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Background: Racial inequities exist in treatment and outcomes in patients with acute stroke. Objectives: Our objective was to determine if racial inequities exist in the time-lapse between patient presentation and provider assessment in patients with stroke-like symptoms in Emergency Departments (ED) across the U.S. Methods: This study is a retrospective, observational study of the National Hospital Ambulatory Medical Care Survey (NHAMCS) 2014–2018. We identified visits with stroke-like symptoms and stratified the proportion of door-to-provider (DTP) times by racial groups. We used broad and narrow definitions of stroke-like symptoms. We performed bivariate and multivariate analyses using race and clinical and demographic characteristics as covariates. Results: Between 2014–2018, there were an average of 138.58 million annual ED visits. Of the total ED visits, 0.36% to 7.39% of the ED visits presented with stroke-like symptoms, and the average DTP time ranged from 39 to 49 min. The proportion of the visits with a triage level of 1 (immediate) or 2 (emergent) ranged from 16.03% to 23.27% for stroke-like symptoms. We did not find statistically significant racial inequities in DTP or ED triage level. We found significantly longer DTP times in non-Hispanic blacks (15.88 min, 95% CI: 4.29–27.48) and Hispanics (by 14.77 min, 95% CI: 3.37–26.16) than non-Hispanic whites that presented with atypical stroke-like symptoms. We observed that non-Hispanic whites were significantly more diagnosed with a stroke/TIA than other racial minority groups (p = 0.045) for atypical stroke-like symptoms. Conclusion: In our population-based analysis, we did not identify systemic racial inequities in the DTP times or ED triage level at ED triage for stroke-like symptoms. [ABSTRACT FROM AUTHOR]

Introduction: We sought to examine the utility of self-reported pain scale by comparing emergency department (ED) triage pain scores of self-reported but non-verifiable painful conditions with those of verifiable painful conditions using a large, nationally representative sample. Methods: We analyzed the National Hospital Ambulatory Medical Care Survey (NHAMCS) 2015. Verifiable painful conditions were identified based on the final diagnoses in the five included International Classification of Diseases 9th revision codes. Non-verifiable painful conditions were identified by the five main reasons for visit. Only adults 18 years of age or older were included. The primary outcome variable was the pain scale from 0 to 10 at triage. We performed descriptive and multivariate analyses to investigate the relationships between the pain scale and whether the painful condition was verifiable, controlling for patient characteristics. Results: There were 55 million pain-related adult ED visits in 2015. The average pain scale was 6.49. For verifiable painful diagnoses, which were about 24% of the total visits, the average was 6.27, statistically significantly lower than that for non-verifiable painful conditions, 6.56. Even after controlling for the confounding of patient characteristics and comorbidities, verifiable painful diagnoses still presented less pain than those with non-verifiable painful complaints. Older age, female gender, and urban residents had significantly higher pain scores than their respective counterparts, controlling for other confounding factors. Psychiatric disorders were independently associated with higher pain scores by about a half point. Conclusion: Self-reported pain scales obtained at ED triage likely have a larger psychological component than a physiological one. Close attention to clinical appropriateness and overall patient comfort are more likely to lead to better health outcomes and patient experiences than focusing on self-reported pain alone. [ABSTRACT FROM AUTHOR]

This study examines racial and ethnic disparities in the financial burden of prescription drugs among older Americans using a market and an egalitarian model. A nationally representative data set, the Medical Expenditure Panel Survey 2002, was used. The financial burden of prescription drugs was measured by the out-of-pocket expenditure and proportion. In the market model (utilization adjustment)., utilization was measured at the annual aggregate level by the total number of prescription drugs, the average refills and the average quantity per prescription drug. In the egalitarian model (need adjustment)., health was measured by 15 chronic and costly diseases and the SF-12. Individuals 65 years or older were included. Nationally representative estimates were calculated. Raw racial and ethnic disparities were observed in the bivariate analyses between non-Hispanic whites and Hispanics in the out-of-pocket expenditure and proportion, and between non-Hispanic whites and non-Hispanic blacks in the out-of-pocket proportion. However, these disparities disappeared after controlling for utilization or health needs. Insurance status contributed the most to the disparities in the financial burden of prescription drugs. In conclusion, The disparities in the financial burden of prescription drugs between non-Hispanic elderly whites and Hispanics may be attributable to differences in utilization patterns. However, whether health disparities contribute to disparities in the financial burden of prescription drugs requires studies of specific diseases. [ABSTRACT FROM AUTHOR]

Background: Although tobacco use in the United States has declined over the past 20 years, cigarette use among college students remains high. Additional research is thus needed to determine how university tobacco control policies and preventive education programs affect college students' smoking behaviors. Methods: Approximately 13,000 undergraduate students at 12 universities or colleges in the state of Texas completed a web-based survey. College smoking policies were obtained from a survey of college administrators and from college websites. Logistic regression analyses were conducted to estimate the effects of individual smoking policies and programs on the odds of cigarette smoking. Results: Of the individual programs, only having a preventive education program on campus was associated with lower odds of smoking. The existence of smoking cessation programs and designated smoking areas were associated with higher odds of smoking. Policies governing the sale and distribution of cigarettes were insignificantly associated with smoking. Conclusion: Rather than focusing on policies restricting cigarette sales and use, college administrators should consider implementing or expanding tobacco prevention and education programs to further reduce student smoking rates. [ABSTRACT FROM AUTHOR]

Objective: The prevalence of asthma among children has been increasing in the United States and it is estimated that there are approximately 5 million children with asthma. This cross-sectional survey sought to estimate the prevalence of asthma and asthma symptoms and potential risk factors among children aged 16 and younger, in a largely rural population in the USA.Methods: This study was a telephone survey of 1500 households in the South Plains/Panhandle region of Texas. Parents of children were interviewed with a response rate of 64%. Having been diagnosed with asthma by a physician and a report of wheezing in the last 12 months were used as dependent variables in multivariate logistic regressions with several sociodemographic and environmental factors as potential confounders.Results: The age-adjusted prevalence of asthma and wheezing among children were approximately 15 and 18%, respectively. The prevalence of asthma was highest (20%) among children aged 11-16 (P < 0.001). Living in urban areas was associated significantly with asthma and wheezing. Non-Hispanic blacks reported significantly increased odds of asthma in their children (adjusted odds ratio (OR) = 2.04, 95%CI 1.02-4.08), whereas Mexican-Americans reported significantly reduced odds of asthma (adjusted OR = 0.48, 95%CI 0.29-0.78) and wheezing (adjusted OR = 0.58, 95%CI 0.37-0.89) in their children. The odds of asthma (adjusted OR = 1.78, 95%CI 1.09-2.92) and wheezing (adjusted OR = 2.45, 95%CI 1.52-3.95) was highest among children in the highest body mass index quartile. No significant association with pet ownership and exposure to second-hand smoke with asthma and wheezing was observed in this study.Conclusion: Urban residence, non-Hispanic black and Mexican-American race/ethnicity, and being overweight were significantly associated with the increased risk of asthma and/or wheezing. [ABSTRACT FROM AUTHOR]

Objective: To compare the effects of having a regular doctor and having a regular site on five preventive services, controlling for the endogeneity of having a usual source of care.Data Source: The Medical Expenditure Panel Survey 1996 conducted by the Agency for Healthcare Research and Quality and the National Center for Health Statistics.Study Design: Mammograms, pap smears, blood pressure checkups, cholesterol level checkups, and flu shots were examined. A modified behavioral model framework was presented, which controlled for the endogeneity of having a usual source of care. Based on this framework, a two-equation empirical model was established to predict the probabilities of having a regular doctor and having a regular site, and use of each type of preventive service.Principal Findings: Having a regular doctor was found to have a greater impact than having a regular site on discretional preventive services, such as blood pressure and cholesterol level checkups. No statistically significant differences were found between the effects a having a regular doctor and having a regular site on the use of flu shots, pap smears, and mammograms. Among the five preventive services, having a usual source of care had the greatest impact on cholesterol level checkups and pap smears.Conclusions: Promoting a stable physician-patient relationship can improve patients' timely receipt of clinical prevention. For certain preventive services, having a regular doctor is more effective than having a regular site. [ABSTRACT FROM AUTHOR]

