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SummaryPercutaneous transcatheter Melody Valve implantation has achieved standard of care for the management of certain patients with right ventricular outflow tract dysfunction. With its widespread use, some rare and potentially fatal complications, such as right ventricular outflow tract rupture and coronary artery compression, have been reported. We report hyperacute flash pulmonary oedema after Melody Valve implantation for the first time in two patients and describe some possible predictors.

There are limited data on acute decompensated heart failure (ADHF) that develops after hospital admission. This study sought to compare patient characteristics, co-morbidities, mortality, and length of stay by timing of ADHF onset. The surveillance component of the Atherosclerosis Risk in Communities study (2005 to 2011) sampled, abstracted, and adjudicated hospitalizations with select International Classification of Disease, Ninth Revision, Clinical Modification discharge codes from 4 United States communities among those aged ≥55 years. We included 5,602 validated ADHF hospitalizations further classified as preadmission or postadmission onset. Vital status was assessed up to 1 year since admission. We estimated multivariate-adjusted associations of in-hospital mortality and 28- and 365-day case fatalities with timing of ADHF onset (postadmission vs preadmission). All analyses were weighted to account for the stratified sampling design. Of 25,862 weighted ADHF hospitalizations, 7% had postadmission onset of ADHF. Patients with postadmission ADHF were more likely to be older, white, and women. The most common primary discharge diagnosis codes for those with postadmission ADHF included diseases of the circulatory or digestive systems or infectious diseases. Short-term mortality among postadmission ADHF was almost 3 times that of preadmission ADHF (in-hospital mortality: odds ratio 2.7, 95% confidence interval 1.9 to 3.9; 28-day case fatality: odds ratio 2.6, 95% confidence interval 1.8 to 3.7). The average hospital stay was almost twice as long among postadmission as preadmission ADHF (9.6 vs 5.0 days). In conclusion, postadmission onset of ADHF is characterized by differences in co-morbidities and worse short-term prognosis, and opportunities for reducing postadmission ADHF occurrence and associated risks need to be studied.

Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48–67 years (1990–1992) through ages 70–89 years (2011–2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors.

Measurement error/misclassification is commonplace in research when variable(s) cannot be measured accurately. A number of statistical methods have been developed to tackle this problem in a variety of settings and contexts. However, relatively few methods are available to handle misclassified categorical exposure variable(s) in the Cox proportional hazards regression model. In this article, we aim to review and compare different methods to handle this problem—naive methods, regression calibration, pooled estimation, multiple imputation, corrected score estimation, and MC-SIMEX—by simulation. These methods are also applied to a life course study with recalled data and historical records. In practice, the issue of measurement error/misclassification should be accounted for in design and analysis, whenever possible. Also, in the analysis, it could be more ideal to implement more than one correction method for estimation and inference, with proper understanding of underlying assumptions.

Introduction Prior assessments of emergency medical services (EMS) stroke capacity found deficiencies in education and training, use of protocols and screening tools, and planning for the transport of patients. A 2001 survey of North Carolina EMS providers found many EMS systems lacked basic stroke services. Recent statewide efforts have sought to standardize and improve prehospital stroke care. The objective of this study was to assess EMS stroke care capacity in North Carolina and evaluate statewide changes since 2001. Methods In June 2012, we conducted a web-based survey on stroke education and training and stroke care practices and policies among all EMS systems in North Carolina. We used the McNemar test to assess changes from 2001 to 2012. Results Of 100 EMS systems in North Carolina, 98 responded to our survey. Most systems reported providing stroke education and training (95%) to EMS personnel, using a validated stroke scale or screening tool (96%), and having a hospital prenotification policy (98%). Many were suboptimal in covering basic stroke educational topics (71%), always communicating stroke screen results to the destination hospital (46%), and always using a written destination plan (49%). Among 70 EMS systems for which we had data for 2001 and 2012, we observed significant improvements in education on stroke scales or screening tools (61% to 93%, P < .001) and use of validated stroke scales or screening tools (23% to 96%, P < .001). Conclusion Major improvements in EMS stroke care, especially in prehospital stroke screening, have occurred in North Carolina in the past decade, whereas other practices and policies, including use of destination plans, remain in need of improvement.

