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Introduction Cross-sectional surveys found behavioral heterogeneity among dual users of combustible and electronic cigarettes. Yet, prior classification did not reflect dynamic interactions between cigarette and e-cigarette consumption, which may reveal changes in product-specific dependence. The contexts of dual use that could inform intervention were also understudied. Methods This study conducted secondary analysis on 13 waves of data from 227 dual users who participated in a 2-year observational study. The k-means method for joint trajectories of cigarette and e-cigarette consumption was adopted to identify the subtypes of dual users. The time-varying effect model was used to characterize the subtype-specific trajectories of cigarette and e-cigarette dependence. The subtypes were also compared in terms of use contexts. Results The four clusters were identified: light dual users, predominant vapers, heavy dual users, and predominant smokers. Although heavy dual users and predominant smokers both smoked heavily at baseline, by maintaining vaping at the weekly to daily level the heavy dual users were able to considerably reduce cigarette use. Yet, the heavy dual users’ drop in cigarette dependence was not as dramatic as their drop in cigarette consumption. Predominant vapers appeared to engage in substitution, as they decreased their smoking and increased their e-cigarette dependence. They were also more likely to live in environments with smoking restrictions and report that their use of e-cigarettes reduced cigarette craving and smoking frequency. Conclusions Environmental constraints can drive substitution behavior and the substitution behavior is able to be sustained if people find the substitute to be effective. Implications This study characterizes subtypes of dual users based on the dynamic interactions between cigarette use and e-cigarette use as well as product-specific trajectories of dependence. The subtypes differ in not only sociodemographic characteristics but also contexts of cigarette and e-cigarette use. Higher motivation to use e-cigarettes to quit smoking and less permissive environment for smoking may promote substitution of cigarettes by e-cigarettes.

Background: The dopamine receptor D4 [DRD4] has been reported to be associated with substance use. Yet, the roles that health conditions and behaviors may play in such association are understudied.Objective: This longitudinal study investigated the potential mediation effects of chronic pain and delinquency in adolescence on the association between the DRD4 2-repeat allele and substance use in adulthood. Sex, witnessing violence, and experiencing violence were also examined as potential moderators for the mediation pathways.Methods: We used the restricted and candidate gene data from the National Longitudinal Study of Adolescent to Adult Health (Waves I-IV) to conduct secondary analysis (N = 8,671; 47% male). A two-step approach was adopted to examine the mediation effects regarding four substance use outcomes in adulthood: number of lifetime alcohol use disorder symptoms, lifetime regular smoker status, past-month smoking, and lifetime "pain killer" misuse. The moderation effects were investigated using stratification and permutation.Results: The DRD4 2-repeat allele was associated with all adulthood substance use outcomes through adolescent chronic pain and delinquency (AORs/IRR range 1.08-3.78; all ps

Background Noise exposure and associated hearing loss affects an estimated 2 million farm youth who are exposed as farm residents, farm family workers, hired workers, children of migrant or seasonal workers, and farm visitors. Risk factors for farm youth include frequent exposure to high farm noise; farm work from an early age, and exposure to high recreational noise (e.g., firearms, ATVs, and personal listening devices). Methods This study compared the effectiveness of two interventions and control. The programs included a community-based interactive youth educational program alone (Group A), a community-based interactive youth educational program followed by an Internet-based booster (Group B), and a no-interaction control (Group C). The study used a cluster randomized control design, with equal allocation ratio to each cluster, without blinding. Inclusion criteria included enrollment in grade 4, parental consent, English speaking, and attending a community-based educational event included in the cluster sampling. A total of 1979 youth were enrolled at 36 sites distributed across the 3 study arms in the following distribution: N = 662 in 13 sites (Group A), N = 680 in 12 sites (Group B), and N = 637 in 11 sites (Group C). Results Comparison with pre-intervention data showed no difference in intent to use hearing conservation strategies in experimental groups. However, knowledge and attitudes toward hearing conservation were improved in the groups receiving the Internet-based booster. Participants reported frequent exposure to sources of hazardous noise (e.g., loud sporting events, firecrackers, personal listening devices). Conclusions It is feasible and acceptable to incorporate hearing health education into an already existing system designed to deliver health and safety educational programming to farm and rural youth. The program was adopted by the partner agency for dissemination to up to 100,000 youth annually. Results of this study inform future intervention studies, interventions aimed at farm youth, and interventions to increase use of hearing conservation strategies, as well as offer a base for developing programs for non-English speaking children. Trial registration Clinicaltrials.gov registration CT02472821. Date of trial registration: 06/09/2015 (retrospectively registered).