Background: Recent efforts to increase access to kidney transplant (KTx) in the United States include increasing referrals to transplant programs, leading to more pretransplant services. Transplant programs reconcile the costs of these services through the Organ Acquisition Cost Center (OACC)., Objective: The aim of this study was to determine the costs associated with pretransplant services by applying microeconomic methods to OACC costs reported by transplant hospitals., Research Design, Subjects, and Measures: For all US adult kidney transplant hospitals from 2013 through 2018 (n=193), we crosslinked the total OACC costs (at the hospital-fiscal year level) to proxy measures of volumes of pretransplant services. We used a multiple-output cost function, regressing total OACC costs against proxy measures for volumes of pretransplant services and adjusting for patient characteristics, to calculate the marginal cost of each pretransplant service., Results: Over 1015 adult hospital-years, median OACC costs attributable to the pretransplant services were $5 million. Marginal costs for the pretransplant services were: initial transplant evaluation, $9k per waitlist addition; waitlist management, $2k per patient-year on the waitlist; deceased donor offer management, $1k per offer; living donor evaluation, procurement and follow-up: $26k per living donor. Longer time on dialysis among patients added to the waitlist was associated with higher OACC costs at the transplant hospital., Conclusions: To achieve the policy goals of more access to KTx, sufficient funding is needed to support the increase in volume of pretransplant services. Future studies should assess the relative value of each service and explore ways to enhance efficiency., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cocaine-one of the most frequently abused illicit drugs among persons living with HIV [people living with HIV (PLWH)]-slows the decline of viral production after antiretroviral therapy and is associated with higher HIV viral load, more rapid HIV progression, and increased mortality., Setting: We examined the impact of cocaine use on the CD4+ T-cell HIV latent reservoir (HLR) in virally suppressed PLWH participating in a national, longitudinal cohort study of the natural and treated history of HIV in the United States., Methods: CD4+ T-cell genomic DNA from 434 women of diverse ancestry (ie, 75% Black, 14% Hispanic, 12% White) who self-reported cocaine use (ie, 160 cocaine users, 59 prior users, 215 non-users) was analyzed using the Intact Proviral HIV DNA Assay, measuring intact provirus per 106 CD4+ T cells., Findings: HIV latent reservoir size differed by cocaine use (ie, median [interquartile range]: 72 [14-193] for never users, 165 [63-387] for prior users, 184 [28-502] for current users), which was statistically significantly larger in both prior (P = 0.023) and current (P = 0.001) cocaine users compared with never users., Conclusions: Cocaine use may contribute to a larger replication competent HLR in CD4+ T cells among virologically suppressed women living with HIV. Our findings are important because women are underrepresented in HIV reservoir studies and in studies of the impact of cocaine use on outcomes among PLWH., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Camrelizumab combined with rivoceranib has been proven effective for treating unresectable hepatocellular carcinoma (uHCC). However, their higher prices than sorafenib could impose a substantial economic burden on patients., Aim: This study aimed to evaluate the relative cost-effectiveness of the combination of camrelizumab and rivoceranib versus sorafenib as first-line therapy for patients with uHCC from the perspective of the US and Chinese payers., Method: Using data from the CARES-310 trial, a partitioned survival model (PSM) was developed, considering the perspectives of the US and Chinese payers. The model employed a 15-year time horizon and a biweekly cycle. Direct medical costs and utility data were collected from previous studies and open-access databases. Primary outcomes included quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). Price simulations, sensitivity analyses, and subgroup analyses were conducted., Results: The ICER for the US and China was $122,388.62/QALY and $30,410.56/QALY, respectively, falling below the willingness-to-pay (WTP) thresholds of $150,000/QALY for the US and $35,898.87/QALY for China. Price simulations indicated the cost-effectiveness of camrelizumab plus rivoceranib when the price of camrelizumab (200 mg) remained below $6275.19 in the US and $558.09 in China. The primary determinant of cost-effectiveness in both regions was the cost of camrelizumab., Conclusion: The combination of camrelizumab and rivoceranib is a cost-effective first-line therapy for uHCC in both the US and China. Lowering their prices could significantly influence their cost-effectiveness and accessibility to patients. These findings will guide clinicians in treating uHCC and help decision-makers formulate value-based drug pricing strategies., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (n combined  = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Dental and mucosal injuries from laryngoscopy in the peri-operative period are common medico-legal complaints. This study investigated lawsuits arising from laryngoscopy., Methods: Westlaw, a legal database containing trial records from across the USA, was retrospectively reviewed. Plaintiff and/or defendant characteristics, claimed injuries, legal outcomes and awards were extracted., Results: Of all laryngoscopy-related dental or mucosal injuries brought before a state or federal court, none (0 per cent) resulted in a defence verdict against the provider or monetary gain for the patient. Rulings in the patient's favour were observed only when laryngoscopy was found to be the proximate cause of multiple compounding complications that culminated in severe medical outcomes such as exsanguination, septic shock or cardiopulmonary arrest., Conclusion: Proper laryngoscopy technique and a robust informed-consent process that accurately sets patients' expectations reduces litigation risk. Future litigation pursuits should consider the low likelihood of malpractice allegation success at trial.

Therapeutic proteins (TPs) comprise a variety of modalities, including antibody-based drugs, coagulation factors, recombinant cytokines, enzymes, growth factors, and hormones. TPs usually cannot traverse cellular barriers and exert their pharmacological activity by interacting with targets on the exterior membrane of cells or with soluble ligands in the tissue interstitial fluid/blood. Due to their large size, lack of cellular permeability, variation in metabolic fate, and distinct physicochemical characteristics, TPs are subject to different absorption, distribution, metabolism, and excretion (ADME) processes as compared with small molecules. Limited regulatory guidance makes it challenging to determine the most relevant ADME data required for regulatory submissions. The TP ADME working group was sponsored by the Translational and ADME Sciences Leadership Group within the Innovation and Quality (IQ) consortium with objectives to: (1) better understand the current practices of ADME data generated for TPs across IQ member companies, (2) learn about their regulatory strategies and interaction experiences, and (3) provide recommendations on best practices for conducting ADME studies for TPs. To understand current ADME practices and regulatory strategies, an industry-wide survey was conducted within IQ member companies. In addition, ADME data submitted to the U.S. Food and Drug Administration was also collated by reviewing regulatory submission packages of TPs approved between 2011 and 2020. This article summarizes the key learnings from the survey and an overview of ADME data presented in biologics license applications along with future perspectives and recommendations for conducting ADME studies for internal decision-making as well as regulatory submissions for TPs. SIGNIFICANCE STATEMENT: This article provides comprehensive assessment of the current practices of absorption, distribution, metabolism, and excretion (ADME) data generated for therapeutic proteins (TPs) across the Innovation and Quality participating companies and the utility of the data in discovery, development, and regulatory submissions. The TP ADME working group also recommends the best practices for condu-cting ADME studies for internal decision-making and regulatory submissions., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Here we report three epigenome-wide association studies (EWAS) of DNA methylation on self-reported race, global genetic ancestry, and local genetic ancestry in admixed Americans from three sets of samples, including internal and external replications (N total  = 1224). Our EWAS on local ancestry (LA) identified the largest number of ancestry-associated DNA methylation sites and also featured the highest replication rate. Furthermore, by incorporating ancestry origins of genetic variations, we identified 36 methylation quantitative trait loci (meQTL) clumps for LA-associated CpGs that cannot be captured by a model that assumes identical genetic effects across ancestry origins. Lead SNPs at 152 meQTL clumps had significantly different genetic effects in the context of an African or European ancestry background. Local ancestry information enables superior capture of ancestry-associated methylation signatures and identification of ancestry-specific genetic effects on DNA methylation. These findings highlight the importance of incorporating local ancestry for EWAS in admixed samples from multi-ancestry cohorts., (© 2022. The Author(s).)

Chimeric antigen receptor (CAR) T cell therapy has shown unprecedented response rates in patients with relapsed/refractory (R/R) multiple myeloma (MM). However, the factors associated with immediate response and durable remission have not been fully elucidated. This study aimed to investigate the impact of prelymphodepletion (pre-LD) absolute lymphocyte count (ALC) on the outcomes of CAR T cell therapy and cytokine release syndrome (CRS). A receiver operating characteristic curve was used to determine the optimal cutoff value of pre-LD ALC. The correlation of pre-LD ALC with deep response (defined as very good partial response or better), CRS, and long-term outcomes was analyzed in 85 patients with R/R MM who received CAR T cell treatment. The median pre-LD ALC was 1.0 × 10 9 /L (range, 0.1 to 2.9× 10 9 /L). The optimal cutoff value of pre-LD ALC was 0.75 × 10 9 /L. Twenty-two patients (26%) had a low pre-LD ALC (<0.75 × 10 9 /L), and 63 patients (74%) had a high pre-LD ALC (≥0.75 × 10 9 /L). The deep response rate was significantly higher in patients with a high pre-LD ALC compared with patients with a low pre-LD ALC (76% versus 41%; P = .002). Patients with a low pre-LD ALC had significantly inferior overall survival (OS) and progression-free survival (PFS) compared with those with a high pre-LD ALC (median OS, 15.4 months versus not reached [P < .001]; median PFS, 8.4 months versus 27.3 months [P < .001]). No correlation between pre-LD ALC and CRS was observed. Our data indicate that pre-LD ALC may be a useful indicator to predict the outcomes of CAR T cell therapy in patients with R/R MM. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: Before community transmission of COVID-19 was recognized in the United States, cruise ship passengers with high risk for exposure to SARS-CoV-2 were repatriated and quarantined. We describe cases of influenza-like illness (ILI) among responders., Methods: We reviewed situation reports and responder illness reports to characterize ill responders, including illness onset date, symptoms, fever, diagnostic tests, potential breaches in PPE use, and return to work status., Results: Among 339 responders, nine (3%) reported ILI. No breaches in PPE were reported. Three responders with ILI were tested for both SARS-CoV-2 infection and influenza A; none tested positive for SARS-CoV-2 infection and two tested positive for influenza A., Conclusions: Despite an outbreak of ILI among responders, none were diagnosed with COVID-19, suggesting preventive measures in place might have been sufficient to prevent responders from SARS-CoV-2 exposure., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

