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Decades of genome-wide mapping have shown that most genetic polymorphisms associated with complex traits are found in non-coding regions of the genome. Characterizing the effect of such genetic variation presents a formidable challenge, and eQTL mapping has been a key approach to understand the non-coding genome. However, comprehensive eQTL maps are available only for a few species like yeast and humans. With the aim of understanding the genetic landscape that regulates transcriptional variation inDrosophila melanogaster, we developed an outbred mapping panel in this species, theDrosophilaOutbred Synthetic Panel (Dros-OSP). Using this community resource, we collected transcriptomic and genomic data for 1800 individual flies and were able to mapcisandtranseQTLs for 98% of the genes expressed inD. melanogaster, increasing by thousands the number of genes for which regulatory loci are known in this species. We described, for the first time in the context of an outbred population, the properties of local and distal regulation of gene expression in terms of genetic diversity, heritability, connectivity, and pleiotropy. We uncovered that, contrary to long-standing assumptions, a significant part of gene co-expression networks is organized in a non-modular fashion. These results bring the fruit fly to the level of understanding that was only available for a few other organisms, and offer a new mapping resource that will expand the possibilities currently available to theDrosophilacommunity. This data is available atDrosophilaeqtl.org.

Validating associations between genotypic and phenotypic variation remains a challenge, despite advancements in association studies. Common approaches for signal validation rely on gene-level perturbations, such as loss-of-function mutations or RNAi, which test the effect of genetic modifications usually not observed in nature. CRISPR-based methods can validate associations at the SNP level, but have significant drawbacks, including resulting off-target effects and being both time-consuming and expensive. Both approaches usually modify the genome of a single genetic background, limiting the generalizability of experiments. To address these challenges, we present a simple, low-cost experimental scheme for validating genetic associations at the SNP level in outbred populations. The approach involves genotyping live outbred individuals at a focal SNP, crossing homozygous individuals with the same genotype at that locus, and contrasting phenotypes across resulting synthetic outbred populations. We tested this method inDrosophila melanogaster, measuring the longevity effects of a polymorphism at a naturally-segregating cis-eQTL for themidwaygene. Our results demonstrate the utility of this method in SNP-level validation of naturally occurring genetic variation regulating complex traits. This method provides a bridge between the statistical discovery of genotype-phenotype associations and their validation in the natural context of heterogeneous genomic contexts.

Gene expression variance has been linked to organismal function and fitness but remains a commonly ne-glected aspect of molecular research. As a result, we lack a comprehensive understanding of the patterns of transcriptional variance across genes, and how this variance is linked to context-specific gene regulation and gene function. Here, we use 57 large publicly available RNA-seq data sets to investigate the landscape of gene expression variance. These studies cover a wide range of tissues and allowed us to assess if there are consistently more or less variable genes across tissues and data sets and what mechanisms drive these patterns. We show that gene expression variance is broadly similar across tissues and studies, indicating that the pattern of transcriptional variance is consistent. We use this similarity to create both global and within-tissue rankings of variation, which we use to show that function, sequence variation, and gene regulatory signatures contribute to gene expression variance. Low-variance genes are associated with fundamental cell processes and have lower levels of genetic polymorphisms, have higher gene-gene connectivity, and tend to be associated with chromatin states associated with transcription. In contrast, high-variance genes are enriched for genes involved in immune response, environmentally responsive genes, immediate early genes, and are associated with higher levels of polymorphisms. These results show that the pattern of transcriptional variance is not noise. Instead, it is a consistent gene trait that seems to be functionally constrained in human populations. Furthermore, this commonly neglected aspect of molecular phenotypic variation harbors important information to understand complex traits and disease.Author SummaryGene expression variance, or the variation in the level of gene expression within a population, can have significant impacts on physiology, disease, and evolutionary adaptations. While the average level of gene expression is typically the focus of research, the variation around this average level (i.e., gene expression variance) can also be important for understanding complex traits and disease. Here, we investigate the landscape of transcriptional variance across tissues, populations, and studies. Using large publicly available RNA-seq data sets, we were able to identify the general properties associated with high- and low-variance genes, as well as factors driving variation in variance across genes. Specifically, we uncovered gene expression variance was significantly associated with gene length, nucleotide diversity, the degree of connectivity and the presence of non-coding RNA. Our results suggest that the mechanisms responsible for maintaining optimal levels of variation in high-versus low-variance differ, and that this variability is the result of different patterns of selection.

