Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs.

Sensing and response to environmental cues, such as pH and chloride (Cl-), is critical in enabling Mycobacterium tuberculosis (Mtb) colonization of its host. Utilizing a fluorescent reporter Mtb strain in a chemical screen, we have identified compounds that dysregulate Mtb response to high Cl- levels, with a subset of the hits also inhibiting Mtb growth in host macrophages. Structure-activity relationship studies on the hit compound "C6," or 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole, demonstrated a correlation between compound perturbation of Mtb Cl- response and inhibition of bacterial growth in macrophages. C6 accumulated in both bacterial and host cells, and inhibited Mtb growth in cholesterol media, but not in rich media. Subsequent examination of the Cl- response of Mtb revealed an intriguing link with bacterial growth in cholesterol, with increased transcription of several Cl--responsive genes in the simultaneous presence of cholesterol and high external Cl- concentration, versus transcript levels observed during exposure to high external Cl- concentration alone. Strikingly, oral administration of C6 was able to inhibit Mtb growth in vivo in a C3HeB/FeJ murine infection model. Our work illustrates how Mtb response to environmental cues can intersect with its metabolism and be exploited in antitubercular drug discovery.

Development of a routine bedside CYP2C19 genotype assessment program for antiplatelet therapy guidance in a community hospital catheterization laboratory.

Genotype based personalized antiplatelet therapy in the setting of percutaneous coronary intervention (PCI) has been studied in clinical trials. Despite the demonstrated risk associated with CYP2C19 loss-of-function (LoF) carriage in clopidogrel-treated PCI patients, real-world implementation of genotyping for PCI has been low. The goal of the current study was to provide CYP2C19 genotype information to the interventionalist prior to the completion of the catheterization to facilitate immediate personalized antiplatelet therapy. Routine personalization of P2Y12 inhibitor therapy for PCI in a community hospital cardiac catheterization laboratory by POC genotyping with the SpartanRx system was first offered in February 2017. A best practice advisory (BPA) based on the Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 genotype and clopidogrel therapy was placed in the electronic health record prescription medication ordering system. By December 2019, 1,052 patients had CYP2C19 genotype testing, 429 patients underwent PCI with genotype guided antiplatelet therapy, and 250 patients underwent PCI without genotype testing and received antiplatelet therapy at the discretion of the treating physician. BPA compliance was 93. 87% of LoF allele carriers were prescribed ticagrelor or prasugrel whereas 96% of non-LoF allele carriers were prescribed clopidogrel. The genotyping results were available within 1 h and made immediately available for decision making by the interventional cardiologist. POC CYP2C19 genotyping is feasible in a community hospital catheterization laboratory and is associated with high rate of best practice compliance.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622.

The influence of heart failure on clinical and economic outcomes among older adults ≥75 years of age with acute myocardial infarction.

BACKGROUND: We aimed to evaluate the influence of heart failure (HF) on clinical and economic outcomes among older adults ≥75 years of age during their acute myocardial infarction (AMI) admission in large population-based study from the United States. We also evaluated the clinical characteristics associated with the presence of HF and the predictors of mortality, healthcare utilization, and cost among older adults with AMI. METHODS: From January 1, 2000, to December 31, 2016, AMI admission was identified using the primary diagnosis and concomitant HF was identified using any non-primary diagnoses in the Premier Healthcare Database. RESULTS: Of the 468,654 patients examined, 42,946 (9%) had concomitant HF during their AMI admission. These patients were older, more often female, and were more likely to be White. Patients with concomitant HF were more likely to be frail than non-HF patients (59% vs 15%, P < .001). The mean (SD) Elixhauser comorbidity index was 2.6 (2.5) vs 0.4 (1.1), P < .001 in the AMI with HF vs AMI only group. The use of percutaneous coronary intervention in those with AMI and HF was lower than those with AMI only (15% vs 31%, P < .001). The overall mortality rate for those with HF was 12%, the median [IQR] hospital length of stay was 5 [3,9] days, and only 25% of patients were discharged home. A higher proportion of patients were discharged to rehabilitation or hospice if they had AMI and HF (Rehabilitation: 33% vs 20%, P < .001; Hospice: 5% vs 3%, P < .001). The mean unadjusted cost of an AMI hospitalization in patients with concomitant HF was lower ($12,411 ± $14,860) than in those without HF ($15,828 ± $19,330). After adjusting for age, gender, race, hypertension, frailty, revascularization strategy, and death, the average cost of hospitalization attributed to concomitant HF was +$1,075 (95% CI +876 to $1,274) when compared to AMI patients without HF. CONCLUSION: In patients ≥75 years of age, AMI with concomitant HF carries higher risk of death, but at ages ≥85 years, the risk difference diminishes due to other competing risks. HF was also associated with longer hospital length of stay and higher likelihood of referral to hospice and rehabilitation facilities when compared to older patients without HF. Care for these older adults is associated with increased hospitalization costs. Measures to identify HF in older adults during their AMI admission are necessary to optimize health outcomes, care delivery, and costs.