Understanding the co-use of e-cigarettes and alcohol, including the situational contexts and subjective effects associated with co-use in real-time is necessary for validating this behavior and informing intervention. Yet, the sparse literature has built upon retrospective data.This study recruited 686 college students who were currently using e-cigarettes from three campuses in the Midwest and South of U.S in Fall 2019-Fall 2021. An on-line survey was conducted to measure e-cigarette use patterns, GPA, e-cigarette and alcohol dependence symptoms, and respiratory symptoms. A 7-day ecological momentary assessment was used to collect real-time data on e-cigarette and alcohol use, situational contexts and subjective effects.Frequent drinking e-cigarette users reported more high-risk use behavior including consuming 6 + drinks/occasion and simultaneous use, and reported more e-cigarettes and alcohol related dependence symptoms and respiratory symptoms, compared to infrequent/non-drinker e-cigarette users. Alcohol quantity was positively associated with e-cigarette quantity among the high frequency drinking group. This study identified important use contexts that were associated with higher e-cigarette consumption including use of menthol or fruit flavored e-cigarettes, being in a car, and the presence of others. E-cigarette use and alcohol use both increased the levels of positive affect, physiological sensation, and craving for e-cigarettes, whereas only alcohol use significantly decreased negative affect. No interaction effects between e-cigarette use and alcohol use were found.The findings highlight the addiction and health risks associated with frequent co-use of e-cigarettes and alcohol, and also call for regulations on nontobacco flavorings in e-cigarette products.

Objectives: To evaluate whether a web-based educational intervention improved personal protective equipment (PPE) use among oncology nurses who handle hazardous drugs. Sample & Setting: From 2015 to 2017, the authors partnered with 12 ambulatory oncology settings in the United States to enroll 396 nurses, 257 of whom completed baseline and primary endpoint surveys. Methods & Variables: In a cluster randomized controlled trial, 136 nurses in control settings received a one-hour educational module on PPE use with quarterly reminders, and 121 nurses in treatment settings received the control intervention plus tailored messages to address perceived barriers and quarterly data gathered on hazardous drug spills across all study settings. The primary outcome was nurse-reported PPE use. Results: Control and intervention sites had suboptimal PPE use before and after the intervention. No significant differences were observed in PPE use knowledge or perceived barriers. Participants reported high satisfaction with the study experience. Implications for Nursing: Hazardous drug exposure confers notable health risks to healthcare workers. To improve hazardous drug handling, occupational healthcare workers, health systems, and professional organizations should consider coordinated efforts to implement policy and practice changes.

PURPOSE: To test the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20) using Rasch-based methods. METHODS: A secondary data analysis was performed using pooled QLQ-CIPN20 data from patients (N = 1008) who had participated in any of four multi-site chemotherapy-induced peripheral neuropathy (CIPN) treatment and prevention trials. QLQ-CIPN20 responses were evaluated using a polytomous Rasch partial credit model. Data were assessed for person-item fit using the chi-square statistic, item scaling based on response proportions, threshold ordering using item characteristic curves and logit threshold locations, differential item response (DIF) (i.e., response bias) using likelihood ratio tests, and unidimensionality using cluster analysis. RESULTS: A statistically significant chi-square test indicated poor fit of the observed to the expected responses. More than 70% of the respondents reported a complete absence of six symptoms, reflecting significant floor effects and poor item scaling. Disordered/non-ordinal or narrow response thresholds were found for 11 of the 20 items. Item responses were significantly different by gender (p < 0.0001) and chemotherapy type (p < 0.0001). Cluster analysis findings suggest that the QLQ-CIPN20 is a unidimensional scale due to the absence of item clusters. CONCLUSIONS: Rasch model testing revealed psychometric weaknesses that could be addressed by revising the QLQ-CIPN20’s problematic items and response options. Alternatively, perhaps the new gold standard CIPN measurement approach in future intervention trials should involve use of only the best items, which would also allow comparisons across previous trials that utilized the QLQ-CIPN20.

Permutation tests are very useful when parametric assumptions are violated or distributions of test statistics are mathematically intractable. The major advantage of permutation tests is that the procedure is so general that it is applicable to most test statistics. The computational expense is, however, impractical in high-dimensional settings such as genomewide association studies. This study provides a comprehensive review of existing methods that can compute very small p-values efficiently. A common issue with existing methods is that they can only be applied to a specific test statistic. To fill in the knowledge gap, we propose a hybrid method of the sequential Monte Carlo and the Edgeworth expansion approximation for a studentized statistic, which is applicable to a variety of test statistics. The simulation results show that the proposed method performs better than competing methods. Furthermore, applications of the proposed method are demonstrated by statistical analysis on the genomewide association studies data from the Study of Addiction: Genetics and Environment (SAGE).

Psychological distress, including anxiety and depression, is commonly reported by patients with implantable left ventricular assist devices (LVADs). Still, the influence of anxiety and depression on global quality of life (QOL) is unknown. Moreover, the empirical data of LVAD patients' QOL is limited to 24 months. This study examined the differences in anxiety, depression, and QOL based on 3 LVAD implant duration groups (≤12, 13-24, and ≥25 months). We also examined the influence of anxiety and depression on QOL. An observational cross-sectional study design was employed using self-administered demographics, anxiety, depression, and global QOL questionnaires. A total of 100 patients (mean age 52 ± 13.3 years) across the United States completed the study. In the 3 implant duration groups, we found no significant differences in anxiety and depression, but the global QOL scores of patients with LVADs ≥ 13 months were significantly worse than those of patients with LVADs ≤ 12 months. Also, the correlations between QOL and either anxiety or depression were significant: Pearson's r ranged from -0.44 to -0.65 with all p values