Background: Acute stroke patients require immediate medical attention. Therefore, American Stroke Association guidelines recommend that for suspected stroke cases, emergency medical services (EMS) personnel spend less than 15 minutes (min) on-scene at least 90% of the time. However, not all EMS providers include specific scene time limits in their stroke patient care protocols. We sought to determine whether a protocol with a specific time goal was associated with less time spent at the scene. Methods: Stroke protocols from each of the 100 EMS systems in North Carolina (NC) were collected and abstracted for scene time instructions. Suspected stroke events occurring in 2009 were analyzed using data from the NC Prehospital Medical Information System, a statewide electronic healthcare record used for evaluation of EMS patient care and system performance. Scene time was defined as the time from EMS arrival at the scene to departure with the patient. Quantile regression was used to estimate how the 90th percentile of the scene time distribution varied by the presence of protocol instructions limiting scene time. Models adjusted for system annual patient volume and metropolitan status. Results: In 2009, NC EMS systems varied in their stroke protocols: 23 had no instructions regarding scene time; 73 had general instructions to minimize scene time; and 4 had a specific limit for scene time (i.e. 10 or 15 min). Among 9,723 eligible suspected stroke events, mean scene time was 15.9 min (standard deviation 6.9 min) and median scene time was 15.0 min (interquartile range 11.0-19.5 min). We observed significantly lower 90th percentile scene times in EMS systems with specific time limit instructions (22.0 min) compared to systems without any instructions on scene time (24.6 min). There was no significant difference between 90th percentile scene times in EMS systems with general instructions compared to systems without instructions (25.0 versus 24.6 min). In adjusted quantile regression models, the estimated reduction in the 90th percentile scene time, comparing specific to no instructions, was 2.2 min (95% confidence interval 1.3, 3.1 min). The adjusted difference in 90th percentile scene time between general and absent instructions was not statistically different (0.7 min (95% confidence interval -0.1, 1.4 min)). Conclusion: Specific scene time limits were associated with EMS crews spending less time at the scene while general instructions were not. These findings suggest that EMS stroke protocols that include specific scene time limits are more likely to reduce on-scene times than those with no or only general instructions.

Declines in case fatality post-myocardial infarction (MI) have been observed over the past 3 decades. Few studies report socioeconomic disparities in survival post-MI.We assessed 1-year case fatality among 9,116 incident MI patients included in the Atherosclerosis Risk in Communities community surveillance from 1992 to 2002. Addresses of hospitalized MI patients were geocoded by a commercial vendor and linked to year 2000 United States Census tract-level neighborhood income (nINC) data. We estimated case fatality odds ratios and 95% CIs with a multinomial logistic model to quantify the association between nINC tertile and case fatality, comparing short- (within 28 days) and long-term (29-365 days) case fatality to no death 1 year post-MI.Overall, 1-year age-adjusted case fatality rates were highest among MI patients living in low-nINC areas, followed by medium- and high-nINC areas, respectively. We found significant odds ratio modification by race (P.10) and formed race-nINC strata with high-nINC whites as the referent group. In multivariable models adjusting for age, gender, study community, and year of MI, low-nINC whites and low- and medium-nINC blacks had higher short-term case fatality than high-nINC whites. Low- and medium-nINC blacks had higher long-term case fatality compared with high-nINC whites.Differences in short- and long-term case fatality by neighborhood socioeconomic factors have not been systematically studied in the United States. Surveillance efforts can be expanded to incorporate measures of the neighborhood context to examine these associations over time.

Activation of the RAS/MAPK pathway occurs via a cascade of protein phosphorylation events which culminate in the phosphorylation & activation of ERK 1/2. Aberrant activation of this pathway has been demonstrated in several human tumor types. Inhibitors of this pathway in clinical development target upstream kinases, BRAF or MEK. Only a few ERK 1/2 has been reported. The goal of the ERK program was to develop a targeted therapy that is guided by a clear patient selection / responder identification plan based on BRAF and K/NRAS mutations. Utilizing an affinity based high-throughput screening strategy (ALIS), we discover a novel class of small molecule ERK 1/2 inhibitors. Optimization of this chemical series led to the discovery of SCH 772984, which is highly selective ERK1/2 inhibitor, inhibiting cell proliferation selectively in tumor cell lines with an activated MAPK pathway and causes significant tumor regression in vivo in BRAF & RAS mutant xenograft models. Based on insights gained through crystallographic analysis, SCH 772984 and related compounds have a unique ERK binding mode which results in a novel dual mechanism of inhibition, blocking ERK phosphorylation by MEK as well as inhibiting ERK kinase activity. This novel mechanism enables the use of ERK phosphorylation as a target engagement biomarker. Biological differences between pathway inhibition at the level or ERK vs. inhibition of upstream kinases are being examined. The SAR and crystal structures of this series ERK inhibitors will be reported. Citation Format: Yongqi Deng, Ahmed Samatar, Gerald Shipps, Alan Cooper, Brian Long, Donnar Carr, Li Xiao, Alan Hruza, Tong Wang, Liang Zhu, Yang Nan, Mehul Patel, Kiran Muppalla, Hugh Zhu, Babu Sobhana Boga, Xiaolei Gao. Discovery of potent and selective inhibitors of ERK1/2 with a unique mechanism of action. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4788.

Objectives: To evaluate whether education level is associated with change in cognitive performance. Design: Prospective cohort study. Setting: The Atherosclerosis Risk in Communities (ARIC) Study, a community-based cohort. Participants: Nine thousand two hundred sixty-eight ARIC participants who underwent cognitive evaluation at least twice over a 15-year period. Measurements: Education was evaluated as a predictor of change in word recall, the Digit Symbol Substitution Test (DSST), and word fluency. A random-effects linear regression model, and a time by educational level interaction was used. Results: Educational level was highly associated with cognitive performance. The effect on performance of a less than high school education (vs more than high school) was equivalent to the effect of as much as 22 years of cognitive aging, but educational level was not associated with change in cognitive performance in whites or blacks, with the exception of the DSST for whites, in whom those with lower levels of education had less decline in scores. Conclusion: Educational level was not associated with change in cognitive performance, although the higher baseline cognitive performance of individuals with more education might explain lower rates of dementia in more-educated individuals, because more decline would have to take place between baseline higher performance and time at which dementia was diagnosed in more-educated individuals.