Transcranial Direct Current Stimulation Modulates Connectivity of Left Dorsolateral Prefrontal Cortex with Distributed Cortical Networks.

Studies have shown that transcranial direct current stimulation increases neuronal excitability of the targeted region and general connectivity of relevant functional networks. However, relatively little is understood of how the stimulation affects the connectivity relationship of the target with regions across the network structure of the brain. Here, we investigated the effects of transcranial direct current stimulation on the functional connectivity of the targeted region using resting-state fMRI scans of the human brain. Anodal direct current stimulation was applied to the left dorsolateral prefrontal cortex (lDLPFC; cathode on the right bicep), which belongs to the frontoparietal control network (FPCN) and is commonly targeted for neuromodulation of various cognitive functions including short-term memory, long-term memory, and cognitive control. lDLPFC's connectivity characteristics were quantified as graph theory measures, from the resting-state fMRI scans obtained prior to and following the stimulation. Critically, we tested pre- to poststimulation changes of the lDLPFC connectivity metrics following an active versus sham stimulation. We found that the stimulation had two distinct effects on the connectivity of lDLPFC: for Brodmann's area (BA) 9, it increased the functional connectivity between BA 9 and other nodes within the FPCN; for BA 46, net connectivity strength was not altered within FPCN, but connectivity distribution across networks (participation coefficient) was decreased. These findings provide insights that the behavioral changes as the functional consequences of stimulation may come about because of the increased role of lDLPFC in the FPCN.

Does study subject diversity influence cardiology research site performance?: Insights from 2 U.S. National Coronary Stent Registries.

BACKGROUND: Minorities and women are underrepresented in cardiovascular research. Whether their higher enrollment can be predicted or influences research site performance is unclear. METHODS: We evaluated 104 sites that enrolled 4,184 patients in the U.S. Platinum Diversity (PD) and Promus Element Plus (PE Plus) studies (2012 to 2016). Research sites were ranked from lowest to highest minority and female enrollment, respectively. United States Census Bureau division and core-based statistical area (CBSA) populations were determined for each site and the following study performance metrics compared across quartiles of minority and female enrollment, respectively: (1) study subject enrollment rate (SER), (2) time to first patient enrolled, (3) rate of follow-up visits not done, (4) rate of follow-up visits out of window, and (5) protocol deviation rate (PDR). Multivariable regression was used to predict SER and PDR. RESULTS: Minority enrollment varied by region (P = .025) and population (P = .024) with highest recruitment noted in the Pacific, West South Central, South Atlantic, Mid-Atlantic and East North Central divisions. Female enrollment bore no relationship to region (P = .67) or population (P = .40). Median SER was similar in sites withi the highest vs lowest quartile of minority enrollment (SER of 4 vs 5 patients per month, respectively, P =0.78) and highest vs. lowest female enrollment (SER of 4 vs 4, respectively, P = .21). Median PDR was lower in sites within the highest vs lowest minority enrollment (0.23 vs 0.50 PDs per patient per month, respectively, P = .01) and highest vs. lowest female enrollment (0.28 vs. 0.37 PDs per patient per month, respectively, P = .04). However, this relationship did not persist after multivariable adjustment. All other site performance metrics were comparable across quartiles of minority and female enrollment. CONCLUSIONS: Minority, but not female enrollment, correlated with research site geographic region and surrounding population. High enrollment of minorities and women did not influence study performance metrics. These findings help inform future strategies aimed at increasing clinical trial diversity. TRIAL REGISTRATION: The PD and PE Plus studies are registered at www.clinicaltrials.gov under identifiers NCT02240810 and NCT01589978, respectively. KEY POINTS: Question: Does the enrollment of more Blacks, Hispanics and women in US cardiovascular research studies influence the overall rate of study subject enrollment and/or other key study site performance metrics and can diverse enrollment be predicted? FINDINGS: In this pooled analysis of 104 sites that enrolled 4,184 patients in the Platinum Diversity and Promus Element Plus Post-Approval Studies, we found that the enrollment of higher proportions of underrepresented minorities and women was univariately associated with lower protocol deviation rates while having no effect on other site performance metrics. A site's geographic location and surrounding population predicted minority, but not female enrollment. Meaning: These findings suggest that cardiovascular research subject diversity may be predicted from site characteristics and enhanced without compromising key study performance metrics. These insights help inform future strategies aimed at improving clinical trial diversity.