This study tested the applicability of the individual and family self-management theory (IFSMT) to self-management (SM) in patients with left ventricular assist devices (LVADs). From an existing data set, we extracted the following variables that correspond to IFSMT's conceptual dimensions: anxiety, depression, and cognition (context dimension); self-efficacy (SM process dimension); adherence and quality of life (QOL; outcome dimensions). Descriptive statistics and partial least squares path modeling procedures were used for data analyses. A total of 100 patients (mean age 52 ± 13.4 years) with continuous flow LVAD designs comprised the present study. Most patients were White (78%), married (69%), college-educated (72%), and on disability (53%). Their mean anxiety and depression scores were slightly above normal, while their cognitive function scores were slightly lower than normal. LVAD care self-efficacy, adherence, and QOL were within normal ranges. Factor loadings ranged from 0.50 to 1.0, and there were significant forward path relationships among the context, process, and outcome dimensions (β ranges from 0.02 to 0.60, all P values < 0.05). In conclusion, the IFSMT provides a good fit for SM in LVAD. Further research is needed to clarify how best to improve LVAD SM practice and treatment outcomes.

Engagement in externalizing behavior is problematic. Deviant peer affiliation increases risk for externalizing behavior. Yet, peer effects vary across individuals and may differ across genes. This study determines gene × environment × development interactions as they apply to externalizing behavior from childhood to adulthood. A sample (n = 687; 68% male, 90% White) of youth from the Michigan Longitudinal Study was assessed from ages 10 to 25. Interactions between γ-amino butyric acid type A receptor γ1 subunit (GABRG1; rs7683876, rs13120165) and maladaptive peer behavior on externalizing behavior were examined using time-varying effect modeling. The findings indicate a sequential risk gradient in the influence of maladaptive peer behavior on externalizing behavior depending on the number of G alleles during childhood through adulthood. Individuals with the GG genotype are most vulnerable to maladaptive peer influences, which results in greater externalizing behavior during late childhood through early adulthood.

Lack of activation in self-care can compromise a patient's ability to monitor and manage cancer treatment-related side effects, such as chemotherapy-induced peripheral neuropathy (CIPN). The web-based Carevive® Care Planning System (CPS) was developed to promote evidence-based symptom assessment and treatment by enhancing patients' involvement in their own care. The purpose of this single-arm, pre-test/post-test, prospective study was to examine whether the CPS can promote patient activation in CIPN symptom assessment and management. Seventy-five women with breast cancer receiving neurotoxic chemotherapy were recruited from a Comprehensive Cancer Center. Using standardized neuropathy measures embedded within the CPS, patients reported their CIPN symptoms over three consecutive clinical visits and completed the Patient Activation Measure (PAM) at the first and third visits. Mean changes in PAM scores between visits were compared using repeated measure analysis of covariance, adjusting for age. At baseline, patients were diagnosed with cancer within the past year (94.7%), highly activated (85% Level III/IV), and had a mean age of 51.3. PAM scores improved significantly from 67.15 (SD = 13.5; range = 47-100) at visit one to 69.29 (SD = 16.18; range = 47-100) (p = 0.02) (n = 62) at visit three. However, patients perceived the CPS to be of minimal value because it solely focused on CIPN and, for many, CIPN was not severe enough to motivate them to seek out symptom management information. Further research is needed to assess the utility of the CPS in promoting activation in the assessment and management of varying cancer treatment-related symptoms.

We propose a new genome-wide association test for mixed binary and continuous phenotypes that uses an efficient numerical method to estimate the empirical distribution of the Fisher’s combination statistic under the null hypothesis. Our simulation study shows that the proposed method controls the type I error rate and also maintains its power at the level of the permutation method. More importantly, the computational efficiency of the proposed method is much higher than the one of the permutation method. The simulation results also indicate that the power of the test increases when the genetic effect increases, the minor allele frequency increases, and the correlation between responses decreases. The statistical analysis on the database of the Study of Addiction: Genetics and Environment demonstrates that the proposed method combining multiple phenotypes can increase the power of identifying markers that may not be, otherwise, chosen using marginal tests.

BACKGROUND: Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved non-white populations. OBJECTIVE: To identify genetic predictors of ICS response in multiple population groups with asthma. METHODS: The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n=244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (i.e., the combined effect of the SNP and SNP x ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in three additional groups – African Americans (n=803 and n=563) and Latinos (n=1,461). RNA-seq data from 408 asthma cases and 405 controls were used to examine whether genotype was associated with gene expression. RESULTS: One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P=7.79×10(−8)) and was jointly associated with asthma exacerbations in three validation cohorts (P=0.023, P=0.029, and P=0.041). RNA-seq analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P=6.10×10(−4)). RNASE2 encodes eosinophil-derived neurotoxin (EDN), and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (i.e., high pre-treatment EDN levels or blood eosinophil counts). CONCLUSION: We identified a variant, rs3827907, which appears to influence response to ICS treatment in multiple population groups, and likely mediates its effect through eosinophils. CLINICAL IMPLICATIONS: African Americans and Latinos are disproportionately affected by asthma and its complications. Here we identify a pharmacogenomic variant that may assist in identifying individuals from these groups who will respond to ICS treatment. CAPSULE SUMMARY: This is the first study to use a non-white study population for the discovery of pharmacogenomic predictors of asthma controller response. Variant rs3827907 genotype appeared to influenced ICS response especially in the setting of eosinophilic inflammation.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is often inadequately assessed and managed by advanced practice providers. Objectives The aim is to explore the impact of CIPN assessment training and electronic care planning system (CPS) use on CIPN assessment documentation and guidelines adherence. Methods The authors used a pre-/post-test, prospective design with two retrospective chart reviews. Six providers received CIPN assessment training and used the CPS to manage CIPN for 75 women receiving neurotoxic chemotherapy. Findings CPS use significantly improved documentation of numbness and nonpainful CIPN management strategies but had no effect on documentation of additional assessment variables or painful CIPN management.