The microbiome contributes to many different host traits, but its role in host adaptation remains enigmatic. The fitness benefits of the microbiome often depend on ecological conditions, but fluctuations in both the microbiome and environment modulate these fitness benefits. Moreover, vertically transmitted bacteria might constrain the ability of both the microbiome and host to respond to changing environments.Drosophila melanogasterprovides an excellent system to investigate the evolutionary effects of interactions between the microbiome and the environment. To address this question, we created field mesocosms ofD. melanogasterundergoing seasonal adaptation with and without the vertically transmitted bacteria,Wolbachia pipientis.Sampling temporal patterns in the microbiome revealed thatWolbachiaconstrained microbial diversity. Furthermore, interactions betweenWolbachiaand the microbiome contributed to fitness-associated traits.Wolbachiaoften exerted negative fitness effects on hosts, and the microbiome modulated these effects. Our work supports recent theoretical advances suggesting that hosts in temporally fluctuating environments benefit from flexible microbial associations with low transmission fidelity—specifically when changes in the microbiome can better enable host phenotypes to match environment change. We conclude by exploring the consequences of complex interactions betweenWolbachiaand the microbiome for our understanding of eco-evolutionary processes and the utility ofWolbachiain combating vector-borne disease.

There are limited data to guide the use of anticoagulation in cirrhotic patients prior to liver transplantation especially when using direct oral anticoagulants. In this article, we present 2 cases. The first is a 42-year-old male with cirrhosis complicated by portal vein thrombosis (PVT) treated with dabigatran who underwent orthotopic liver transplantation without complication. The second case is a 65-year-old man with alcoholic cirrhosis complicated by PVT treated with dabigatran who underwent orthotopic liver transplantation and required reoperation for surgical bleeding. Both patients were treated with dabigatran’s reversal agent idarucizumab prior to incision. In this case series, we discuss the treatment of cirrhotic patients with various anticoagulants, considerations for anticoagulant selection and reversal prior to liver transplant, and questions for future investigation.

Advances in digital technology have put music libraries at people’s fingertips, giving them immediate access to more music than ever before. Here we overcome limitations of prior research by leveraging ecologically valid streaming data: 17.6 million songs and over 662,000 hr of music listened to by 5,808 Spotify users spanning a 3-month period. Building on interactionist theories, we investigated the link between personality traits and music listening behavior, described by an extensive set of 211 mood, genre, demographic, and behavioral metrics. Findings from machine learning showed that the Big Five personality traits are predicted by musical preferences and habitual listening behaviors with moderate to high accuracy. Importantly, our work contrasts a recent self-report-based meta-analysis, which suggested that personality traits play only a small role in musical preferences; rather, we show with big data and advanced machine learning methods that personality is indeed important and warrants continued rigorous investigation.

Next-generation sequencing provides a more efficient way to characterize the transcriptome; meanwhile, it introduces significant issues for the effective analysis of large-scale sequencing data. To counteract this growing problem, we developed a robust and modular pipeline for examining whole transcriptome sequencing data quickly. Utilizing a Docker for containerization and unanimous cross-platform support, we modularized the pipeline and created a practical, automated structure for pragmatic use. Furthermore, we have developed segregated implementations of the pipeline sections to allow end-users to craft custom pipelines easily. We applied our tool to various datasets and showed that our pipeline offered high-quality sequencing data analysis.