Review Objective: There have been several advances in the field of myelodysplastic syndromes over the past year, yielding two new US Food and Drug Administration drug approvals. The pharmacology, pharmacokinetics, clinical trials, therapeutic use, adverse effects, clinical use controversies, product description, and upcoming trials for myelodysplastic syndromes novel agents luspatercept-aamt and decitabine/cedazuridine are reviewed., Data Sources: This review article utilized primary information obtained from both the published studies involved in the approval of luspatercept-aamt and decitabine/cedazuridine and package inserts for the respective medications. This review article utilized secondary information obtained from National Comprehensive Cancer Network guidelines using filters and keywords to sustain information relevancy as well as key studies using the keywords, "luspatercept-aamt, myelodysplastic syndromes, decitabine, cedazuridine, hypomethylating agent, ASTX727" from scholarly journal database PubMed., Data Summary: Myelodysplastic syndromes consist of myeloid clonal hemopathies with a diverse range of presentation. Until recently, there have been relatively few new therapies in the myelodysplastic syndromes treatment landscape. On April 3, 2020 the US Food and Drug Administration approved Reblozyl ® (luspatercept-aamt), then on July 7, 2020, the US Food and Drug Administration approved INQOVI ® (decitabine and cedazuridine). Luspatercept-aamt acts as a erythroid maturation agent through differentiation of late-stage erythroid precursors. The safety and efficacy of luspatercept-aamt was demonstrated in the MEDALIST trial, a phase III trial in patients with very low-intermediate risk refractory myelodysplastic syndromes and ring sideroblasts. Luspatercept-aamt met both primary and secondary endpoints of transfusion independence of 8 weeks or longer and transfusion independence of 12 weeks or longer, respectively. Decitabine/cedazuridine has a unique mechanism of action in which decitabine acts as a nucleoside metabolic inhibitor promoting DNA hypomethylation and cedazuridine then prevents degradation of decitabine. The safety and efficacy of decitabine/cedazuridine was shown in the ASCERTAIN study, a phase III trial in patients with intermediate or high risk myelodysplastic syndromes or chronic myelomonocytic leukemia. The primary outcome evaluated was 5-day cumulative area under the curve between decitabine/cedazuridine and IV decitabine as well as additional outcomes including safety. Decitabine/cedazuridine met primary outcome and had a similar safety profile to IV decitabine., Conclusion: The novel myelodysplastic syndromes agents luspatercept-aamt and decitabine/cedazuridine provide a clinical benefit in the studied populations.

Background: Chronic tobacco smoke exposure results in a broad range of lung pathologies including emphysema, airway disease and parenchymal fibrosis as well as a multitude of extra-pulmonary comorbidities. Prior work using CT imaging has identified several clinically relevant subgroups of smoking related lung disease, but these investigations have generally lacked organ specific molecular correlates., Research Question: Can CT imaging be used to identify clinical phenotypes of smoking related lung disease that have specific bronchial epithelial gene expression patterns to better understand disease pathogenesis?, Study Design and Methods: Using K-means clustering, we clustered participants from the COPDGene study (n = 5,273) based on CT imaging characteristics and then evaluated their clinical phenotypes. These clusters were replicated in the Detection of Early Lung Cancer Among Military Personnel (DECAMP) cohort (n = 360), and were further characterized using bronchial epithelial gene expression., Results: Three clusters (preserved, interstitial predominant and emphysema predominant) were identified. Compared to the preserved cluster, the interstitial and emphysema clusters had worse lung function, exercise capacity and quality of life. In longitudinal follow-up, individuals from the emphysema group had greater declines in exercise capacity and lung function, more emphysema, more exacerbations, and higher mortality. Similarly, genes involved in inflammatory pathways (tumor necrosis factor-α, interferon-β) are more highly expressed in bronchial epithelial cells from individuals in the emphysema cluster, while genes associated with T-cell related biology are decreased in these samples. Samples from individuals in the interstitial cluster generally had intermediate levels of expression of these genes., Interpretation: Using quantitative CT imaging, we identified three groups of individuals in older ever-smokers that replicate in two cohorts. Airway gene expression differences between the three groups suggests increased levels of inflammation in the most severe clinical phenotype, possibly mediated by the tumor necrosis factor-α and interferon-β pathways., Clinical Trial Registration: COPDGene (NCT00608764), DECAMP-1 (NCT01785342), DECAMP-2 (NCT02504697)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: There have been increasing calls for clinicians to document social determinants of health (SDOH) in electronic health records (EHRs). One potential source of SDOH in the EHRs is in the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) Z codes (Z55-Z65). In February 2018, ICD-10-CM Official Guidelines for Coding and Reporting approved that all clinicians, not just the physicians, involved in the care of a patient can document SDOH using these Z codes.To examine the utilization rate of the ICD-10-CM Z codes using data from a large network of EHRs.We conducted a retrospective analysis of EHR data between 2015 to 2018 in the OneFlorida Clinical Research Consortium, 1 of the 13 Clinical Data Research Networks funded by Patient-Centered Outcomes Research Institute. We calculated the Z code utilization rate at both the encounter and patient levels.We found a low rate of utilization for these Z codes (270.61 per 100,000 at the encounter level and 2.03% at the patient level). We also found that the rate of utilization for these Z codes increased (from 255.62 to 292.79 per 100,000) since the official approval of Z code reporting from all clinicians by the American Hospital Association Coding Clinic and ICD-10-CM Official Guidelines for Coding and Reporting became effective in February 2018.The SDOH Z codes are rarely used by clinicians. Providing clear guidelines and incentives for documenting the Z codes can promote their use in EHRs. Improvements in the EHR systems are probably needed to better document SDOH., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.)

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the vulnerability of residents and staff members in long-term care facilities (LTCFs) (1). Although skilled nursing facilities (SNFs) certified by the Centers for Medicare & Medicaid Services (CMS) have federal COVID-19 reporting requirements, national surveillance data are less readily available for other types of LTCFs, such as assisted living facilities (ALFs) and those providing similar residential care. However, many state and territorial health departments publicly report COVID-19 surveillance data across various types of LTCFs. These data were systematically retrieved from health department websites to characterize COVID-19 cases and deaths in ALF residents and staff members. Limited ALF COVID-19 data were available for 39 states, although reporting varied. By October 15, 2020, among 28,623 ALFs, 6,440 (22%) had at least one COVID-19 case among residents or staff members. Among the states with available data, the proportion of COVID-19 cases that were fatal was 21.2% for ALF residents, 0.3% for ALF staff members, and 2.5% overall for the general population of these states. To prevent the introduction and spread of SARS-CoV-2, the virus that causes COVID-19, in their facilities, ALFs should 1) identify a point of contact at the local health department; 2) educate residents, families, and staff members about COVID-19; 3) have a plan for visitor and staff member restrictions; 4) encourage social (physical) distancing and the use of masks, as appropriate; 5) implement recommended infection prevention and control practices and provide access to supplies; 6) rapidly identify and properly respond to suspected or confirmed COVID-19 cases in residents and staff members; and 7) conduct surveillance of COVID-19 cases and deaths, facility staffing, and supply information (2)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Importance: With the current opioid crisis, it is important to improve understanding of the biological mechanisms of opioid use disorder (OUD)., Objectives: To detect genetic risk variants for OUD and determine genetic correlations and causal association with OUD and other traits., Design, Setting, and Participants: A genome-wide association study of electronic health record-defined OUD in the Million Veteran Program sample was conducted, comprising 8529 affected European American individuals and 71 200 opioid-exposed European American controls (defined by electronic health record trajectory analysis) and 4032 affected African American individuals and 26 029 opioid-exposed African American controls. Participants were enrolled from January 10, 2011, to May 21, 2018, with electronic health record data for OUD diagnosis from October 1, 1999, to February 7, 2018. Million Veteran Program results and additional OUD case-control genome-wide association study results from the Yale-Penn and Study of Addiction: Genetics and Environment samples were meta-analyzed (total numbers: European American individuals, 10 544 OUD cases and 72 163 opioid-exposed controls; African American individuals, 5212 cases and 26 876 controls). Data on Yale-Penn participants were collected from February 14, 1999, to April 1, 2017, and data on Study of Addiction: Genetics and Environment participants were collected from 1990 to 2007. The key result was replicated in 2 independent cohorts: proxy-phenotype buprenorphine treatment in the UK Biobank and newly genotyped Yale-Penn participants. Genetic correlations between OUD and other traits were tested, and mendelian randomization analysis was conducted to identify potential causal associations., Main Outcomes and Measures: Main outcomes were International Classification of Diseases, Ninth Revision-diagnosed OUD or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision-diagnosed OUD (Million Veteran Program), and DSM-IV-defined opioid dependence (Yale-Penn and Study of Addiction: Genetics and Environment)., Results: A total of 114 759 individuals (101 016 men [88%]; mean [SD] age, 60.1 [12.8] years) were included. In 82 707 European American individuals, a functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 (μ-opioid receptor gene, the main biological target for opioid drugs; OMIM 600018) reached genome-wide significance (G allele: β = -0.066 [SE = 0.012]; P = 1.51 × 10-8). The finding was replicated in 2 independent samples. Single-nucleotide polymorphism-based heritability of OUD was 11.3% (SE = 1.8%). Opioid use disorder was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, and others. Mendelian randomization analysis revealed the following associations with OUD: risk of tobacco smoking, depression, neuroticism, worry neuroticism subcluster, and cognitive performance. No genome-wide significant association was detected for African American individuals or in transpopulation meta-analysis., Conclusions and Relevance: This genome-wide meta-analysis identified a significant association of OUD with an OPRM1 variant, which was replicated in 2 independent samples. Post-genome-wide association study analysis revealed associated pleiotropic characteristics. Recruitment of additional individuals with OUD for future studies-especially those of non-European ancestry-is a crucial next step in identifying additional significant risk loci.