Purpose: To test a reduced version—CIPN15—of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy scale (QLQ-CIPN20) to establish a possible gold-standard patient-reported outcome measure for chemotherapy-induced peripheral neuropathy (CIPN). Methods: Using a prospective, longitudinal, case–control design, patients (n = 121) receiving neurotoxic chemotherapy completed the CIPN15 at baseline and 12 weeks and underwent objective neurological assessment using the 5-item Total Neuropathy Score-Clinical (TNSc). Healthy controls (n = 30) completed the CIPN15 once. Structural validity was evaluated using factor analysis. Because a stable factor structure was not found, a sum score was used to evaluate measures of the CIPN15’s psychometric properties—reliability, validity, sensitivity, and responsiveness—as follows: internal consistency via Cronbach’s α and item–item correlations; test–retest reliability via correlation between 2 CIPN15 scores from each patient; concurrent validity via correlation between CIPN15 and 5-item TNSc scores; contrasting group validity via comparison of CIPN15 scores from patients and healthy controls; sensitivity via descriptive statistics (means, standard deviation, ranges); and responsiveness via Cohen’s d effect size. Results: Most patients received single agent oxaliplatin (33.7%), paclitaxel (21.2%), or more than 1 neurotoxic drug concurrently (29.8%). Factor analysis revealed no stable factor structure. Cronbach’s α for the CIPN15 sum score was 0.91 (confidence interval [CI] = 0.89-0.93). Test–retest reliability was demonstrated based on strong correlations between the 2 scores obtained at the 12-week time point ( r = 0.86; CI = 0.80-0.90). The CIPN15 and 5-item TNSc items reflecting symptoms (not signs) were moderately correlated ( r range 0.57-0.72): concurrent validity. Statistically significant differences were found between patient and healthy control CIPN15 mean scores ( P < .0001): contrasting group validity. All items encompassed the full score range but the CIPN15 linearly converted sum score did not: sensitivity. The CIPN15 was responsive based on a Cohen’s d of 0.52 (CI = 0.25-0.79). Conclusion: The sum-scored CIPN15 is reliable, valid, sensitive, and responsive when used to assess taxane- and platinum-induced CIPN.

To explore the context and the influence of night-time care routine interactions (NCRIs) on night-time sleep effectiveness (NSE) and daytime sleepiness (DSS) of patients in the cardiac surgery critical-care and progressive-care units of a hospital.There exists a paucity of empirical data regarding the influence of NCRIs on sleep and associated outcomes in hospitalised adult cardiac surgery patients.An exploratory repeated-measures research design was employed on the data provided by 38 elective cardiac surgery patients (mean age 60.0 ± 15.9 years). NCRI forms were completed by the bedside nurses and patients completed a 9-item Visual Analogue Sleep Scale (100-mm horizontal lines measuring NSE and DSS variables). All data were collected during postoperative nights/days (PON/POD) 1 through 5 and analysed with IBM SPSS software.Patient assessment, medication administration and laboratory/diagnostic procedures were the top three NCRIs reported between midnight and 6:00 a.m. During PON/POD 1 through 5, the respective mean NSE and DSS scores ranged from 52.9 ± 17.2 to 57.8 ± 13.5 and from 27.0 ± 22.6 to 45.6 ± 16.5. Repeated-measures ANOVA showed significant changes in DSS scores (p .05). NSE and DSS were negatively correlated (r = -.44, p .05), but changes in NSE scores were not significant (p .05). Finally, of 8 NCRIs, only 1 (postoperative exercises) was significantly related to sleep variables (r .40, p .05).Frequent NCRIs are a common occurrence in cardiac surgery units of a hospital. Further research is needed to make a definitive conclusion about the impact of NCRIs on sleep/sleep disruptions and daytime sleepiness in adult cardiac surgery. Worldwide, acute and critical-care nurses are well positioned to lead initiatives aimed at improving sleep and clinical outcomes in cardiac surgery.

The impact of sleep on LVAD patients' self-care behaviors is unknown. This study examined the patterns and changes of patients sleep quality (SQ), daytime sleepiness (DS), instrumental activities of daily living (IADL), and self-care capability (SCC) before and after LVAD. In addition, the relationships among these variables were explored. This observational study consisted of 38 subjects from two VAD Centers in Michigan. The subjects completed self-reported demographics and psychometrically sound SQ, DS, IADL, and SCC questionnaires before LVAD implant and at 1, 3, and 6 months after implant. Data were analyzed using descriptive statistics, linear mixed models, and partial least square models. Subjects (mean age, 56.3 ± 10.3 years) were predominantly white (63%), male (68%), married (60%), and living with caregivers (92%). Over 70% had axial flow LVADs implanted as bridge-to-transplant (55%). Subjects' SQ was poor throughout the study period, along with high normal-to-excessive levels of DS. Problems with IADL before implant were significantly reduced at 1 through 6 months after implant. SCC ranged from "good" to "excellent" before and after implant. Significant relationships between SQ and IADL (β = 0.43, p