Purpose Reputational crisis negatively affects brands and companies. This chapter, based on a single case study, aims to explore how prejudicial corporate statements directed toward lesbian, gay, bisexual, and transgender (LGBT) individuals have affected the Italian multinational Barilla S.p.A., as well as how the company responded both internally and to the market in order to attempt to overcome the highly damaging consequences. Design/Methodology This chapter uses a single case-study methodology, which constitutes “a research strategy that focuses on understanding the dynamics present within single settings to create theoretical constructs, propositions and/or midrange theory from empirical evidence” (Eisenhardt, 1989, p. 534). The case-study design was chosen as it has been demonstrated to provide a methodological tool for both theory generation and theory testing (Gibbert et al., 2008). Findings Conclusions from the chapter indicate that negative, incendiary, and oftentimes comments citing either religious or stereotypical-based ideology negatively impact both the consumers and its associated publics in terms of product branding or reputation image. Research Limitations The study’s limitations, which rely primarily on a single case study and secondary research data, may motivate further investigative avenues, particularly as similarly referenced events continue to unfold almost daily, such as the study’s referenced incident with Philippine boxer Manny Pacquiao, as well as action taken by social media giants (Apple and Facebook) against the controversial media figure Alex Jones. Practical and Social Implications This chapter also looks at family succession roadblocks and navigating social media gaffes. These contemporary issues highlight challenges, strategies, sales and market share dynamics for the company, and suggestions for navigating the road ahead. The research concludes with possible linkages and insights for both ongoing management issues and potential areas for future research. Other findings indicate that rapid responses, particularly those citing concrete corporate policy changes or tangible actions, help to reverse and mitigate reputational damage, and contemporary approaches utilizing social media appear to buttress these efforts. Originality/Value This case study of Barilla as well as other firms mentioned, such as Chick-fil-A and Nike (which have experienced parallel situational crises), indicates that in only the last five years of contemporary international business practice, MNEs are continually and at times unexpectedly challenged by the lack of sensitivity demonstrated by their owners and spokespeople who utter comments which may be seen by the public as potentially harmful to the LGBT community. This study hopes to illuminate this challenge while offering tangible solutions to turning around future, similar situational crises.

Introduction Uptake of preventive therapies for breast cancer is low. We examined whether women at increased risk of breast cancer can be categorized into groups with similar medication beliefs, and whether belief group membership was prospectively associated with uptake of preventive therapy. Patients and Methods Women (n = 732) attending an appointment to discuss breast cancer risk were approached; 408 (55.7%) completed the Beliefs About Medicines and the Perceived Sensitivity to Medicines questionnaires. Uptake of tamoxifen at 3 months was reported in 258 (63.2%). The optimal number of belief groups were identified using latent profile analysis. Results Uptake of tamoxifen was 14.7% (38/258). One in 5 women (19.4%; 78/402) reported a strong need for tamoxifen. The model fit statistics supported a 2-group model. Both groups held weak beliefs about their need for tamoxifen for current and future health. Group 2 (38%; 154/406 of the sample) reported stronger concerns about tamoxifen and medicines in general, and stronger perceived sensitivity to the negative effects of medicines compared with group 1 (62%; 252/406). Women with low necessity and lower concerns (group 1) were more likely to initiate tamoxifen (18.3%; 33/180) than those with low necessity and higher concerns (group 2) (6.4%; 5/78). After adjusting for demographic and clinical factors, the odds ratio was 3.37 (95% confidence interval, 1.08-10.51; P = .036). Conclusion Uptake of breast cancer preventive therapy was low. A subgroup of women reported low need for preventive therapy and strong medication concerns. These women were less likely to initiate tamoxifen. Medication beliefs are targets for supporting informed decision-making., Micro-Abstract Preventive therapies, such as tamoxifen, are a risk reduction option for women at increased risk of breast cancer. Little is known about the psychological factors influencing the decision to use chemoprevention. Using latent profile analysis, women who reported a low need for preventive therapy and strong medication concerns were less likely to initiate tamoxifen treatment. Medication beliefs are targets for supporting informed decision-making.