As of September 21, 2020, the coronavirus disease 2019 (COVID-19) pandemic had resulted in 6,786,352 cases and 199,024 deaths in the United States.* Health care personnel (HCP) are essential workers at risk for exposure to patients or infectious materials (1). The impact of COVID-19 on U.S. HCP was first described using national case surveillance data in April 2020 (2). Since then, the number of reported HCP with COVID-19 has increased tenfold. This update describes demographic characteristics, underlying medical conditions, hospitalizations, and intensive care unit (ICU) admissions, stratified by vital status, among 100,570 HCP with COVID-19 reported to CDC during February 12-July 16, 2020. HCP occupation type and job setting are newly reported. HCP status was available for 571,708 (22%) of 2,633,585 cases reported to CDC. Most HCP with COVID-19 were female (79%), aged 16-44 years (57%), not hospitalized (92%), and lacked all 10 underlying medical conditions specified on the case report form † (56%). Of HCP with COVID-19, 641 died. Compared with nonfatal COVID-19 HCP cases, a higher percentage of fatal cases occurred in males (38% versus 22%), persons aged ≥65 years (44% versus 4%), non-Hispanic Asians (Asians) (20% versus 9%), non-Hispanic Blacks (Blacks) (32% versus 25%), and persons with any of the 10 underlying medical conditions specified on the case report form (92% versus 41%). From a subset of jurisdictions reporting occupation type or job setting for HCP with COVID-19, nurses were the most frequently identified single occupation type (30%), and nursing and residential care facilities were the most common job setting (67%). Ensuring access to personal protective equipment (PPE) and training, and practices such as universal use of face masks at work, wearing masks in the community, and observing social distancing remain critical strategies to protect HCP and those they serve., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

The 2019 13 th Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA on 1-5 April 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on the 2018 FDA BMV guidance, 2019 ICH M10 BMV draft guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy. Part 1 (Innovation in small molecules and oligonucleotides and mass spectrometry method development strategies for large molecules bioanalysis) and Part 3 (New insights in biomarker assay validation, current and effective strategies for critical reagent management, flow cytometry validation in drug discovery and development and CLSI H62, interpretation of the 2019 FDA immunogenicity guidance and gene therapy bioanalytical challenges) are published in volume 10 of Bioanalysis , issues 22 and 24 (2019), respectively.

Background: Hazardous alcohol consumption has significant adverse medical consequences. These effects may be mediated, in part, by alterations in DNA methylation. Thus, DNA methylation signatures in peripheral cells may provide biomarkers of the medical impact of alcohol use and the risk for future alcohol consumption., Method: Using a high-density methylation array, we characterized epigenome-wide DNA methylation in saliva cells with respect to alcohol consumption in a large cohort of male European American veterans. In this study, DNA methylation of over 870,000 CpG DNA sites was profiled in 1,135 European American men. Alcohol consumption was assessed using the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Linear regression was applied in an epigenome-wide association study (EWAS), adjusted for confounders. Gene set enrichment analysis was performed in the KEGG database with a correction for gene length., Results: We found that a total of 70 CpG sites reached EWAS-corrected significance (p < 6E-08) with small effects on alcohol consumption for individual CpG sites, including 64 new CpG sites and 6 CpG sites that were previously reported as associated with alcohol use disorder, liver function, body mass index, and lipid metabolism. The most significant CpG site was located in SLC7A11 (t = -11.34, p = 2.66E-28), a gene involved specifically in cysteine and glutamate transportation. The 70 significant CpG sites were located on 44 genes, including genes involved in amino acid transport and metabolism systems. We identified 68 pathways with a false discovery rate < 0.05., Conclusions: We identified novel DNA methylation sites associated with alcohol consumption. Results may shed light on peripheral mechanisms of alcohol consumption on adverse health outcomes among heavy drinkers., (© 2019 by the Research Society on Alcoholism.)

Background and Objectives: National guidelines for gastrointestinal (GI) cancers offer surveillance algorithms to facilitate detection of recurrent disease, yet adherence rates are unknown. We sought to characterize postoperative surveillance patterns for veterans with GI cancer at a tertiary care Veterans Affairs Hospital., Methods: A single-center retrospective cohort study identified patients who underwent surgical resection for colorectal, gastroesophageal or hepatopancreaticobiliary malignancy from 2010-2016. We calculated the annual rate of cancer-directed clinic visits and abdominal imaging and used National Comprehensive Cancer Network guidelines as a benchmark by which to assess adequate surveillance., Results: Ninety-seven patients met inclusion criteria. Median surveillance time was 1203 days. Overall, 44% of patients had insufficient surveillance. Specifically, 11% received no postoperative imaging and 7% had no cancer-directed clinic visits. An additional 30% received less than recommended surveillance imaging and 12% attended fewer than recommended clinic visits. By disease site, insufficient imaging was most common for patients with hepatopancreaticobiliary cancer (63%), while inadequate clinic follow-up was highest for colorectal cancer (24%)., Conclusion: A significant proportion of veterans with GI cancer received either inadequate postoperative surveillance based on national guidelines. This deficiency represents an opportunity for improvement through targeted efforts, including telemedicine and education of patients and providers., (© 2018 Wiley Periodicals, Inc.)

Background and Aims: Longitudinal electronic health record (EHR) data offer a large-scale, untapped source of phenotypical information on harmful alcohol use. Using established, alcohol-associated variants in the gene that encodes the enzyme alcohol dehydrogenase 1B (ADH1B) as criterion standards, we compared the individual and combined validity of three longitudinal EHR-based phenotypes of harmful alcohol use: Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) trajectories; mean age-adjusted AUDIT-C; and diagnoses of alcohol use disorder (AUD)., Design: With longitudinal EHR data from the Million Veteran Program (MVP) linked to genetic data, we used two population-specific polymorphisms in ADH1B that are associated strongly with AUD in African Americans (AAs) and European Americans (EAs): rs2066702 (Arg369Cys, AAs) and rs1229984 (Arg48His, EAs) as criterion measures., Setting: United States Department of Veterans Affairs Healthcare System., Participants: A total of 167 721 veterans (57 677 AAs and 110 044 EAs; 92% male, mean age = 63 years) took part in this study. Data were collected from 1  October 2007 to 1 May 2017., Measurements: Using all AUDIT-C scores and AUD diagnostic codes recorded in the EHR, we calculated age-adjusted mean AUDIT-C values, longitudinal statistical trajectories of AUDIT-C scores and ICD-9/10 diagnostic groupings for AUD., Findings: A total of 19 793 AAs (34.3%) had one or two minor alleles at rs2066702 [minor allele frequency (MAF) = 0.190] and 6933 EAs (6.3%) had one or two minor alleles at rs1229984 (MAF = 0.032). In both populations, trajectories and age-adjusted mean AUDIT-C were correlated (r = 0.90) but, when considered separately, highest score (8+ versus 0) of age-adjusted mean AUDIT-C demonstrated a stronger association with the ADH1B variants [adjusted odds ratio (aOR) 0.54 in AAs and 0.37 in AAs] than did the highest trajectory (aOR 0.71 in AAs and 0.53 in EAs); combining AUDIT-C metrics did not improve discrimination. When age-adjusted mean AUDIT-C score and AUD diagnoses were considered together, age-adjusted mean AUDIT-C (8+ versus 0) was associated with lower odds of having the ADH1B minor allele than were AUD diagnostic codes: aOR = 0.59 versus 0.86 in AAs and 0.48 versus 0.68 in EAs. These independent associations combine to yield an even lower aOR of 0.51 for AAs and 0.33 for EAs., Conclusions: The age-adjusted mean AUDIT-C score is associated more strongly with genetic polymorphisms of known risk for alcohol use disorder than are longitudinal trajectories of AUDIT-C or AUD diagnostic codes. AUD diagnostic codes modestly enhance this association., (© 2018 Society for the Study of Addiction.)