Thymosin β4 (Tβ4), a G-actin-sequestering peptide, improves neurological outcome in rat models of neurological injury. Tissue inflammation results from neurological injury, and regulation of the inflammatory response is vital for neurological recovery. The innate immune response system, which includes the Toll-like receptor (TLR) proinflammatory signaling pathway, regulates tissue injury. We hypothesized that Tβ4 regulates the TLR proinflammatory signaling pathway. Because oligodendrogenesis plays an important role in neurological recovery, we employed an in vitro primary rat embryonic cell model of oligodendrocyte progenitor cells (OPCs) and a mouse N20.1 OPC cell line to measure the effects of Tβ4 on the TLR pathway. Cells were grown in the presence of Tβ4, ranging from 25 to 100 ng/ml (RegeneRx Biopharmaceuticals Inc., Rockville, MD), for 4 days. Quantitative real-time PCR data demonstrated that Tβ4 treatment increased expression of microRNA-146a (miR-146a), a negative regulator the TLR signaling pathway, in these two cell models. Western blot analysis showed that Tβ4 treatment suppressed expression of IL-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), two proinflammatory cytokines of the TLR signaling pathway. Transfection of miR-146a into both primary rat embryonic OPCs and mouse N20.1 OPCs treated with Tβ4 demonstrated an amplification of myelin basic protein (MBP) expression and differentiation of OPC into mature MBP-expressing oligodendrocytes. Transfection of anti-miR-146a nucleotides reversed the inhibitory effect of Tβ4 on IRAK1 and TRAF6 and decreased expression of MBP. These data suggest that Tβ4 suppresses the TLR proinflammatory pathway by up-regulating miR-146a.

Inhaled short-acting beta-agonist (SABA) medication is commonly used in asthma patients to rapidly reverse airway obstruction and improve acute symptoms. We performed a genome-wide association study of SABA medication response using gene-based association tests. A linear mixed model approach was first used for single-nucleotide polymorphism associations, and the results were later combined using GATES to generate gene-based associations. Our results identified SPATA13-AS1 as being significantly associated with SABA bronchodilator response in 328 healthy African Americans. In replication, this gene was associated with SABA response among the two separate groups of African Americans with asthma (n=1073, P=0.011 and n=1968, P=0.014), 149 healthy African Americans (P=0.003) and 556 European Americans with asthma (P=0.041). SPATA13-AS1 was also associated with longitudinal SABA medication usage in the two separate groups of African Americans with asthma (n=658, P=0.047 and n=1968, P=0.025). Future studies are needed to delineate the precise mechanism by which SPATA13-AS1 may influence SABA response.

Here, for the first time, we test a novel hypothesis that systemic treatment of stroke with exosomes derived from multipotent mesenchymal stromal cells (MSCs) promote neurovascular remodeling and functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo) followed by tail vein injection of 100 μg protein from MSC exosome precipitates or an equal volume of vehicle phosphate-buffered saline (PBS) ( n = 6/group) 24 hours later. Animals were killed at 28 days after stroke and histopathology and immunohistochemistry were employed to identify neurite remodeling, neurogenesis, and angiogenesis. Systemic administration of MSC-generated exosomes significantly improved functional recovery in stroke rats compared with PBS-treated controls. Axonal density and synaptophysin-positive areas were significantly increased along the ischemic boundary zone of the cortex and striatum in MCAo rats treated with exosomes compared with PBS control. Exosome treatment significantly increased the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells. Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery and enhances neurite remodeling, neurogenesis, and angiogenesis and represents a novel treatment for stroke.

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

Improving time to diagnosis and intervention has positively impacted outcomes in acute myocardial infarction, stroke, and trauma through elucidating the early pathogenesis of those diseases. This insight may partly explain the futility of time-insensitive immunotherapy trials for severe sepsis and septic shock. The aim of this study was to examine the early natural history of circulatory biomarker activity in sepsis, relative to previous animal and human outcome trials. We conducted a literature search using PubMed, MEDLINE, and Google Scholar to identify outcome trials targeting biomarkers with emphasis on the timing of therapy. These findings were compared with the biomarker activity observed over the first 72 h of hospital presentation in a cohort of severe sepsis and septic shock patients. Biomarker levels in animal and human research models are elevated within 30 min after exposure to an inflammatory septic stimulus. Consistent with these findings, the biomarker cascade is activated at the most proximal point of hospital presentation in our patient cohort. These circulatory biomarkers overlap; some have bimodal patterns and generally peak between 3 and 36 h while diminishing over the subsequent 72 h of observation. When this is taken into account, prior outcome immunotherapy trials have generally enrolled patients after peak circulatory biomarker concentrations. In previous immunotherapy sepsis trials, intervention was delayed after the optimal window of peak biomarker activity. As a result, future studies need to recalibrate the timing of enrollment and administration of immunotherapy agents that still may hold great promise for this deadly disease.