Transradial access in acute myocardial infarction complicated by cardiogenic shock: Stratified analysis by shock severity.

BACKGROUND: Transradial access (TRA) is associated with improved survival and reduced vascular complications in acute myocardial infarction (AMI). Limited data exist regarding TRA utilization and outcomes for AMI complicated by cardiogenic shock (CS). We sought to assess the safety, feasibility, and clinical outcomes of TRA in AMI-CS. METHODS: One-hundred and fifty-three patients with AMI-CS were stratified into tertiles of disease severity using the CardShock score. The primary endpoint was successful percutaneous coronary intervention (PCI), defined as Thrombolysis in Myocardial Infarction III flow with survival to 30 days. RESULTS: Mean age was 66 years, 72% were men, and 47% had diabetes. TRA was the preferred access site in patients with low and intermediate disease severity. Overall, 50 (32%) patients experienced major adverse cardiac and cerebrovascular events; most events (78%) occurred in patients undergoing transfemoral access (TFA) in the intermediate-high tertiles of CS severity. Of the 41 (27%) total bleeding events, 32% occurred at the coronary angiography access site, of which 92% were in the TFA group. The use of ultrasound (US) guidance for TFA resulted in reduced coronary access-site bleeding (8.5 vs. 33.0%, p = .01). In a hierarchical logistic regression model, utilizing TRA did not result in lower odds of successful PCI (Odds ratio [OR]: 1.36; 95% confidence interval [CI]: 0.54-3.40). CONCLUSION: This study suggests that TRA is feasible across the entire spectrum of AMI-CS and is associated with reduced coronary access-site bleeding. In addition, US-guided TFA is associated with reductions in access-site bleeding and vascular complications. Concerted efforts should be made to incorporate vascular access protocols into existing CS algorithms in dedicated shock care centers.

Relationship Between Operator Volume and Long-Term Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: Although many studies show an inverse association between operator procedural volume and short-term adverse outcomes after percutaneous coronary intervention (PCI), the association between procedural volume and longer-term outcomes is unknown. METHODS: Using the National Cardiovascular Data Registry CathPCI registry data linked with Medicare claims data, we examined the association between operator PCI volume and long-term outcomes among patients ≥65 years of age. Operators were stratified by average annual PCI volume (counting PCIs performed in patients of all ages): low- (<50 PCIs), intermediate- (50-100), and high- (>100) volume operators. One-year unadjusted rates of death and major adverse coronary events (MACEs; defined as death, readmission for myocardial infarction, or unplanned coronary revascularization) were calculated with Kaplan-Meier methods. The proportional hazards assumption was not met, and risk-adjusted associations between operator volume and outcomes were calculated separately from the time of PCI to hospital discharge and from hospital discharge to 1-year follow-up. RESULTS: Between July 1, 2009, and December 31, 2014, 723 644 PCI procedures were performed by 8936 operators: 2553 high-, 2878 intermediate-, and 3505 low-volume operators. Compared with high- and intermediate-volume operators, low-volume operators more often performed emergency PCI, and their patients had fewer cardiovascular comorbidities. Over 1-year follow-up, 15.9% of patients treated by low-volume operators had a MACE compared with 16.9% of patients treated by high-volume operators ( P=0.004). After multivariable adjustment, intermediate- and high-volume operators had a significantly lower rate of in-hospital death than low-volume operators (odds ratio, 0.91; 95% CI, 0.86-0.96 for intermediate versus low; odds ratio, 0.79; 95% CI, 0.75-0.83 for high versus low). There were no significant differences in rates of MACEs, death, myocardial infarction, or unplanned revascularization between operator cohorts from hospital discharge to 1-year follow-up (adjusted hazard ratio for MACEs, 0.99; 95% CI, 0.96-1.01 for intermediate versus low; hazard ratio, 1.01; 95% CI, 0.99-1.04 for high versus low). CONCLUSIONS: Unadjusted 1-year outcomes after PCI were worse for older adults treated by operators with higher annual volume; however, patients treated by these operators had more cardiovascular comorbidities. After risk adjustment, higher operator volume was associated with lower in-hospital mortality and no difference in postdischarge MACEs.