Occupational data are a common source of workplace exposure and socioeconomic information in epidemiologic research. We compared the performance of two occupation coding methods, an automated software and a manual coder, using occupation and industry titles from U.S. historical records.We collected parental occupational data from 1920-40s birth certificates, Census records, and city directories on 3,135 deceased individuals in the Atherosclerosis Risk in Communities (ARIC) study. Unique occupation-industry narratives were assigned codes by a manual coder and the Standardized Occupation and Industry Coding software program. We calculated agreement between coding methods of classification into major Census occupational groups.Automated coding software assigned codes to 71% of occupations and 76% of industries. Of this subset coded by software, 73% of occupation codes and 69% of industry codes matched between automated and manual coding. For major occupational groups, agreement improved to 89% (kappa = 0.86).Automated occupational coding is a cost-efficient alternative to manual coding. However, some manual coding is required to code incomplete information. We found substantial variability between coders in the assignment of occupations although not as large for major groups.

In some regions of the US, emergency medical services (EMS) policies recommend transporting acute stroke patients directly to specialized stroke centers, bypassing local facilities unable to provide appropriate care. However, this prehospital care practice has not been thoroughly studied. We describe the pattern of bypass in a random sample of 301 suspected stroke patients transported by EMS from 53 of 100 North Carolina (NC) counties in 2010. We geocoded scene and destination addresses and calculated driving distances using GIS network analysis (ArcGIS 9.2, ESRI). EMS bypass was defined as the transport of a patient to a hospital other than the closest in driving distance. We characterized each destination as either a Joint Commission certified Primary Stroke Center (PSC) or not (non-PSC). The 301 stroke incidents were transported by EMS to 59 hospitals, including 16 designated as PSCs. EMS bypassed the closest facility for 91 patients (30%). On average, bypass resulted in an additional 10.0 miles of travel [median 4.7 miles (IQR 1.7, 10.6)]. Bypass did not vary widely by patient age, sex, or race. Bypass was more likely to occur in urban counties compared to rural counties (34% vs. 26%), with the mean additional travel distance shorter in urban counties (5.0 miles vs. 16.1 miles). Overall, 151 (of 301) patients were transported to a PSC while only 125 patients would have gone to a PSC if all had been transported to the closest hospital. Therefore, we found EMS bypass resulted in an additional 26 patients transported to a PSC. Further, EMS bypassed a closer non-PSC for a PSC in 36 cases while 10 patients were taken to a non-PSC instead of a closer PSC. Of these 10, the majority, 8, were transported based on patient or family choice. Our data suggest EMS bypass practices can increase access to specialized stroke care centers. Bypassing local hospitals appears to occur more frequently in urban areas where PSCs are more prevalent and in closer proximity. Yet, EMS bypass is not uncommon in rural areas of NC. EMS care, geographic location, and patient choice are all influential in determining a stroke patient's destination. Future studies should incorporate travel times in addressing access to timely stroke care.

Background Tissue plasminogen activator therapy (t-PA) is associated with improved neurologic outcomes and reduced disability from ischemic stroke. The current guidelines stipulate that patients receive t-PA within 3 hours of symptom onset. However, actual practice patterns vary, and little is known about patient outcomes when t-PA is received outside of the recommended time window. Methods We examined mean length of hospital stay, t-PA–related complications, and in-hospital death by time of t-PA administration in North Carolina Stroke Care Collaborative (NCSCC) patients. The NCSCC includes 53 hospitals that enroll patients presenting with stroke-like symptoms. Of 40,907 patients enrolled between January 2005 and February 2010, 1070 (2.6%) received t-PA. Of these, 88.2% received t-PA within 3 hours of symptom onset ("early") and 30.3% received t-PA between 3 and 6 hours after symptom onset ("late"). Results Unadjusted mean length of stay (days) was longer among early patients (5.0 days; 95% confidence interval [CI], 4.7-5.3) than late patients (3.6 days; 95% CI, 3.1-4.2). t-PA–related complications were similar among early (7.0%; 55/781) and late patients (6.7%; 7/102; P = .89). The proportion of in-hospital deaths was similar among late (10.5%) and early patients (12.0%). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% CIs for the associations between late t-PA status and patient outcomes. Conclusions In models controlling for age, race, sex, arrival mode, and ambulatory status on admission, late t-PA was not associated with increased odds of complications or in-hospital deaths (OR, 0.89; 95% CI, 0.49-1.62). The risks and benefits of expansion of the t-PA time window in stroke patients merit further investigation.