin (PV) interneurons, caused by reduced PV intrinsic excitability. This included elevated PV spike threshold, which is associated with an increase in low-threshold, voltage-activated delayed rectifier (presumed Kv1) and A-type potassium currents. Excitatory synaptic input and unitary inhibitory output of PV cells were unaffected. Functionally, the loss of feedforward inhibition and excitation was precisely coordinated in L2/3 PYR cells, so that peak feedforward synaptic depolarization remained stable. Thus, the rapid plasticity of PV intrinsic excitability offsets early weakening of excitatory circuits to homeostatically stabilize synaptic potentials in PYR cells of sensory cortex.SIGNIFICANCE STATEMENT Inhibitory circuits in cerebral cortex are highly plastic, but the cellular mechanisms and functional importance of this plasticity are incompletely understood. We show that brief (1 d) sensory deprivation rapidly weakens parvalbumin (PV) inhibitory circuits by reducing the intrinsic excitability of PV neurons. This involved a rapid increase in voltage-gated potassium conductances that control near-threshold spiking excitability. Functionally, the loss of PV-mediated feedforward inhibition in L2/3 pyramidal cells was precisely balanced with the separate loss of feedforward excitation, resulting in a net homeostatic stabilization of synaptic potentials. Thus, rapid plasticity of PV intrinsic excitability implements network-level homeostasis to stabilize synaptic potentials in sensory cortex.

Frequency and outcomes of brain metastases in patients with HER2-mutant lung cancers.

BACKGROUND: Mutations in human epidermal growth factor receptor 2 (HER2; also known as ERBB2) are found in approximately 2% of lung adenocarcinomas. The frequency and clinical course of brain metastases in this oncogenic subset are ill defined. METHODS: Baseline and subsequent development of brain metastases was evaluated in consecutive patients with HER2-mutant (n = 98), epidermal growth factor receptor (EGFR)-mutant (n = 200), and KRAS-mutant lung cancers (n = 200). RESULTS: At metastatic diagnosis, the odds ratio (ORs) for brain metastases was similar for patients whose tumors harbored HER2 mutations (19%) in comparison with patients with KRAS mutations (24%; OR for HER2 vs KRAS, 0.7; P = .33) but lower compared to patients with EGFR mutations (31%; OR for HER2 vs EGFR, 0.5; P = .03). Patients with lung cancer and HER2 mutations developed more brain metastases on treatment than patients with KRAS mutations (28% vs 8%; hazard ratio [HR], 5.2; P < .001) and trended more than patients with EGFR mutations (28% vs 16%; HR, 1.7; P = .06). Patients with HER2 YVMA mutations also developed more brain metastases on treatment than patients with KRAS mutations (HR, 5.9; P < .001). The median overall survival (OS) was shorter for patients with HER2-mutant (1.6 years; P < .001) or KRAS-mutant lung cancers (1.1 years; P < .001) than patients with EGFR-mutant lung cancers (3.0 years). Brain metastases occurred in 47% of patients with HER2-mutant lung cancers, which imparted shorter OS (HR, 2.7; P < .001). CONCLUSIONS: These data provide a framework for brain imaging surveillance in patients with HER2-mutant lung cancers and underpin the need to develop HER2-targeted agents with central nervous system activity.

Gravity-Independent Upbeat Nystagmus in Syndrome of Anti-GAD Antibodies.

An autoimmune disorder of the central nervous system, stiff person syndrome, frequently presents with increased titers of 65KD anti-glutamic acid decarboxylase (anti-GAD) antibodies. The clinical phenomenology of this syndrome includes stiffness, ataxia, vertigo due to horizontal gaze-evoked and downbeat vertical nystagmus, and dysmetria of saccades and reaching movements. Here, we describe a novel phenomenology of syndrome of anti-GAD antibody, non-position-dependent upbeat nystagmus and superimposed horizontal gaze-evoked nystagmus. Lack of gravity dependence of primary position upbeat nystagmus, intense nystagmus on up-gaze, relatively stable gaze on downward orientation, and the exponentially decaying waveform suggests neural integrator dysfunction. The titer of anti-GAD in our patient (30 U/ml) was consistent with a variant called "low-titer anti-GAD syndrome". In addition of presenting as an unusual manifestation of a rare neurological syndrome, this case presents a neurochemical correlate of upbeat nystagmus in GABA-mediated control system involving horizontal and vertical neural integrators. Furthermore, the variant of "low-titer anti-GAD syndrome" suggests that GABAergic system may be affected at lower level or antibodies, and/or the epitopes of antibody in those with full-blown clinical syndrome, but low titers of anti-GAD may be different.