Background A multivariate genome-wide association test is proposed for analyzing data on multivariate quantitative phenotypes collected from related subjects. The proposed method is a two-step approach. The first step models the association between the genotype and marginal phenotype using a linear mixed model. The second step uses the correlation between residuals of the linear mixed model to estimate the null distribution of the Fisher combination test statistic. Results The simulation results show that the proposed method controls the type I error rate and is more powerful than the marginal tests across different population structures (admixed or non-admixed) and relatedness (related or independent). The statistical analysis on the database of the Study of Addiction: Genetics and Environment (SAGE) demonstrates that applying the multivariate association test may facilitate identification of the pleiotropic genes contributing to the risk for alcohol dependence commonly expressed by four correlated phenotypes. Conclusions This study proposes a multivariate method for identifying pleiotropic genes while adjusting for cryptic relatedness and population structure between subjects. The two-step approach is not only powerful but also computationally efficient even when the number of subjects and the number of phenotypes are both very large.

Cancer genetic services (counseling/testing) are recommended for women diagnosed with breast cancer younger than 45 years old (young breast cancer survivors—YBCS) and at-risk relatives. We present recruitment of YBCS, identification and recruitment of at-risk relatives, and YBCS willingness to contact their cancer-free, female relatives. A random sample of 3,000 YBCS, stratified by race (Black vs. White/Other), was identified through a population-based cancer registry and recruited in a randomized trial designed to increase use of cancer genetic services. Baseline demographic, clinical, and family characteristics, and variables associated with the Theory of Planned Behavior (TPB) were assessed as predictors of YBCS’ willingness to contact at-risk relatives. The 883 YBCS (33.2% response rate; 40% Black) who returned a survey had 1,875 at-risk relatives and were willing to contact 1,360 (72.5%). From 853 invited at-risk relatives (up to two relatives per YBCS), 442 responded (51.6% response rate). YBCS with larger families, with a previous diagnosis of depression, and motivated to comply with recommendations from family members were likely to contact a greater number of relatives. Black YBCS were more likely to contact younger relatives and those living further than 50 miles compared to White/Other YBCS. It is feasible to recruit diverse families at risk for hereditary cancer from a population-based cancer registry. This recruitment approach can be used as a paradigm for harmonizing processes and increasing internal and external validity of large-scale public health genomic initiatives in the era of precision medicine.

This study determined the effectiveness of the Tobacco Tactics intervention.This was a pragmatic, quasi-experimental study conducted from 2010 to 2013 and analyzed from 2014 to 2015 in five Michigan community hospitals; three received the Tobacco Tactics intervention, and two received usual care. Smokers (N=1,528) were identified during hospitalization, and sent surveys and cotinine tests after 6 months. Changes in pre- to post-intervention quit rates in the intervention sites were compared with usual care control sites.The toolkit for nurses included: (1) 1 continuing education unit contact hour for training; (2) a PowerPoint presentation on behavioral and pharmaceutical interventions; (3) a pocket card entitled "Helping Smokers Quit: A Guide for Clinicians"; (4) behavioral and pharmaceutical protocols; and (5) a computerized template for documentation. The toolkit for patients included: (1) a brochure; (2) a cessation DVD; (3) the Tobacco Tactics manual; (4) a 1-800-QUIT-NOW card; (5) nurse behavioral counseling and pharmaceuticals; (6) physician reminders to offer brief advice to quit coupled with medication sign-off; and (7) follow-up phone calls by trained hospital volunteers.The effectiveness of the intervention was measured by 6-month 30-day point prevalence; self-reported quit rates with NicAlert(®) urinary biochemical verification (48-hour detection period); and the use of electronic medical record data among non-responders.There were significant improvements in pre- to post-intervention self-reported quit rates (5.7% vs 16.5%, p0.001) and cotinine-verified quit rates (4.3% vs 8.0%, p0.05) in the intervention sites compared with no change in the control sites. Propensity-adjusted multivariable analyses showed a significant improvement in self-reported 6-month quit rates from the pre- to post-intervention time periods in the intervention sites compared to the control sites (p=0.044) and a non-statistically significant improvement in the cotinine-verified 6-month quit rate.The Tobacco Tactics intervention, which meets the Joint Commission standards for inpatient smoking, has the potential to significantly decrease smoking among inpatient smokers.This study is registered at www.clinicaltrial.gov NCT01309217.

There is no empirical study about the context and influence of self-management (SM) factors on quality of life (QOL) among adults with left ventricular assist device (LVADs). The purpose of this study was to close this knowledge gap by: (1) differentiating select SM factors (e.g., cognition) and overall QOL based on LVAD implant durations; (2) examining the relationships among SM factors and QOL variables; and (3) identifying which SM factors predict QOL.An observational study was employed including 87 LVAD patients, ages 20 to 80 years, with mean implant durations of 18.5 ± 15.1 months. Patients completed 1 demographic questionnaire and 6 measures of SM factors (cognition-general and executive function, LVAD self-efficacy, care dependency and adherence) and QOL. Data were analyzed with descriptive and inferential statistical procedures.There was no significant difference in SM factors and overall QOL by LVAD implant durations. SM factors, including cognitive function, LVAD self-efficacy, and adherence, correlated positively with QOL (r = 0.35 to 0.48, p0.05), but LVAD care dependency correlated negatively with QOL (r = -0.21, p0.05). The general and executive function of cognition and LVAD adherence were significant predictors of QOL.The data inferred that higher level of cognitive function is associated with higher self-efficacy, adherence and greater QOL, whereas lower care dependency is associated with greater QOL. Higher cognitive function and adherence to the LVAD care regimen predicted better QOL outcome. Further research is needed to elucidate the mechanism by which SM factors influence QOL in adults with long-term LVADs.