Background: In previous work, extravascular expansion was observed to be enhanced by isoflurane anesthesia in sheep when a crystalloid bolus was administered. The aim of the current study was to further elaborate these investigations to humans and to explore the use of population kinetics in the analysis of fluid shifts. Methods: Eleven healthy volunteers participated in two experiments each, either awake or isoflurane anesthetized, during which they received 25 ml/kg saline, 0.9%, intravenously over 20 min. Plasma dilution data were derived from repeated sampling of hemoglobin concentration, and population pharmacokinetic analysis was conducted using the WinNonMix 2.0.1 software (Pharsight Corporation, Mountain View, CA). Plasma hormones were measured, and hemodynamic values were monitored. Results: Fluid infusion during isoflurane anesthesia was followed by a higher cardiac output, lower arterial pressure, and lower urinary excretion as compared with the awake protocol (P < 0.05). Albumin dilution was greater than hemoglobin concentration‐derived plasma dilution, which indicates a transcapillary leak of albumin. A two-compartment model with an isoflurane-depressed, intercompartmental distribution parameter predicted that more than 50% of the infused volume was retained in the peripheral compartment at 180 min in both protocols. Isoflurane markedly increased the plasma levels of renin and aldosterone, whereas vasopressin was mostly unchanged. Conclusion: Fluid retention after rapid infusion of 0.9% saline was prominent in both awake and isoflurane-anesthetized subjects. Altered kinetics of infused 0.9% saline during isoflurane anesthesia was expressed as reduced clearance and a slower distribution, resulting in a small but significant increase in fluid accumulation in the body fluid compartments. These changes may be due to the associated decreasing of mean arterial pressure and increased release of renin and aldosterone. INTRAVENOUS administration of fluid is important during anesthesia and surgery. However, inability to correctly predict fluid shifts between tissues impedes precise matching of the rate of infusion with ongoing losses and volume demands. Volume kinetics has previously been applied to data from awake 1 and anesthetized 2 humans to study fluid shifts between different body fluid compartments. The current view is that fluid retention and postoperative tissue edema after surgery are promoted by trauma-induced stress 3,4 and by mechanical ventilation 5 rather than by the administration of an anesthetic per se. However, a study in sheep 6 demonstrated that the combination of isoflurane anesthesia and mechanical ventilation significantly alters the disposition of crystalloid fluid in comparison with conscious, spontaneously ventilating sheep. In a follow-up study in sheep, isoflurane was singled out as the cause for reduced urinary excretion and peripheral fluid accumulation. 7 The first aim of the current study was to investigate the hypothesis that isoflurane anesthesia promotes peripheral fluid retention and reduces urinary excretion in humans. To further develop kinetic modeling, a second aim was to apply population kinetic analysis to the plasma dilution data. With the development of a population kinetic model, it could be possible to attribute differences in fluid distribution to such parameters as body weight, age, and sex.

Background Functional deficits are common in patients with asthma. If there is cooccurring depression, these deficits may be more severe and/or more persistent. Objective This study was undertaken to determine 1) the prevalence and severity of depressive symptoms in a sample of inner-city patients being treated for asthma and 2) the impact of these symptoms on functional status. Methods Three hundred seventeen enrollees in an inner-city asthma program were evaluated using the health status questionnaire and the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline and at 3- and 6-month followups. Two groups were created based on patients' CES-D baseline scores, using a commonly used cutpoint to define "caseness" for depression. The two groups were compared using ANOVA, χ 2 , and the general linear model for repeated measures. Results Of the sample, 55.01% had a CES-D score greater than the cutpoint for depression. The mean was 29.3 ± 11.95, well above the scores commonly used to indicate the presence of depression. The depressed group had lower scores on many measures of functional capacity at baseline; whereas both depressed and nondepressed patients improved over time on the physical performance measure (the physical performance measure subscale of the health status questionnaire), the mean score for the depressed group was consistently lower. Conclusions The prevalence of depressive symptoms was greater than expected. Depression was persistent and had a major impact on functional capacity. Routine depression screening may be especially important in inner-city patients and other groups thought to be at increased risk for poor outcome.

Objective: The purpose of this study was to evaluate the effects of a recently implemented disease management programme [Asthma Control and Education Program (ACE)] on patient outcomes (clinical and functional) and on resource utilisation in socio-economically disadvantaged (and largely Hispanic) individuals with asthma treated at Hartford Hospital. Design and Setting: Using standardised measures (i.e. the Health Status Questionnaire [HSQ] and the Center for Epidemiologic Studies Depression Scale) and conducting serial assessments the investigators determined: 1. functional status at intake and follow-up; 2. change in the level of illness severity over time; 3. patients' acquisition of self-management skills; and 4. the type and frequency of acute care services utilised pre- and post-enrolment in ACE. Patient Population: The study participants consisted of consenting individuals, aged 18 years or older, enrolled in ACE from 1 January 1997 to 30 September 1998. Each individual had a comprehensive intake interview (data collected included clinical and financial status) followed by 3 educational sessions. Results: While only 34.7% (n = 282) of the 813 patients referred from Hartford Hospital to physicians or emergency department services elected to participate in the programme, 60% of participants completed the educational sessions. 73% of these enrollees returned for the 3-month follow-up. On the HSQ, the mean Physical Composite Summary (PCS) scores increased from 33.3 +- 10.01 at baseline to 41.6 +- 11.48 at the 3-month follow up and 45.3 +- 10.30 at the 6-month follow-up. In an analysis using only those patients (n = 50) with HSQ scores at baseline and 3- and 6-month follow-ups, there were statistically significant increases in both the PCS and the Mental Composite Summary scores (p