Sarcopenia and health-related quality of life in older adults after transcatheter aortic valve replacement.

BACKGROUND: Skeletal muscle wasting, or sarcopenia, affects a significant proportion of patients undergoing transcatheter aortic valve replacement (TAVR). However, its influence on post-TAVR recovery and 1-year health-related quality of life (HR-QOL) remains unknown. We examined the relationship between skeletal muscle index (SMI), post-TAVR length of hospital stay (LOS), and 1-year QOL. METHODS: The study sample consisted of 300 consecutive patients undergoing TAVR from 2012 to 2018 who had pre-TAVR computed tomographic scans suitable for analysis of body composition. Skeletal muscle mass was quantified as cm2 of skeletal mass per m2 of body surface area from the cross-sectional computed tomographic image at the third lumbar vertebra. Sarcopenia was defined using established sex-specific cutoffs (women: SMI < 39 cm2/m2; men: < 55 cm2/m2). Multivariable linear regression analysis was used to determine the relationship between SMI, LOS, and HR-QOL using the Kansas City Cardiomyopathy Questionnaire. RESULTS: Sarcopenia was present in most (59%) patients and associated with older age (82 vs 76 years; P < .001) and lower body mass index (27 vs 33 kg/m2; P < .001). There were no other differences in baseline clinical or echocardiographic characteristics among the 4 quartiles of SMI. SMI was positively correlated with LOS and 1-year QOL. After adjusting for age, gender, race, and body mass index, SMI remained a significant predictor of both LOS (P = .01) and 1-year QOL (P = .012). For every 10 cm2/m2 higher SMI, there was an 8-point increase in Kansas City Cardiomyopathy Questionnaire score, a difference that is clinically meaningful. CONCLUSIONS: Sarcopenia is prevalent in TAVR patients. Higher SMI is associated with shorter LOS and better 1-year HR-QOL. To achieve optimal TAVR benefits, further study into how body composition influences post-TAVR recovery and durable improvement in QOL is warranted.

Triage considerations for patients referred for structural heart disease intervention during the COVID-19 pandemic: An ACC/SCAI position statement.

The coronavirus disease-2019 (COVID-19) pandemic has strained health care resources around the world, causing many institutions to curtail or stop elective procedures. This has resulted in an inability to care for patients with valvular and structural heart disease in a timely fashion, potentially placing these patients at increased risk for adverse cardiovascular complications, including CHF and death. The effective triage of these patients has become challenging in the current environment, as clinicians have had to weigh the risk of bringing susceptible patients into the hospital environment during the COVID-19 pandemic against the risk of delaying a needed procedure. In this document, the authors suggest guidelines for how to triage patients in need of structural heart disease interventions and provide a framework for how to decide when it may be appropriate to proceed with intervention despite the ongoing pandemic. In particular, the authors address the triage of patients in need of transcatheter aortic valve replacement and percutaneous mitral valve repair. The authors also address procedural issues and considerations for the function of structural heart disease teams during the COVID-19 pandemic.

Machine Learning Platform to Discover Novel Growth Inhibitors of Neisseria gonorrhoeae.

PURPOSE: To advance fundamental biological and translational research with the bacterium Neisseria gonorrhoeae through the prediction of novel small molecule growth inhibitors via naïve Bayesian modeling methodology. METHODS: Inspection and curation of data from the publicly available ChEMBL web site for small molecule growth inhibition data of the bacterium Neisseria gonorrhoeae resulted in a training set for the construction of machine learning models. A naïve Bayesian model for bacterial growth inhibition was utilized in a workflow to predict novel antibacterial agents against this bacterium of global health relevance from a commercial library of >105 drug-like small molecules. Follow-up efforts involved empirical assessment of the predictions and validation of the hits. RESULTS: Specifically, two small molecules were found that exhibited promising activity profiles and represent novel chemotypes for agents against N. gonorrrhoeae. CONCLUSIONS: This represents, to the best of our knowledge, the first machine learning approach to successfully predict novel growth inhibitors of this bacterium. To assist the chemical tool and drug discovery fields, we have made our curated training set available as part of the Supplementary Material and the Bayesian model is accessible via the web. Graphical Abstract.