Background Current US guidelines recommend the Asthma Control Test (ACT) for assessing disease control and selecting treatment. Objective The goal of this study was to prospectively assess the ACT and its component questions for their utility in predicting the risk of severe asthma exacerbations. Methods Individuals were participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity, and those included in the current analysis had the following characteristics: age 18 years or more, physician-diagnosed asthma, and longitudinal care received at a large health system in southeastern Michigan. Study participants underwent a baseline evaluation, which included answering the ACT. A severe asthma exacerbation was defined as one requiring oral steroids, an emergency department visit, or inpatient admission. Receiver-operator characteristic curves were used to measure and compare the predictive utility of the ACT and its component questions for severe asthma exacerbations. Results Of 1180 participants, 354 (30.0%) experienced a severe asthma exacerbation within 6 months of their baseline evaluation. When compared with the individual questions that composed the ACT, the composite score was significantly better at predicting severe exacerbations with 1 exception; the composite ACT score and the question assessing rescue medication use were not significantly different (P = .580). Pharmacy-based records of metered-dose inhaler short-acting beta-agonist use and asthma severity were also not significantly different from the composite ACT score. Conclusions Our study demonstrates that although the ACT is modestly predictive for exacerbations, the composite score may not be superior to assessing rescue medication use alone for predicting the risk of severe asthma exacerbations.

Background Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk. Objectives We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis. Methods We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case–parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis. Results Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos. Conclusions This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations.

AT(2)Rs [AngII (angiotensin II) type 2 receptors] contribute to the cardioprotective effects of angiotensin II receptor blockers, possibly via kinins acting on the B(1)R (B(1) receptor) and B(2)R (B(2) receptor). Recent studies have shown that a lack of B(2)R up-regulates B(1)R and AT(2)R; however, the pathophysiological relevance of such an event remains unclear. We hypothesized that up-regulation of AT(2)R and B(1)R compensates for the loss of B(2)R. Blockade of AT(2)R and/or B(1)R worsens cardiac remodelling and dysfunction following MI (myocardial infarction) in B(2)R(-/-) (B(2)-receptor-knockout mice). B(2)R(-/-) mice and WT (wild-type) controls were subjected to sham MI or MI and treated for 4 weeks with (i) vehicle, (ii) a B(1)R-ant (B(1)R antagonist; 300 μg/kg of body weight per day), (iii) an AT(2)R-ant [AT(2) receptor antagonist (PD123319); 20 mg/kg of body weight per day], or (iv) B(1)R-ant+AT(2)R-ant. B(2)R(-/-) mice had a greater MCSA (myocyte cross-sectional area) and ICF (interstitial collagen fraction) at baseline and after MI compared with WT controls. Cardiac function and increase in macrophage infiltration, TGFβ(1) (transforming growth factor β(1)) expression and ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation post-MI were similar in both strains. Blockade of AT(2)R or B(1)R worsened cardiac remodelling, hypertrophy and dysfunction associated with increased inflammation and ERK1/2 phosphorylation and decreased NO excretion in B(2)R(-/-) mice, which were exacerbated by dual blockade of B(1)R and AT(2)R. No such effects were seen in WT mice. Our results suggest that, in the absence of B(2)R, both B(1)R and AT(2)R play important compensatory roles in preventing deterioration of cardiac function and remodelling post-MI possibly via suppression of inflammation, TGFβ(1) and ERK1/2 signalling.

To compare the needleless securing clamp to the traditional suture-secured clamp for central venous catheters.Compare the holding strength of each type of clamps by measuring the amount of kinetic energy absorbed, ask 20 physicians to evaluate the clamp placement using sutures or staples, and summarise the clamps effectiveness and complications in 10 patients.Compared to sutured clamp, the needleless clamp was more secure. The needleless clamp was also significantly better with regard to ease of use, safety, perceived strength (p value0.002), and insertion time was reduced by 63%. No adverse events or skin infections occurred while using the needleless clamps.Without incurring complications or increasing risk to patients, the needleless clamp is secure and improves safety and efficiency for physicians.