Short Time-Scale Sensory Coding in S1 during Discrimination of Whisker Vibrotactile Sequences.

Rodent whisker input consists of dense microvibration sequences that are often temporally integrated for perceptual discrimination. Whether primary somatosensory cortex (S1) participates in temporal integration is unknown. We trained rats to discriminate whisker impulse sequences that varied in single-impulse kinematics (5-20-ms time scale) and mean speed (150-ms time scale). Rats appeared to use the integrated feature, mean speed, to guide discrimination in this task, consistent with similar prior studies. Despite this, 52% of S1 units, including 73% of units in L4 and L2/3, encoded sequences at fast time scales (≤20 ms, mostly 5-10 ms), accurately reflecting single impulse kinematics. 17% of units, mostly in L5, showed weaker impulse responses and a slow firing rate increase during sequences. However, these units did not effectively integrate whisker impulses, but instead combined weak impulse responses with a distinct, slow signal correlated to behavioral choice. A neural decoder could identify sequences from fast unit spike trains and behavioral choice from slow units. Thus, S1 encoded fast time scale whisker input without substantial temporal integration across whisker impulses.

MALDI mass spectrometry imaging analysis of pituitary adenomas for near-real-time tumor delineation.

We present a proof of concept study designed to support the clinical development of mass spectrometry imaging (MSI) for the detection of pituitary tumors during surgery. We analyzed by matrix-assisted laser desorption/ionization (MALDI) MSI six nonpathological (NP) human pituitary glands and 45 hormone secreting and nonsecreting (NS) human pituitary adenomas. We show that the distribution of pituitary hormones such as prolactin (PRL), growth hormone (GH), adrenocorticotropic hormone (ACTH), and thyroid stimulating hormone (TSH) in both normal and tumor tissues can be assessed by using this approach. The presence of most of the pituitary hormones was confirmed by using MS/MS and pseudo-MS/MS methods, and subtyping of pituitary adenomas was performed by using principal component analysis (PCA) and support vector machine (SVM). Our proof of concept study demonstrates that MALDI MSI could be used to directly detect excessive hormonal production from functional pituitary adenomas and generally classify pituitary adenomas by using statistical and machine learning analyses. The tissue characterization can be completed in fewer than 30 min and could therefore be applied for the near-real-time detection and delineation of pituitary tumors for intraoperative surgical decision-making.

Synaptic mechanisms for plasticity in neocortex.

Sensory experience and learning alter sensory representations in cerebral cortex. The synaptic mechanisms underlying sensory cortical plasticity have long been sought. Recent work indicates that long-term cortical plasticity is a complex, multicomponent process involving multiple synaptic and cellular mechanisms. Sensory use, disuse, and training drive long-term potentiation and depression (LTP and LTD), homeostatic synaptic plasticity and plasticity of intrinsic excitability, and structural changes including formation, removal, and morphological remodeling of cortical synapses and dendritic spines. Both excitatory and inhibitory circuits are strongly regulated by experience. This review summarizes these findings and proposes that these mechanisms map onto specific functional components of plasticity, which occur in common across the primary somatosensory, visual, and auditory cortices.

P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis.