Detailed thrombogenicity phenotyping and 1 year outcomes in patients undergoing WATCHMAN implantation: (TARGET-WATCHMAN) a case-control study.

The relation of device related thrombosis (DRT) and major bleeding after left atrial appendage closure (LAAC) to laboratory thrombosis and hemostasis markers has not been studied. We performed a prospective case control study to identify clinical characteristics and laboratory markers in patients who developed DRT and major bleeding following WATCHMAN LAAC. Thromboelastography, platelet aggregation (PA), urinary 11-dehydrothromboxane B2 (UTX), fibrinogen, D-dimer, thrombin time and von Willebrand factor activity were determined at baseline, immediately following, and at 45 and 180 days post-LAAC (n = 32) and outcomes were followed for 1 year. Baseline characteristics and thrombogenic profiles of patients with and without DRT and/or BARC bleeding were compared. Mean age was 76 ± 8 years and CHADS2 VASc score was 4.4 ± 1.4. There were 3 DRTs (2 within 6 months, and 1 at 12 months), 4 Type 3A BARC bleeds, and 2 non-cardiac deaths. Patients with DRT had higher baseline thrombin-induced platelet-fibrin clot strength (68.0 ± 1.8 vs. 62.7 ± 4.7 mm, p = 0.06); FCS (35.6 ± 6.0 vs. 24.4 ± 6.6 mm, p = 0.009); and D-dimer (1712 ± 2330 vs. 283 ± 213 ng/mL, p = 0.001). At baseline, 5 patients had all 3 factors associated with high thrombotic risk and 2 experienced a DRT within 6 months. Patients with Type 3A BARC bleeding had lower baseline collagen-induced and 45-day ADP-induced PA (p < 0.01 for both). DRT following LAAC was associated with a baseline prothrombogenic profile whereas bleeding was associated with low platelet reactivity. These preliminary findings warrant further validation and have future implications on patient selection and adjunctive antithrombotic therapy following LAAC.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622 .

Periprocedural Outcomes of Direct Oral Anticoagulants Versus Warfarin in Nonvalvular Atrial Fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) are surpassing warfarin as the anticoagulant of choice for stroke prevention in nonvalvular atrial fibrillation. DOAC outcomes in elective periprocedural settings have not been well elucidated and remain a source of concern for clinicians. The aim of this meta-analysis was to evaluate the periprocedural safety and efficacy of DOACs versus warfarin in patients with nonvalvular atrial fibrillation. METHODS: We reviewed the literature for data from phase III randomized controlled trials comparing DOACs with warfarin in the periprocedural period among patients with nonvalvular atrial fibrillation. Substudies from 4 trials (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation], and ENGAGE-AF [Effective Anticoagulation With Factor xA Next Generation in Atrial Fibrillation]) were included in the meta-analysis. DOACs as a group and warfarin were compared in terms of the 30-day pooled risk for stroke/systemic embolism, major bleeding, and death, according to whether the study drug was interrupted or not periprocedurally. The overall relative risk (RR) was estimated with a random-effects model. The I2 test was used to assess heterogeneity in RR among the studies. RESULTS: In the uninterrupted anticoagulant strategy, there were no differences in the rates of stroke/systemic embolism (pooled risk, 0.6% [29 events/4519 procedures] versus 1.1% [31/2971]; RR, 0.70; 95% confidence interval [CI], 0.41-1.18) and death (1.4% versus 1.8%; RR, 0.77; 95% CI, 0.53-1.12) between DOACs and warfarin and significantly fewer major bleeding events (2.0% versus 3.3%; RR, 0.62; 95% CI, 0.47-0.82) with DOACs compared to warfarin. Under an interrupted strategy, there was no significant difference between DOACs versus warfarin for stroke/systemic embolism (0.4% [41/9260] versus 0.5% [31/7168]; RR, 0.95; 95% CI, 0.59-1.55), major bleeding (2.1% versus 2.0%; RR, 1.05; 95% CI, 0.85-1.30), and death (0.7% versus 0.6%; RR, 1.24; 95% CI, 0.76-2.04). The studies were homogeneous ( I2=0.0%) for all calculated pooled associations except for the RR of death in the interrupted strategy ( I2=26.3%). CONCLUSIONS: The short-term safety and efficacy of DOACs and warfarin are not different in patients with nonvalvular atrial fibrillation periprocedurally. Under an uninterrupted anticoagulation strategy, DOACs are associated with a 38% lower risk of major bleeding compared with warfarin.