Background: Improved outcomes for severe sepsis and septic shock have been consistently observed with implementation of early best practice intervention strategies or the 6-hour resuscitation bundle (RB) in single-center studies. This multicenter study examines the in-hospital mortality effect of GENeralized Early Sepsis Intervention Strategies (GENESIS) when utilized in community and tertiary care settings. Methods: This study was comprised of 2 strategies to assess treatment. The first was a prospective before-and-after observational comparison of historical controls to patients receiving the RB after implementation of GENESIS in 4 community and 4 tertiary hospitals. The second was a concurrent examination comparing patients not achieving all components of the RB to those achieving all components of the RB in 1 community and 2 tertiary care hospitals after implementation of GENESIS. These 4 subgroups merged to comprise a control (historical controls treated before GENESIS and RB not achieved after GENESIS) group and treatment (patients treated after GENESIS and RB achieved after GENESIS) group for comparison. Results: The control group comprised 1554 patients not receiving the RB (952 before GENESIS and 602 RB not achieved after GENESIS). The treatment group comprised 4801 patients receiving the RB (4109 after GENESIS and 692 RB achieved after GENESIS). Patients receiving the RB (treatment group) experienced an in-hospital mortality reduction of 14% (42.8%-28.8%, P < .001) and a 5.1 day decrease in hospital length of stay (20.7 vs 15.6, P < .001) compared to those not receiving the RB (control group). Similar mortality reductions were seen in the before-and-after (43% vs 29%, P < .001) or concurrent RB not achieved versus achieved (42.5% vs 27.2%, P < .001) subgroup comparisons. Conclusions: Patients with severe sepsis and septic shock receiving the RB in community and tertiary hospitals experience similar and significant reductions in mortality and hospital length of stay. These findings remained consistent when examined in both before-and-after and concurrent analyses. Early sepsis intervention strategies are associated with 1 life being saved for every 7 treated.

Objective Emergency physicians (EPs) estimate the underlying hemodynamics of acutely ill patients and use them to help both diagnose and formulate a treatment plan. This trial compared the EP clinically derived estimates of cardiac output (CO) and systemic vascular resistance (SVR) to those measured noninvasively. Methods Forty acutely ill emergency department patients with a broad range of diagnosis and blood pressure (BP) and pulse were monitored for 2 hours using novel noninvasive finger cuff technology (Nexfin; BMEYE, Amsterdam, The Netherlands). The Nexfin device provides continuous BP monitoring and, from the resulting pulse pressure waveform, calculates beat-to-beat CO and SVR. At baseline assessment and after 2 hours of testing and therapy, treating EPs were asked to estimate the CO and SVR (low, normal, or high), and these were compared with Nexfin measurements. Results Twenty-five men and 15 women were enrolled with a mean age of 62.2 years (SD, 12.6 years). Eighteen had acute shortness of breath; 11, with probable stroke syndrome; 3, with suspected sepsis; and 8, with a systolic BP greater than 180 or less than 100 mm Hg. Concordance tables showed that there was very little agreement ( κ values) between either the compared initial CO (−0.0873) and SVR (−0.0645) or the 2-hour values (−0.0645 and −0.1949, respectively). Conclusions Emergency physicians cannot accurately estimate the underlying hemodynamic profiles of acutely ill patients when compared with more objective measurements. This inaccuracy may have important clinical ramifications. Further study is needed to determine how to use these measured continuous CO and SVR monitoring values.

Measuring workplace performance is important to emergency department management. If anunreliable model is used, the results will be inaccurate. Use of inaccurate results to make decisions,such as how to distribute the incentive pay, will lead to rewarding the wrong people and will potentiallydemoralize top performers. This article demonstrates a statistical model to reliably measure the workaccomplished, which can then be used as a performance measurement.

Measuring workplace performance is important to emergency department management. If an unreliable model is used, the results will be inaccurate. Use of inaccurate results to make decisions, such as how to distribute the incentive pay, will lead to rewarding the wrong people and will potentially demoralize top performers. This article demonstrates a statistical model to reliably measure the work accomplished, which can then be used as a performance measurement. [West J Emerg Med.2012;13(2):176–180.]

While clinicians' management of severe sepsis and septic shock has been positively influenced by a number of clinical research studies in the last decade, challenges remain regarding early hemodynamic optimization as envisioned in the Surviving Sepsis Campaign’s (SSC) resuscitation bundle (RB). We examined the impact of a hospital-wide continuous quality improvement (CQI) initiative on patients presenting with severe sepsis and septic shock, and the impact of the sepsis RB on patient outcomes when completed beyond the 6-hour recommendation period. The study was an 18-month, prospective cohort study enrolling patients who met the definition of severe sepsis or septic shock. Compliance with the hemodynamic components of the sepsis RB was defined as achieving goal mean arterial pressure (MAP) ≥65 mm Hg, central venous pressure (CVP) ≥8 mm Hg, and central venous oxygen saturation (ScvO2) ≥70%. Compliance was assessed at 6 hours and 18 hours after diagnosis of severe sepsis or septic shock. In all, 498 patients with severe sepsis and/or septic shock were evaluated to determine the upper limit of the range of hours that compliance with the RB would still improve outcomes. Using 18 hours as a marker, Compliers at 18 hrs and Non-Compliers at 18 hrs were compared. There were 202 patients who had the RB completed in less than or equal to 18 hours. There were 296 patients who did not complete the RB at 18 hours. The Compliers at 18 hrs had a significant 10.2% lower hospital mortality 37.1% (22% relative reduction) compared to the Non-Compliers at 18 hrs hospital mortality of 47.3% ( P < .03). When the two groups were adjusted for differences in baseline illness severity, the Compliers at 18 hrs had a greater reduction in predicted mortality of 26.8% versus 9.4%, P < 0.01.Conclusions: Initiating the sepsis RB for patients with severe sepsis and/or septic shock decreased mortality. A CQI initiative that monitored the implementation in real-time allowed for improvement in compliance and efficacy of the bundle on outcomes. Multiple studies have shown that compliance to the RB within 6 hours lowers hospital mortality. This study uniquely shows that when bundle completion is extended to 18 hours, the mortality reduction remains significant.