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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.

Nostalgia was once considered a medical disease but is now understood as a beneficial, identity-affirming emotion. Yet what induces feelings of nostalgia is not fully understood. Are nostalgic feelings prompted by changes in a person’s life, and do certain events prompt nostalgia across whole populations? In this paper, we analyze when people listen to nostalgic music. We use data from a large, cross-national survey to train a classifier to detect which tracks are nostalgic for individual listeners. We then analyze a comprehensive dataset of listening histories from a 5.5 year period. Despite it being a complex concept, we were able to predict nostalgic listening with relatively high precision. We compare our results across listeners from four countries to understand how consistent behavior toward nostalgic music is. We find people listen to nostalgic music more often as they age. We also find people tend to listen to nostalgic music consistently in their day-to-day lives. We do not find evidence that listening to personally nostalgic music increases in response to particular traditions, seasons, or events. However, we do find traditions and events can affect how much “back catalog” music people listen to. These trends are consistent across the national contexts we studied. Our results advance prior findings about nostalgia and the life course, and demonstrate a novel methodological consideration for studies of nostalgic listening.

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.

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