Self-directed down-regulation of auditory cortex activity mediated by real-time fMRI neurofeedback augments attentional processes, resting cerebral perfusion, and auditory activation.

In this work, we investigated the use of real-time functional magnetic resonance imaging (fMRI) with neurofeedback training (NFT) to teach volitional down-regulation of the auditory cortex (AC) using directed attention strategies as there is a growing interest in the application of fMRI-NFT to treat neurologic disorders. Healthy participants were separated into two groups: the experimental group received real feedback regarding activity in the AC; the control group was supplied sham feedback yoked from a random participant in the experimental group and matched for fMRI-NFT experience. Each participant underwent five fMRI-NFT sessions. Each session contained 2 neurofeedback runs where participants completed alternating blocks of "rest" and "lower" conditions while viewing a continuously-updated bar representing AC activation and listening to continuous noise. Average AC deactivation was extracted from each closed-loop neuromodulation run and used to quantify the control over AC (AC control), which was found to significantly increase across training in the experimental group. Additionally, behavioral testing was completed outside of the MRI on sessions 1 and 5 consisting of a subjective questionnaire to assess attentional control and two quantitative tests of attention. No significant changes in behavior were observed; however, there was a significant correlation between changes in AC control and attentional control. Also, in a neural assessment before and after fMRI-NFT, AC activity in response to continuous noise stimulation was found to significantly decrease across training while changes in AC resting perfusion were found to be significantly greater in the experimental group. These results may be useful in formulating effective therapies outside of the MRI, specifically for chronic tinnitus which is often characterized by hyperactivity of the primary auditory cortex and altered attentional processes. Furthermore, the modulation of attention may be useful in developing therapies for other disorders such as chronic pain.

Apixaban following acute coronary syndromes in patients with prior stroke: Insights from the APPRAISE-2 trial.

BACKGROUND AND PURPOSE: Patients with prior stroke are at greater risk for recurrent cardiovascular events post-acute coronary syndromes (ACS) and may have a different risk/benefit profile with antithrombotic therapy than patients without prior stroke. METHODS: We studied 7391 patients with ACS from APPRAISE-2, stratified by the presence or absence of prior stroke. Baseline characteristics and outcomes of cardiovascular death, myocardial infarction (MI), or stroke were compared between groups. Interactions between prior stroke, treatment assignment (apixaban vs placebo), and outcomes were tested before and after multivariable adjustment with Cox proportional hazards models. RESULTS: A total of 902 patients (12%) had prior stroke. Those with prior stroke were older (69 vs 67 years), had more hypertension (91% vs 77%), peripheral vascular disease (22% vs18%), and impaired renal function (38% vs 30%) but less diabetes (44% vs 48%) than those without prior stroke. Patients with prior stroke vs no prior stroke had higher unadjusted rates of cardiovascular death (4.8% vs 4.0%), MI (11.2% vs 7.1%), and ischemic stroke (3.2% vs 0.9%). Patients with prior stroke assigned to apixaban had similar rates of the composite of cardiovascular death, MI, or stroke compared with those assigned to placebo (HR 1.39; 95% CI 0.92-2.08). Patients without prior stroke assigned to apixaban had similar rates of cardiovascular death, MI, or ischemic stroke compared with those assigned to placebo (HR 0.87; 95% CI 0.73-1.04; P-interaction=.041). Median follow-up was 240 days. CONCLUSIONS: Patients with prior stroke are at higher risk for recurrent cardiovascular events post-ACS and had a differential risk/benefit profile with oral anticoagulation.

Percutaneous coronary intervention and antiplatelet therapy in patients with atrial fibrillation receiving apixaban or warfarin: Insights from the ARISTOTLE trial.