Disease management, a new treatment model that may improve outcomes for patients with chronic illness, emphasises the need for formal assessments often not included in traditional approaches to healthcare, such as environmental exposures, self-care skills and functional status. This article discusses the importance of these measures in designing a disease management programme for asthma and presents the results of a study of patients referred to this programme. The objectives of the programme were to determine: (i) baseline functional status; (ii) any barriers to treatment; (iii) home exposure to patient-reported asthma triggers; and (iv) patients’ self-care skills. The proportion of referred patients who actually enrolled in the programme and, among those patients, the proportion who completed the prescribed educational component and attended the scheduled follow-up visits were also calculated. The investigators developed a structured assessment battery that included standardised measures of functioning; this battery was administered by clinical and research staff at enrolment and at 3- and 6-month follow-up. The patients (n = 228) had significantly lower functioning compared with the Medical Outcomes Study general US population norms and for patients with chronic lung disease. 71% (n = 127) of patients endorsed 1 or more of the 3 items on a depression screen. 85.5% of patients completed the 3 educational sessions; 104 of 228 patients (45.6%) returned for the 6-month follow-up visit. This study contributes data about the design of disease management programmes and about asthma in inner city and minority patients, which are important topics in current research.

Many facilities in the northwest such as K--12 schools, community colleges, and military installations are implementing resource-efficiency awareness programs. These programs are generally referred to as resource efficiency manager (REM) or resource conservation manager (RCM) programs. Resource efficiency management is a systems approach to managing a facility`s energy, water, and solid waste. Its aim is to reduce utility budgets by focusing on behavioral changes, maintenance and operation procedures, resource accounting, education and training, and a comprehensive awareness campaign that involves everyone in the organization.

Despite evidence that specific therapies improve outcomes in patients with asthma, they are often not used. Combining several evidence-based therapies into a treatment "bundle" to be offered at the time of discharge from the emergency department, might reduce variation and potentially optimize clinical outcomes.To assess the utilization of four evidence-based therapies for asthma by analyzing the visits of patients with acute exacerbations of asthma discharged from the emergency department.A retrospective chart review.Single 650-bed inner-city hospital emergency department.Two hundred and twenty six patients discharged from the emergency department after 500 acute exacerbations of asthma.All visits were reviewed for the presence of the four evidence-based components of asthma treatment upon discharge: follow-up referral, oral steroids, asthma education, and inhaled corticosteroids. Visits were also assessed for medications prescribed upon discharge, medication history, and patient's asthma severity based on national guidelines.The four components of asthma treatment were documented as follows: follow-up referral (86.2%), oral steroids (67.8%), asthma education (19.6%), and inhaled corticosteroids (16.2%). Only 3.4% of visits documented all four components in the aggregate. Twenty-three distinct combinations of medication were prescribed upon discharge. The majority of visits failed to document asthma severity.This retrospective chart review reveals significant variation in the discharge management of patients with asthma, specifically regarding medications prescribed. While follow-up referral was sufficiently documented, the remaining three components were not. With only 3.4% of visits containing all four components, implementing an asthma "bundle" may present an opportunity to improve outcomes in asthma management.

The health-care systems in urban communities are facing major challenges. They are being forced to reduce costs while maintaining and improving quality. Compounding these systems issues are the inequalities in health access and barriers that persist within certain segments of the population. Hispanic Americans make up a significant and growing segment of American society; one particularly important issue for Hispanics is staying healthy. Lack of health insurance, environmental stressors, limited access to provider services, and language barrier are a few of the social inequalities that add to the difficulty in receiving health care. To reduce the inequalities and improve access to quality health care, an assessment may be necessary. An investigation into the trends in the health status, beliefs, and practices of Hispanics would be appropriate in order to address their health needs. These inquiries must go beyond having knowledge of different countries of familial origin to include knowledge of differing cultures, socioeconomic status, and experiences within the health-care system.