The rich data generated and read by millions of users on social media tells what is happening in the real world in a rapid and accurate fashion. In recent years many researchers have explored real-time streaming data from Twitter for a broad range of applications, including predicting stock markets and public health trend. In this paper we design, implement, and evaluate a prototype system to collect and analyze influenza statuses over different geographical locations with real-time tweet streams. We investigate the correlation between the Twitter flu counts and the official statistics from the Center for Disease Control and Prevention (CDC) and discover that real-time tweet streams capture the dynamics of influenza cases at both national and regional level and could potentially serve as an early warning system of influenza epidemics. Furthermore, we propose a dynamic mathematical model which can forecast Twitter flu counts with high accuracy.

Background: This study sought to evaluate the impact of atrial fibrillation (AF) on clinical outcomes in patients undergoing transcatheter aortic valve replacement., Methods and Results: Data were evaluated in 1879 patients with baseline and discharge ECGs who underwent transcatheter aortic valve replacement in the Placement of AoRTic TraNscathetER Valve (PARTNER) trial. A total of 1262 patients manifested sinus rhythm (SR) at baseline/SR at discharge, 113 SR baseline/AF discharge, and 470 AF baseline/AF discharge. Patients who converted from SR to AF by discharge had the highest rates of all-cause mortality at 30 days (P<0.0001 across all groups; 14.2% SR/AF versus 2.6% SR/SR; adjusted hazard ratio [HR]=3.41; P=0.0002) and over 2-fold difference at 1 year (P<0.0001 across all groups; 35.7% SR/AF versus 15.8% SR/SR; adjusted HR=2.14; P<0.0001). The presence of AF on baseline or discharge ECG was a predictor of 1-year mortality (adjusted HR=2.14 for SR/AF group and HR=1.88 for AF/AF groups; P<0.0001 for both groups versus SR/SR). For patients discharged in AF, those with lower ventricular response (ie, <90 bpm) experienced less 1-year all-cause mortality (HR=0.74; P=0.04)., Conclusions: After transcatheter aortic valve replacement, the presence of AF at discharge, and particularly, the conversion to AF by discharge and higher ventricular response are associated with increased mortality. These data underscore the deleterious impact of AF, as well as the need for targeted interventions to improve clinical outcomes, in patients undergoing transcatheter aortic valve replacement., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894., (© 2016 American Heart Association, Inc.)

Objective: Pulmonary hypertension (PH) is associated with increased mortality after surgical or transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS), and when the pulmonary artery pressure is particularly elevated, there may be questions about the clinical benefit of TAVR. We aimed to identify clinical and haemodynamic factors associated with increased mortality after TAVR among those with moderate/severe PH., Methods: Among patients with symptomatic AS at high or prohibitive surgical risk receiving TAVR in the Placement of Aortic Transcatheter Valves (PARTNER) I randomised trial or registry, 2180 patients with an invasive measurement of mean pulmonary artery pressure (mPAP) recorded were included, and moderate/severe PH was defined as an mPAP ≥35 mm Hg., Results: Increasing severity of PH was associated with progressively worse 1-year all-cause mortality: none (n=785, 18.6%), mild (n=838, 22.7%) and moderate/severe (n=557, 25.0%) (p=0.01). The increased hazard of mortality associated with moderate/severe PH was observed in females, but not males (interaction p=0.03). In adjusted analyses, females with moderate/severe PH had an increased hazard of death at 1 year compared with females without PH (adjusted HR 2.14, 95% CI 1.44 to 3.18), whereas those with mild PH did not. Among males, there was no increased hazard of death associated with any severity of PH. In a multivariable Cox model of patients with moderate/severe PH, oxygen-dependent lung disease, inability to perform a 6 min walk, impaired renal function and lower aortic valve mean gradient were independently associated with increased 1-year mortality (p<0.05 for all), whereas several haemodynamic indices were not. A risk score, including these factors, was able to identify patients with a 15% vs 59% 1-year mortality., Conclusions: The relationship between moderate/severe PH and increased mortality after TAVR is altered by sex, and clinical factors appear to be more influential in stratifying risk than haemodynamic indices. These findings may have implications for the evaluation of and treatment decisions for patients referred for TAVR with significant PH., Trial Registration: NCT00530894., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Many patients undergoing transcatheter aortic valve implantation (TAVI) have a pre-existing, permanent pacemaker (PPM) or receive one as a consequence of the procedure. We hypothesised that chronic pacing may have adverse effects on TAVI outcomes., Methods and Results: Four groups of patients undergoing TAVI in the Placement of Aortic Transcatheter Valves (PARTNER) trial and registries were compared: prior PPM (n=586), new PPM (n=173), no PPM (n=1612), and left bundle branch block (LBBB)/no PPM (n=160). At 1 year, prior PPM, new PPM and LBBB/no PPM had higher all-cause mortality than no PPM (27.4%, 26.3%, 27.7% and 20.0%, p<0.05), and prior PPM or new PPM had higher rehospitalisation or mortality/rehospitalisation (p<0.04). By Cox regression analysis, new PPM (HR 1.38, 1.00 to 1.89, p=0.05) and prior PPM (HR 1.31, 1.08 to 1.60, p=0.006) were independently associated with 1-year mortality. Surviving prior PPM, new PPM and LBBB/no PPM patients had lower LVEF at 1 year relative to no PPM (50.5%, 55.4%, 48.9% and 57.6%, p<0.01). Prior PPM had worsened recovery of LVEF after TAVI (Δ=10.0 prior vs 19.7% no PPM for baseline LVEF <35%, p<0.0001; Δ=4.1 prior vs 7.4% no PPM for baseline LVEF 35-50%, p=0.006). Paced ECGs displayed a high prevalence of RV pacing (>88%)., Conclusions: In the PARTNER trial, prior PPM, along with new PPM and chronic LBBB patients, had worsened clinical and echocardiographic outcomes relative to no PPM patients, and the presence of a PPM was independently associated with 1-year mortality. Ventricular dyssynchrony due to chronic RV pacing may be mechanistically responsible for these findings., Trial Registration Number: (ClinicalTrials.gov NCT00530894)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Transcatheter aortic valve replacement (TAVR) with the balloon-expandable Sapien transcatheter heart valve improves survival compared to standard therapy in patients with severe aortic stenosis (AS) and is noninferior to surgical aortic valve replacement (AVR) in patients at high operative risk. Nonetheless, a significant proportion of patients may require pre-emptive or emergent support with cardiopulmonary bypass (CPB) and/or intra-aortic balloon pump (IABP) during TAVR due to pre-existing comorbid conditions or as a result of procedural complications., Objectives: We hypothesized that patients who required CPB or IABP would have increased periprocedural complications and reduced long-term survival. In addition, we sought to determine whether preprocedural variables could predict the need for CPB and IABP., Methods: The study population included 2,525 patients in the PARTNER Trial (Cohort A and B) and the continuing access registry (CAR). Patients that received CPB or IABP were compared to patients that did not receive either, and then further divided into those that received support pre-TAVR and those that were placed on support emergently., Results: One-hundred sixty-three patients (6.5%) were placed on CPB and/or IABP. The use of CPB or IABP was associated with higher 1 year mortality (49.1% vs. 21.6%, P < 0.001). In multivariable analysis, utilization of CPB or IABP was an independent predictor of 30 day (HR 6.95) and 1-year (HR 2.56) mortality. Although mortality was highest in emergent cases, mortality was also greater in planned CPB and IABP cases compared with non-CPB/IABP cases (53.3% and 40.3% vs. 21.6%, P < 0.001)., Conclusions: These findings indicate that CPB and IABP use in TAVR portends a poor prognosis and its utilization, particularly in the setting of pre-emptive use, needs reconsideration., (© 2015 Wiley Periodicals, Inc.)