BACKGROUND: We assessed antiplatelet therapy use and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ARISTOTLE trial. METHODS: Patients were categorized based on the occurrence of PCI during follow-up (median 1.8 years); PCI details and outcomes post-PCI are reported. Of the 18,201 trial participants, 316 (1.7%) underwent PCI (152 in apixaban group, 164 in warfarin group). RESULTS: At the time of PCI, 84% (267) were on study drug (either apixaban or warfarin). Of these, 19% did not stop study drug during PCI, 49% stopped and restarted <5 days post-PCI, and 30% stopped and restarted >5 days post-PCI. At 30 days post-PCI, 35% of patients received dual -antiplatelet therapy (DAPT), 23% received aspirin only, and 13% received a P2Y12 inhibitor only; 29% received no antiplatelet therapy. Triple therapy (DAPT + oral anticoagulant [OAC]) was used in 21% of patients, 23% received OAC only, 15% received OAC plus aspirin, and 9% received OAC plus a P2Y12 inhibitor; 32% received antiplatelet agents without OAC. Post-PCI, patients assigned to apixaban versus warfarin had numerically similar rates of major bleeding (5.93 vs 6.73 events/100 patient-years; P = .95) and stroke (2.74 vs 1.84 events/100 patient-years; P = .62). CONCLUSIONS: PCI occurred infrequently during follow-up. Most patients on study drug at the time of PCI remained on study drug in the peri-PCI period; 19% continued the study drug without interruption. Antiplatelet therapy use post-PCI was variable, although most patients received DAPT. Additional data are needed to guide the use of antithrombotics in patients undergoing PCI.

Variation in post-TAVR antiplatelet therapy utilization and associated outcomes: Insights from the STS/ACC TVT Registry.

BACKGROUND: Dual antiplatelet therapy (DAPT) is recommended following transcatheter aortic valve replacement (TAVR); however, the optimal antiplatelet strategy is undefined, and little is known about practice patterns. We aimed to describe contemporary practice patterns of antiplatelet therapy and their relationship to outcomes post-TAVR. METHODS: The population was derived from the National Cardiovascular Data Registry, Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry with Center for Medical Services linkage for 1-year outcomes from October 1, 2011 to June 30,2016. The primary outcome measured was DAPT use in patients without anticoagulation. Secondary outcomes included death, major bleeding, myocardial infarction (MI), and stroke at 1 year. RESULTS: Overall, 16,694 patients underwent transfemoral TAVR at 444 hospitals and were discharged without anticoagulation. Among these, 13,546 (81.1%) patients were discharged on DAPT, whereas 3,148 patients (18.9%) were discharged on monotherapy. Patients discharged on DAPT versus monotherapy were similar in age, sex, and most comorbid illnesses but had higher rates of coronary artery disease (64.6% vs 52.3%; P < .01) and peripheral artery disease (25.2% vs 22.3%; P < .01). Hospital prescribing patterns varied significantly (median frequency of DAPT 85.7%, interquartile range 94.1%-74.2%). DAPT (vs monotherapy) patients had a similar mortality risk at 1 year (adjusted hazard ratio 0.92, 95% CI 0.81-1.05), significantly higher risk for major bleeding (1.48, 1.10-1.99), and similar hazard for stroke (1.04, 0.83-1.31) and MI (1.00, 0.72-1.39). CONCLUSIONS: In the United States, most patients were discharged on DAPT following TAVR. Practice patterns varied significantly among hospitals. Patients discharged with DAPT had a similar adjusted risk of mortality, stroke, and MI compared to antiplatelet monotherapy, although risk for bleeding was significantly higher. Future investigation is needed to define the optimal antiplatelet therapy for patients undergoing TAVR.

Challenges in Aortic Stenosis: Review of Antiplatelet/Anticoagulant Therapy Management with Transcatheter Aortic Valve Replacement (TAVR): TAVR with Recent PCI, TAVR in the Patient with Atrial Fibrillation, and TAVR Thrombosis Management.