Human saphenous vein (HSV) is harvested and prepared prior to implantation as an arterial bypass graft. Injury and the response to injury from surgical harvest and preparation trigger cascades of molecular events and contribute to graft remodeling and intimal hyperplasia. Apoptosis is an early response after implantation that contributes the development of neointimal lesions. Here, we showed that surgical harvest and preparation of HSV leads to vasomotor dysfunction, increased apoptosis and downregulation of the phosphorylation of the anti-apoptotic protein, Niban. A model of subfailure overstretch injury in rat aorta (RA) was used to demonstrate impaired vasomotor function, increased extracellular ATP (eATP) release, and increased apoptosis following pathological vascular injury. The subfailure overstretch injury was associated with activation of p38 MAPK stress pathway and decreases in the phosphorylation of the anti-apoptotic protein Niban. Treatment of RA after overstretch injury with antagonists to purinergic P2X7 receptor (P2X7R) antagonists or P2X7R/pannexin (PanX1) complex, but not PanX1 alone, restored vasomotor function. Inhibitors to P2X7R and PanX1 reduced stretch-induced eATP release. P2X7R/PanX1 antagonism led to decrease in p38 MAPK phosphorylation, restoration of Niban phosphorylation and increases in the phosphorylation of the anti-apoptotic protein Akt in RA and reduced TNFα-stimulated caspase 3/7 activity in cultured rat vascular smooth muscle cells. In conclusion, inhibition of P2X7R after overstretch injury restored vasomotor function and inhibited apoptosis. Treatment with P2X7R/PanX1 complex inhibitors after harvest and preparation injury of blood vessels used for bypass conduits may prevent the subsequent response to injury that lead to apoptosis and represents a novel therapeutic approach to prevent graft failure.

Elliptic Cylinder Airborne Sampling and Geostatistical Mass Balance Approach for Quantifying Local Greenhouse Gas Emissions.

In this study, we explore observational, experimental, methodological, and practical aspects of the flux quantification of greenhouse gases from local point sources by using in situ airborne observations, and suggest a series of conceptual changes to improve flux estimates. We address the major sources of uncertainty reported in previous studies by modifying (1) the shape of the typical flight path, (2) the modeling of covariance and anisotropy, and (3) the type of interpolation tools used. We show that a cylindrical flight profile offers considerable advantages compared to traditional profiles collected as curtains, although this new approach brings with it the need for a more comprehensive subsequent analysis. The proposed flight pattern design does not require prior knowledge of wind direction and allows for the derivation of an ad hoc empirical correction factor to partially alleviate errors resulting from interpolation and measurement inaccuracies. The modified approach is applied to a use-case for quantifying CH4 emission from an oil field south of San Ardo, CA, and compared to a bottom-up CH4 emission estimate.

Rapid homeostasis by disinhibition during whisker map plasticity.

How homeostatic processes contribute to map plasticity and stability in sensory cortex is not well-understood. Classically, sensory deprivation first drives rapid Hebbian weakening of spiking responses to deprived inputs, which is followed days later by a slow homeostatic increase in spiking responses mediated by excitatory synaptic scaling. Recently, more rapid homeostasis by inhibitory circuit plasticity has been discovered in visual cortex, but whether this process occurs in other brain areas is not known. We tested for rapid homeostasis in layer 2/3 (L2/3) of rodent somatosensory cortex, where D-row whisker deprivation drives Hebbian weakening of whisker-evoked spiking responses after an unexplained initial delay, but no homeostasis of deprived whisker responses is known. We hypothesized that the delay reflects rapid homeostasis through disinhibition, which masks the onset of Hebbian weakening of L2/3 excitatory input. We found that deprivation (3 d) transiently increased whisker-evoked spiking responses in L2/3 single units before classical Hebbian weakening (≥5 d), whereas whisker-evoked synaptic input was reduced during both periods. This finding suggests a transient homeostatic increase in L2/3 excitability. In whole-cell recordings from L2/3 neurons in vivo, brief deprivation decreased whisker-evoked inhibition more than excitation and increased the excitation-inhibition ratio. In contrast, synaptic scaling and increased intrinsic excitability were absent. Thus, disinhibition is a rapid homeostatic plasticity mechanism in rodent somatosensory cortex that transiently maintains whisker-evoked spiking in L2/3, despite the onset of Hebbian weakening of excitatory input.