Transcatheter aortic valve replacement (TAVR) is an effective treatment for severe symptomatic aortic stenosis (AS) in patients who are inoperable or at high risk for surgery. However, the intermediate- to long-term mortality is high, emphasizing the importance of patient selection. We, therefore, sought to evaluate the prognostic value of frailty in older recipients of TAVR, hypothesizing that frail patients would experience a higher mortality rate and a higher likelihood of poor outcome 1 year after TAVR. This substudy of the Placement of Aortic Transcatheter Valves trial was conducted at 3 high-enrolling sites where frailty was assessed systematically before TAVR. In total, 244 patients received TAVR at the participating sites. Frailty was assessed using a composite of 4 markers (serum albumin, dominant handgrip strength, gait speed, and Katz activity of daily living survey), which were combined into a frailty score. The cohort was dichotomized at median frailty score. Outcomes measures were the time to death from any cause for >1 year of follow-up and poor outcome at 1 year. Poor outcome was defined as (1) death, (2) Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score <60, or (3) decrease of ≥10 points in the KCCQ-OS score from baseline to 1 year. At 1 year, the Kaplan-Meier-estimated all-cause mortality rate was 32.7% in the frail group and 15.9% in the nonfrail group (log-rank p = 0.004). At 1 year, poor outcome occurred in 50.0% of the frail group and 31.5% of the nonfrail group (p = 0.02). In conclusion, frailty was associated with increased mortality and a higher rate of poor outcome 1 year after TAVR., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The relation between left anterior descending coronary artery (LAD) anatomic features and clinical outcomes in patients with anterior ST-segment elevation myocardial infarction has not been fully investigated. The Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction (INFUSE-AMI) trial randomized 452 patients with anterior ST-segment elevation myocardial infarctions who underwent mechanical revascularization to intralesional abciximab versus no abciximab and to manual thrombus aspiration versus no aspiration. The primary end point was infarct size (percentage left ventricular mass) on contrast magnetic resonance imaging at 30 days. "Wraparound LAD" was defined as an LAD reaching the apex and supplying the apical inferior aspect of the heart. Among complete data available in 338 patients, 258 (76.3%) had wraparound LADs. Global infarct size (17.4% vs 16.1%, p = 0.64) and the left ventricular ejection fraction (49.7% vs 48.7%, p = 0.98) by contrast magnetic resonance imaging at 30 days were comparable between patients with and those without wraparound LADs. Regional apical anterior infarct size was comparable (59.5% vs 55.8%, p = 0.559) between the groups; however, apical septal (61.3% vs 48.9%, p = 0.005), apical inferior (19.0% vs 3.7%, p <0.0001), and apical lateral (12.2% vs 4.8%, p = 0.0584) infarct sizes were larger in patients with wraparound LADs compared with those with nonwraparound LADs. The incidence of new-onset severe heart failure at 1 year was significantly higher in patients with compared with those without wraparound LADs (6.3% vs 0%, p = 0.02). In conclusion, in patients with anterior ST-segment elevation myocardial infarctions, as compared with the LAD not supplying the inferior aspect of the heart, a wraparound LAD was associated with a larger left ventricular apex infarct size, resulting in worse adverse events at 1 year., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The accuracy of the 12-lead electrocardiogram in detecting coronary artery occlusion is limited. We sought to determine the incidence, distribution, and outcomes of patients who have total occlusion of the culprit artery but present with non-ST-segment elevation myocardial infarction (NSTEMI). The randomized Acute Catheterization and Urgent Intervention Triage Strategy trial enrolled 13,819 patients presenting with non-ST-segment elevation acute coronary syndromes who underwent an early invasive strategy. The present study includes 1,319 patients with baseline biomarker elevation (NSTEMI) and no history of coronary artery bypass graft who underwent percutaneous coronary intervention of a single culprit vessel. We compared the baseline characteristics and outcomes according to whether the culprit vessel was occluded (baseline Thrombolysis In Myocardial Infarction [TIMI] 0 to 1) or patent (TIMI 2 to 3 flow) by angiographic core laboratory assessment. TIMI 0 to 1 flow in the culprit artery was present in 262 of 1,319 (19.9%) patients. The incidence of coronary occlusion was 28.4%, 19.3%, and 12.6% in patients with NSTEMI because of right coronary, left circumflex, and left anterior descending artery disease, respectively. Patients with an occluded culprit artery were more commonly men and had ST-segment deviation ≥1 mm. One-year outcomes, including death (3.5% vs 3.0%, p = 0.68) and myocardial infarction (8.4% vs 9.6%, p = 0.47), did not differ significantly between patients with versus without occluded culprit arteries, respectively. In conclusion, the present study demonstrates that the culprit artery is totally occluded in approximately 1 in 5 patients presenting with NSTEMI and single-vessel disease; however, the presence of total occlusion in NSTEMI was not associated with an incremental hazard of death or reinfarction at 1 year., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This paper represents the consensus views of a cross-section of companies and organizations from the USA and Canada regarding the validation and application of liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for bioanalysis of protein biotherapeutics in regulated studies. It was prepared under the auspices of the AAPS Bioanalytical Focus Group's Protein LC-MS Bioanalysis Subteam and is intended to serve as a guide to drive harmonization of best practices within the bioanalytical community and provide regulators with an overview of current industry thinking on applying LC-MS/MS technology for protein bioanalysis. For simplicity, the scope was limited to the most common current approach in which the protein is indirectly quantified using LC-MS/MS measurement of one or more of its surrogate peptide(s) produced by proteolytic digestion. Within this context, we considered a range of sample preparation approaches from simple in-matrix protein denaturation and digestion to complex procedures involving affinity capture enrichment. Consideration was given to the method validation experiments normally associated with traditional LC-MS/MS and ligand-binding assays. Our collective experience, thus far, is that LC-MS/MS methods for protein bioanalysis require different development and validation considerations than those used for small molecules. The method development and validation plans need to be tailored to the particular assay format being established, taking into account a number of important factors: the intended use of the assay, the test species or study population, the characteristics of the protein biotherapeutic and its similarity to endogenous proteins, potential interferences, as well as the nature, quality, and availability of reference and internal standard materials.

In high-risk or inoperable patients with severe symptomatic aortic stenosis, transcatheter aortic valve implantation (TAVI) is a proven alternative to standard (i.e., medical) therapy or surgical aortic valve replacement. Concerns have been raised, however, about patients who survive the procedure but have short subsequent survival. The aim of this study was therefore to identify correlates of early out-of-hospital mortality (EOHM) in patients who underwent successful TAVI, rendering TAVI potentially "futile." Patients who were discharged from the hospital and survived >30 days but <12 months after TAVI were identified (the EOHM group). Independent predictors of EOHM were explored, including patient-level factors and procedural nonfatal major complications (NFMCs). A sensitivity analysis was also performed, excluding patients with NFMCs. Among 485 patients who were discharged from the hospital and survived 30 days after TAVI, 101 (21%) were dead within 1 year. Independent predictors of EOHM included serum creatinine, liver disease, coagulopathy, mental status, body mass index, male gender, and Society of Thoracic Surgeons score. Although NFMCs were strongly associated with EOHM, patient-level risk factors for EOHM were similar between patients who did and those who did not experience NFMCs. Compared with standard therapy, TAVI patients with EOHM had similar 6-month 6-minute walk distances and functional classes, with higher rates of repeat hospitalization. In conclusion, in high-risk or inoperable patients who underwent TAVI and were discharged and alive at 30 days, EOHM was not infrequent and was determined largely by presenting characteristics and the occurrence of periprocedural NFMCs. Careful screening and minimization of NFMCs may maximize the benefit of TAVI., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Rapid reperfusion with primary percutaneous coronary intervention improves survival in patients with ST-segment elevation myocardial infarction. Preprocedural cardiopulmonary instability and adverse events (IAE) may delay reperfusion time and worsen prognosis. The aim of this study was to evaluate the relation between preprocedural cardiopulmonary IAE, door-to-balloon time (DBT), and outcomes in the Harmonizing Outcomes With Revascularization and Stents in AMI (HORIZONS-AMI) trial. Preprocedural cardiopulmonary IAE included sustained ventricular or supraventricular tachycardia or fibrillation requiring cardioversion or defibrillation, heart block or bradycardia requiring pacemaker implantation, severe hypotension requiring vasopressors or intra-aortic balloon counterpulsation, respiratory failure requiring mechanical ventilation, and cardiopulmonary resuscitation. Three-year outcomes of patients with and without IAE according to DBT were compared. Among 3,602 patients, 159 (4.4%) had ≥1 IAE. DBT did not differ significantly in patients with and without IAE; however, patients with IAE were less likely to have Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow after percutaneous coronary intervention. Mortality at 3 years was significantly higher in patients with versus those without IAE (17.0% vs 6.3%, p<0.0001), and IAE was an independent predictor of mortality, whereas DBT was not. However, a significant interaction was present such that 3-year mortality was reduced in patients with DBT<99 minutes (the median) versus ≥99 minutes to a greater extent in patients with IAE (9.9% vs 20.7%, hazard ratio 0.43, 95% confidence interval 0.16 to 1.16) compared with those without IAE (5.0% vs 7.2%, hazard ratio 0.69, 95% confidence interval 0.50 to 0.95) (p for interaction=0.004). In conclusion, IAE before PCI is an independent predictor of death and identifies a high-risk group in whom faster reperfusion may be particularly important to improve survival., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The Placement of Aortic Transcatheter Valves (PARTNER) trial reported a reduced rate of mortality in patients with previous coronary bypass grafting (CABG) operation who received surgical aortic valve replacement (SAVR) in comparison with transcatheter aortic valve replacement (TAVR). We sought to further evaluate these groups., Methods: We reviewed the database of the 699 patients enrolled in the PARTNER trial. The cohort for this study consisted of 288 patients (41.2%) who had a history of CABG operation before enrollment in the PARTNER trial. All patients were followed up for 2 years., Results: The mean age was 81.5±6.6 years, and 231 patients (80.2%) were men. The preoperative characteristics were similar in 140 patients (48.6%) who received SAVR and 148 (51.4%) who received TAVR. There were no differences between the two groups with respect to the operative outcomes of death, stroke, and myocardial infarction, but the TAVR patients experienced more paravalvular regurgitation (p<0.0001). At 2 years, there was a trend toward greater all-cause mortality in the TAVR patients (hazard ratio [HR] 1.53; 95% confidence interval [CI]: 0.99, 2.35; p=0.052). Furthermore, the TAVR patients had more repeated hospitalization (HR 1.75; 95% CI: 0.99, 3.07; p=0.05), death of any cause or repeated hospitalization (HR 1.52; 95% CI: 1.06, 2.19; p=0.02), and death of any cause or stroke (HR 1.51; 95% CI: 1.00, 2.27; p=0.05)., Conclusions: The 2-year follow-up of patients with a history of previous CABG operation in the PARTNER trial demonstrated improved outcomes with SAVR in comparison with TAVR. Further longitudinal assessment is necessary to corroborate these findings and to understand the possible causes., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