PURPOSE OF REVIEW: This review aims to describe the current evidence and consensus recommendations around antiplatelet and anticoagulant management in three common clinical scenarios in transcatheter aortic valve replacement (TAVR): (1) recent percutaneous coronary intervention (PCI) preceding TAVR, (2) atrial fibrillation (AF) management in patients undergoing TAVR, and (3) bioprosthetic valve thrombosis management in TAVR. RECENT FINDINGS: Several small clinical trials have evaluated the use of single vs. dual antiplatelet therapy in patients undergoing TAVR, with most recent data favoring single antiplatelet therapy. There are several trials currently enrolling and in follow-up that evaluate the use of anticoagulants in combination with single and dual antiplatelet therapy for patients with AF undergoing TAVR, but as yet, there is no data to support a clear strategy. The use of DAPT after PCI continues to potentially shorten in patients undergoing elective PCI, thus prolonged DAPT may not be necessary post TAVR for the sake of PCI. Bioprosthetic valve thrombosis occurs more commonly than previously thought, but has uncertain clinical significance. In observational studies, antiplatelet therapy has little effect on bioprosthetic valve thrombosis, whereas anticoagulation is effective in both prevention and treatment of thrombosis. DAPT is currently recommended for 1-6 months for all patients without an indication for oral anticoagulation who undergo TAVR; however, there is a growing amount of evidence for single antiplatelet therapy. In the special situation of patients who have recently undergone PCI, the length of DAPT will depend on stent selection (BMS vs. DES), but may not be significantly prolonged unless the patient experienced an acute coronary syndrome prior to TAVR. There is no clear, optimal antithrombotic strategy for patients with AF who undergo TAVR, but avoidance of triple therapy by using OAC and low-dose ASA seems to be reasonable. OAC, not DAPT, is now known to prevent bioprosthetic valve thrombosis in TAVR and SAVR patients; however, the optimal therapy remains unknown. For patients who develop bioprosthetic valve thrombosis, OAC for 3-6 months, and repeat imaging is recommended to document resolution.

Repetitive Transcranial Electrical Stimulation Induces Quantified Changes in Resting Cerebral Perfusion Measured from Arterial Spin Labeling.

The use of transcranial electrical stimulation (TES) as a method to augment neural activity has increased in popularity in the last decade and a half. The specific application of TES to the left prefrontal cortex has been shown to produce broad cognitive effects; however, the neural mechanisms underlying these effects remain unknown. In this work, we evaluated the effect of repetitive TES on cerebral perfusion. Stimulation was applied to the left prefrontal cortex on three consecutive days, and resting cerebral perfusion was quantified before and after stimulation using arterial spin labeling. Perfusion was found to decrease significantly more in a matched sham stimulation group than in a group receiving active stimulation across many areas of the brain. These changes were found to originate in the locus coeruleus and were broadly distributed in the neocortex. The changes in the neocortex may be a direct result of the stimulation or an indirect result via the changes in the noradrenergic system produced from the altered activity of the locus coeruleus. These findings indicate that anodal left prefrontal stimulation alters the activity of the locus coeruleus, and this altered activity may excite the noradrenergic system producing the broad behavioral effects that have been reported.

Regional Systems of Care Demonstration Project: American Heart Association Mission: Lifeline STEMI Systems Accelerator.

BACKGROUND: Up to 50% of patients fail to meet ST-segment-elevation myocardial infarction (STEMI) guideline goals recommending a first medical contact-to-device time of <90 minutes for patients directly presenting to percutaneous coronary intervention-capable hospitals and <120 minutes for transferred patients. We sought to increase the proportion of patients treated within guideline goals by organizing coordinated regional reperfusion plans. METHODS: We established leadership teams, coordinated protocols, and provided regular feedback for 484 hospitals and 1253 emergency medical services (EMS) agencies in 16 regions across the United States. RESULTS: Between July 2012 and December 2013, 23 809 patients presented with acute STEMI (direct to percutaneous coronary intervention hospital: 11 765 EMS transported and 6502 self-transported; 5542 transferred). EMS-transported patients differed from self-transported patients in symptom onset to first medical contact time (median, 47 versus 114 minutes), incidence of cardiac arrest (10% versus 3%), shock on admission (11% versus 3%), and in-hospital mortality (8% versus 3%; P<0.001 for all comparisons). There was a significant increase in the proportion of patients meeting guideline goals of first medical contact-to-device time, including those directly presenting via EMS (50% to 55%; P<0.001) and transferred patients (44%-48%; P=0.002). Despite regional variability, the greatest gains occurred among patients in the 5 most improved regions, increasing from 45% to 57% (direct EMS; P<0.001) and 38% to 50% (transfers; P<0.001). CONCLUSIONS: This Mission: Lifeline STEMI Systems Accelerator demonstration project represents the largest national effort to organize regional STEMI care. By focusing on first medical contact-to-device time, coordinated treatment protocols, and regional data collection and reporting, we were able to increase significantly the proportion of patients treated within guideline goals.