It is not known whether the extent and severity of nonculprit coronary lesions correlate with outcomes in patients with ST-segment elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention (PCI). We sought to quantify complex plaques in patients with STEMI referred for primary PCI and to determine their effect on short- and long-term clinical outcomes by examining the core laboratory database for plaque analysis from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction study. Baseline demographic, angiographic, and procedural details were compared between patients with single versus multiple complex plaques who underwent single-vessel PCI. Multivariable analysis was performed for predictors of long-term major adverse cardiac events (MACEs), a combined end point of death, reinfarction, ischemic target-vessel revascularization, or stroke, and for death alone. Single-vessel PCI was performed in 3,137 patients (87%): 2,174 (69%) had multiple complex plaques and 963 (31%) had a single complex plaque. Compared with those with a single complex plaque, patients with multiple complex plaques were older (p <0.0001) and had more co-morbidities. The presence of multiple complex plaques was an independent predictor of 3-year MACE (hazard ratio 1.58, 95% confidence interval 1.26 to 1.98, p <0.0001), and death alone (hazard ratio 1.68, 95% confidence interval 1.05 to 2.70, p = 0.03). In conclusion, multiple complex plaques are present in the majority of patients with STEMI who underwent primary PCI, and their presence is an independent predictor of short- and long-term MACE, including death (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; NCT00433966)., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: This study evaluated the impact of nonculprit vessel myocardial perfusion on outcomes of non-ST-segment elevation acute coronary syndromes (NSTE-ACS) patients., Background: ST-segment elevation myocardial infarction patients have decreased perfusion in areas remote from the infarct-related vessel. The impact of myocardial hypoperfusion of regions supplied by nonculprit vessels in NSTE-ACS patients treated with percutaneous coronary intervention (PCI) is unknown., Methods: The angiographic substudy of the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial included 6,921 NSTE-ACS patients. Complete 3-vessel assessments of baseline coronary TIMI (Thrombolysis In Myocardial Infarction) flow grade and myocardial blush grade (MBG) were performed. We examined the outcomes of PCI-treated patients according to the worst nonculprit vessel MBG identified per patient., Results: Among the 3,826 patients treated with PCI, the worst nonculprit MBG was determined in 3,426 (89.5%) patients, including 375 (10.9%) MBG 0/1 patients, 475 (13.9%) MBG 2 patients, and 2,576 (75.2%) MBG 3 patients. Nonculprit MBG 0/1 was associated with worse baseline clinical characteristics. Patients with nonculprit MBG 0/1 versus MBG 3 had increased rates of 30-day (3.0% vs. 0.7%, p < 0.0001) and 1-year (4.4% vs. 1.0%, p < 0.0001) death. Similar results were found among patients with pre-procedural TIMI flow grade 3 in the culprit vessel, where nonculprit vessel MBG 0/1 (hazard ratio: 2.81 [95% confidence interval: 1.63 to 4.84], p = 0.0002) was the strongest predictor of 1-year mortality., Conclusions: Reduced myocardial perfusion in an area supplied by a nonculprit vessel is associated with increased short- and long-term mortality rates in NSTE-ACS patients undergoing PCI. Furthermore, worst nonculprit MBG is able to risk-stratify patients with normal baseline flow of the culprit vessel., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The study aimed to evaluate the impact of chronic lung disease (CLD) on outcomes of severe aortic stenosis patients across all treatment modalities., Background: Outcomes of patients with CLD undergoing transcatheter aortic valve replacement (TAVR) have not been systematically examined., Methods: All patients who underwent TAVR in the PARTNER (Placement of AoRTic TraNscathetER Valve) trial, including the continued access registry (n = 2,553; 1,108 with CLD), were evaluated according to CLD clinical severity. Additionally, outcomes of CLD patients included in the randomization arms of the PARTNER trial were compared: Cohort A patients (high-risk operable) treated by either TAVR (n = 149) or surgical aortic valve replacement (SAVR); (n = 138); and Cohort B patients (inoperable) treated by either TAVR (n = 72) or standard therapy only (n = 95)., Results: Among all TAVR-treated patients, at 1-year follow-up, patients with CLD had higher mortality than those without it (23.4% vs. 19.6%, p = 0.02). Baseline characteristics of CLD patients who underwent TAVR were similar to respective controls. In Cohort A, 2-year all-cause death rates were similar (TAVR 35.2% and SAVR 33.6%, p = 0.92), whereas in Cohort B, the death rate was lower after TAVR (52.0% vs. 69.6% after standard therapy only, p = 0.04). Independent predictors for mortality in CLD patients undergoing TAVR included poor mobility (6-min walk test <50 m; hazard ratio: 1.67, p = 0.0009) and oxygen-dependency (hazard ratio: 1.44, p = 0.02). Although CLD patients undergoing TAVR have worse outcomes than patients without CLD, TAVR is better in these patients than standard therapy and is similar to SAVR., Conclusions: Although patients with CLD undergoing TAVR had worse outcomes than patients without CLD, TAVR performed better in these patients than standard therapy and was similar to SAVR. However, CLD patients who were either poorly mobile or oxygen-dependent had poor outcomes. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) has been associated with worse outcomes after primary percutaneous coronary intervention (PCI) for acute myocardial infarction. The aim of this study was to evaluate the incidence and impact of new-onset AF after primary PCI in patients with ST-segment elevation myocardial infarctions from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. HORIZONS-AMI was a large-scale, multicenter, international, randomized trial comparing different antithrombotic regimens and stents during primary PCI in patients with ST-segment elevation myocardial infarctions. Three-year ischemic and bleeding end points were compared between patients with and without new-onset AF after PCI. Of the 3,602 patients included in the HORIZONS-AMI study, 3,281 (91.1%) with sinus rhythm at initial presentation had primary PCI as their primary management strategy. Of these, new-onset AF developed in 147 (4.5%). Compared with patients without AF after PCI, patients with new-onset AF had higher 3-year rates of net adverse clinical events (46.5% vs 25.7%, p <0.0001), mortality (11.9% vs 6.3%, p = 0.01), reinfarction (16.4% vs 7.0%, p <0.0001), stroke (5.8% vs 1.5%, p <0.0001), and major bleeding (20.9% vs 8.2%, p <0.0001). By multivariate analysis, new-onset AF after PCI was a powerful independent predictor of net adverse clinical events (hazard ratio 1.74, 95% confidence interval 1.30 to 2.34, p = 0.0002) and major adverse cardiac events (hazard ratio 1.73, 95% confidence interval 1.27 to 2.36) at 3 years. In conclusion, new-onset AF after PCI for ST-segment elevation myocardial infarction was associated with markedly higher rates of adverse events and mortality., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The present study sought to determine the extent to which adverse angiographic events encountered during percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI) are associated with adverse clinical outcomes. Patients with STEMI represent a cohort at particularly high risk of intraprocedural thrombotic events (IPTEs). The overall frequency and implications of IPTEs occurring in patients with STEMI have not been systematically quantified in previous studies. A total of 3,163 patients undergoing primary percutaneous coronary intervention with stent implantation for STEMI in the Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial underwent detailed frame-by-frame core laboratory angiographic analysis to assess IPTEs. The clinical outcomes at 30 days were compared between the patients with and without IPTEs. IPTEs, defined as the development of new or increasing thrombus, abrupt vessel closure, no reflow, slow reflow, and distal embolization at any point during the procedure, occurred in 386 patients (12.2%). The independent predictors of IPTE were thrombus at baseline, lesion length, and randomization to bivalirudin; the patients with IPTEs were also more likely to receive bailout glycoprotein IIb/IIIa inhibitors and unplanned thrombectomy. Compared with patients without IPTEs, the patients with IPTEs had higher 30-day rates of composite major adverse cardiovascular events (death, myocardial infarction, ischemic target vessel revascularization, and stroke; 7.8% vs 4.2%, p = 0.002), major bleeding not related to coronary artery bypass grafting (11.8% vs 6.5%, p <0.001), and all-cause death (4.2% vs 1.8%, p = 0.002). On multivariate analysis, IPTEs were independently associated with 30-day major adverse cardiovascular events, major bleeding, and death. In conclusion, the development of IPTEs in patients undergoing primary percutaneous coronary intervention for STEMI was associated with subsequent adverse outcomes, including major adverse cardiovascular events, major bleeding, and death. Additional studies of strategies to decrease the occurrence of IPTEs are warranted., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To compare outcomes between US and non-US (OUS) sites in patients with non ST-elevation acute coronary syndromes (NSTEACS) and to evaluate potential reasons for differences in outcomes., Background: There are little data comparing outcomes at US versus OUS sites in patients with NSTEACS managed with an invasive strategy., Methods: The ACUITY trial randomized 13,819 patients with NSTEACS in 17 countries to an invasive approach with one of three strategies: (1) heparin plus glycoprotein platelet inhibitors (GPI), (2) bivalirudin plus GPI, or (3) bivalirudin alone., Results: US patients were more often female, were younger, heavier, and had more diabetes, prior myocardial infarction (MI), and prior bypass surgery. US patients were less often treated with percutaneous coronary intervention but had more frequent drug-eluting stent use. US patients had lower mortality and higher MI rates at 30 days and 1 year and higher composite ischemic outcome at 30 days. After adjusting for differences in baseline variables, US patients had higher rates of MI and composite ischemic outcome at 30 days and higher rates of MI at 1 year {HR [95% confidence interval (CI)] = 1.36 [1.18-1.56], P < 0.0001} with no differences in mortality. There were no differences in treatment effects comparing bivalirudin with the other strategies between US and OUS sites., Conclusions: US versus OUS patients with NSTEACS had higher adjusted rates of MI and ischemia. The reasons for these differences are not clear but may be due to unmeasured confounders, different thresholds for event reporting, or valid differences in systems of care which may impact outcomes., (Copyright © 2012 Wiley Periodicals, Inc.)

Previous studies have suggested that angiographically detected persistent contrast staining (PSS) at follow-up may predict subsequent very late stent thrombosis. The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial was a dual-arm, factorial, randomized trial in patients with ST-segment elevation myocardial infarctions. All follow-up angiograms (1,330 lesions in 1,115 patients, median time 13.3 months) without major cardiovascular events before follow-up angiography were analyzed at a core laboratory blinded to clinical events for the presence of PSS (defined as contrast staining outside the stent contour extending to ≥20% of the stent diameter). Corresponding follow-up intravascular ultrasound (IVUS) data (275 lesions in 248 patients) were also evaluated to assess the mechanisms of PSS. PSS was present in 23 patients (2.1%) at follow-up and was not more common with paclitaxel-eluting than with bare-metal stents. All 6 PSS patients with follow-up IVUS had stent malapposition (vs 41.2% malapposition in the follow-up IVUS cohort). Comparing poststent and follow-up IVUS, 2 patients had late acquired and 4 had persistent malapposition; all 6 showed positive vessel remodeling from baseline to follow-up (mean vessel area 22.0 ± 8.0 to 32.4 ± 11.7 mm(2), p = 0.07). During 3-year follow-up, stent thrombosis developed in no patient with PSS compared with 8 PSS-negative patients (0% vs 0.8%, p = 0.68). The rates of revascularization and major adverse cardiovascular events were also not increased in PSS patients. In conclusion, in the large-scale HORIZONS-AMI trial, PSS at angiographic follow-up was infrequent and was associated with late stent malapposition and positive remodeling but was independent of stent type. Identification of PSS was not associated with subsequent stent thrombosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This article compares Positive and Negative Syndrome Scale (PANSS) data from Chinese and American inpatients with chronic schizophrenia to show how differences in item ratings may reflect cultural attitudes of raters. The Chinese sample (N = 504) came from Beijing Huilongguan Hospital. The American sample came from 268 PANSS assessments of Clinical Antipsychotic Trials of Intervention Effectiveness subjects hospitalized for 15 days or more to optimize equivalence of the samples. When controlling for age and sex, the Chinese sample scored significantly lower for total score by 25% (p < 0.0001), for the positive subscale by 35% (p < 0.0001), and on the general subscale by 32% (p < 0.0001) but not significantly different on the negative subscale score (+0.26%; p = 0.76). However, the Chinese sample scored 26% higher on the item on poor rapport (p < 0.0001), 10.2% higher on passive social withdrawal (p = 0.003), and most notably 46% higher on the item on lack of judgment and insight (p < 0.0001). These results remain broadly consistent across sex subgroup analyses. Differences seem to be best explained by both cultural differences in patient clinical presentations and varying American and Chinese cultural values affecting rater judgment.

Objectives: The 1983 US Orphan Drug Act (ODA) provided incentives to stimulate treatment product development for patients with rare disease. This article highlights a decade of ODA contributions to this goal for children with RDs., Methods: An internal US Food and Drug Administration database was the information source for orphan designations, marketing approvals, and prevalence numbers for 2000 to 2009. Product categorization was based on the disease age of onset for which they received designation. Category 1 products were for diseases with onset exclusively in Childhood; Category 2 products were for diseases with onset at any age; and Category 3 products were for diseases with adult onset only. Disease prevalence distributions were analyzed by using population intervals of 20 000., Results: From 2000 to 2009, 1138 orphan drugs were designated and 148 received marketing approval, of which 38 (26%) were for pediatric diseases. The proportion of approvals for pediatric products increased from 17.5% (10 of 57) in the first half of the decade, to 30.8% (28 of 91) in the second. More products received designation and marketing approval for pediatric diseases with prevalence numbers fewer than 20 000 than for any other prevalence subgroup. The median disease prevalence for all pediatric orphan designations that received marketing approval was 8972. Among the pediatric orphan drug approvals categorized by therapeutic class, the endocrine/metabolic drugs had the largest representation (39%)., Conclusions: The ODA incentives have led to increased product availability for RDs overall, with an increasing number of marketing approvals for children this past decade.

Objectives: This study sought to assess the extent and composition of atherosclerosis contributing to acute coronary syndrome events in women compared with men., Background: Pathological studies suggest that plaque composition and burden may differ by sex. It is unclear whether sex impacts the extent, characteristics, and potential vulnerability of coronary plaques., Methods: A total of 697 patients (24% women) with acute coronary syndromes were enrolled in the prospective, multicenter PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study. Three-vessel multimodality intracoronary imaging (quantitative coronary angiography, grayscale, and radiofrequency intravascular ultrasound [IVUS]) was performed after treatment of the culprit lesion(s). Events during a median 3.4-year follow-up were ascribed to recurrent culprit versus untreated nonculprit lesions. The authors performed a post hoc, sex-based subgroup analysis., Results: Women were older and had more comorbid disease than men. By angiography, women had a similar number of angiographic culprit (p = 0.53) but fewer nonculprit (p = 0.05) lesions, and fewer vessels with nonculprit lesions (p = 0.048) compared with men even after multivariable adjustment (p = 0.002). By IVUS, women had fewer nonculprit lesions (p = 0.002), but similar plaque burden (PB) per lesion (55.6% vs. 55.3%; p = 0.35), and female sex was not predictive of severe (> 70%) PB (p = 0.052). Plaque rupture was less common in women (6.6% vs. 16.3%; p = 0.002) even after adjusting for comorbidities (p = 0.004), as was the total necrotic core volume (p < 0.0001). The frequency of other plaque phenotypes was similar for men and women including pathological intimal thickening, thin-cap fibroatheromas (TCFA), and thick-cap fibroatheromas. Rates of major adverse cardiovascular events attributed to culprit and nonculprit lesions at 1-, 2-, and 3-year follow-up were not significantly different between men and women, although women were rehospitalized more frequently due to culprit lesion-related angina. For men, nonculprit lesion minimal lumen area ≤ 4.0 mm(2), PB ≥70%, and TCFA predicted nonculprit MACE at 3 years, whereas for women, only TCFA and PB were predictive., Conclusions: The PROSPECT study validates that despite having more comorbid risk factors than men, women have less extensive coronary artery disease by both angiographic and IVUS measures, and that lesions in women compared with men have less plaque rupture, less necrotic core and calcium, similar plaque burden, and smaller lumens. TCFA may also be a stronger marker of plaque vulnerability in women than men., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)