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Background Previous findings indicate important effects of stress, disrupted sleep, and dysregulated circadian rhythms on the progression of cancer. Our understanding of these relationships, however, has been limited by the absence of data from 24-h continuous physiologic monitoring of hormonal and immune activity with simultaneous collection of objective sleep data. The present study successfully employed such an intensive protocol among women with advanced breast cancer. Purpose In this paper we describe our protocol in detail. We provide methodological and practical suggestions for assessing sleep and circadian rhythms in the medically ill. Finally, we offer psychological and physical safety guidelines for future studies that aim to utilize similar protocols. Results We enrolled 123 women with advanced breast cancer; 18 dropped out, 105 participated (6 provided incomplete data, and 99 completed the protocol). The protocol included: (1) psychological/medical screenings and assessments; (2) a 2-week at-home sleep study, including wrist actigraphy and two nights of polysomnography (PSG); and (3) 28 h in-hospital collection of measures of hormones and immune function, in conjunction with one night of PSG for assessing sleep stages, respiration, and leg movement. Based on the implementation challenges we faced, protocol adjustments were made to address feasibility limitations and to accommodate participant preferences and medical/physiological needs. Conclusions By combining and modifying the gold standard protocols for sleep and circadian assessments, researchers can compassionately optimize participant enrollment and protocol compliance, and minimize attrition.

Eating disorders (EDs) contribute considerably to the global burden of disease. However, most affected individuals do not receive treatment. Mobile apps present an enormous opportunity to increase access to mental healthcare services. This study examined whether the degree of usage of a self-help app for EDs mediated the app's effects on the clinical response by individuals with EDs.App usage measures included the total number of cognitive-behavioral meal logs, total number of days spent using the app, and the last day the app was used during the study period. Mediation analysis was performed using the MacArthur framework.All usage variables met the analytic requirements for testing mediation (group means (sd) for app and standard app, respectively: logs = 74 (108) vs. 51.4 (88.1), days spent = 14.3 (17.5) vs. 10.6 (15.0), p-values from Wilcox rank sum tests p .01). Regression coefficients indicated mediation effects. The mediation effects demonstrated support that increased engagement (as measured by logs and time spent on the app) was related to an increased likelihood of achieving a significant clinical change by the end of the trial.Greater and longer engagement in an ED app mediates its efficacy in terms of ED remission.

BACKGROUND Posttraumatic stress disorder is an impairing mental health condition that disproportionately affects veterans. Although PTSD is treatable, there are many barriers to accessing traditional in-person care. Mobile applications may help to address unmet need for services by offering tools for users to self-manage PTSD symptoms. OBJECTIVE Renew is a mobile mental health application that focuses on exposure therapy and incorporates a social support function designed to promote user engagement. METHODS In this pilot randomized controlled trial, we compared the effects of Renew with support and without support from a research staff member (No Support) to Delayed Use among ninety-three veterans with clinically significant PTSD symptoms. Participants were recruited through online advertisements. The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) was used to measure PTSD symptoms at pre-, post (6-weeks later), and 6-week follow up. Usage data were collected to assess engagement with Renew. RESULTS Results indicated a small effect size (d = -0.39) favoring those in the two active use conditions (n = 31; n =31) relative to the Delayed Use condition (n = 31), but the between group difference did not reach statistical significance. There were no differences between those in the Support and the No Support condition on indices of app engagement or PTSD symptom reduction. Contact with support persons is a core feature of Renew, and exploratory analyses suggest that the number of support persons users added to the app, but not the number of support messages received, was positively correlated with app engagement. CONCLUSIONS Findings suggest Renew may hold promise as a self-management tool to reduce PTSD symptoms in veterans and that involving friends and family in mobile mental health applications may help bolster engagement. CLINICALTRIAL NCT04155736

Controlled Breathwork practices have emerged as tools for stress management and well-being. Here we report a remote, randomized, controlled study (NCT05304000) of three different daily five-minute Breathwork exercises in comparison to an equivalent period of Mindfulness Meditation (MM), over one month. The three breathing conditions are 1) Cyclic Sighing (CS), which emphasizes relatively prolonged exhalations, 2) Box Breathing, which is equal duration of inhalations, breath retentions and exhalations, and 3) Cyclic Hyperventilation with Retention, with longer inhalations and shorter exhalations. MM involves passive attention to breath. The primary endpoints are improvement in mood and anxiety as well as physiological arousal (respiratory rate (RR), heart rate, and heart rate variability). Breathwork produces greater improvement in mood and a significant effect of adherence on mood improvement was found using a mixed-effects model. Breathwork also results in greater reduction in RR. Among the Breathwork types, CS produces significantly more positive mood and reduction in RR than MM.Daily CS is superior to daily MM in improving mood and decreasing overall average RR.

PURPOSE Microaggressions are subtle verbal or nonverbal everyday behaviors that arise from unconscious bias, covert prejudice, or hostility. They may contribute to the persistent disparities faced by women in medicine. In this study, the authors sought to identify common microaggressions experienced by women faculty in medicine and to determine if specific demographic characteristics affect the reported frequencies of these microaggressions. METHOD The authors used chain referral sampling to collect real-life anecdotes about microaggressions from women faculty across the nation. Thirty-four unique experiences from those reported were identified and scripted then reenacted using professional actors to create 34 videos of the real-life microaggressions and 34 corresponding fictional "control" versions of the same situations. The videos, presented in a random order, were evaluated by faculty from 4 academic medical centers from 2016 to 2018. RESULTS A total of 124 faculty (79 women, 45 men) participated. Women reported higher frequencies of microaggressions than men in 33 of the 34 videos depicting microaggressions (P value range: < .001 to .042, area under the curve range: 0.60-0.69). No such differences were seen with the control videos. Women identified 21 microaggressions as occurring frequently. No significant differences were found with respect to participants' age, race/ethnicity, academic rank, or years in medicine. Post hoc analyses showed that the microaggressions fell into 6 themes: encountering sexism, encountering pregnancy- and child care-related bias, having abilities underestimated, encountering sexually inappropriate comments, being relegated to mundane tasks, and feeling excluded/marginalized. CONCLUSIONS Privilege is often invisible to those who have it, whereas bias and discrimination are readily apparent to those who experience it. Knowledge of common microaggressions will allow for targeted individual, interpersonal, and institutional solutions to mitigate disparities in medicine.

Background Currently, there are eight meta‐analyses that address the question whether psychosocial intervention can prolong survival with widely disparate conclusions. One reason for inconsistent findings may be the methods by which previous meta‐analyses were conducted. Methods Databases were searched to identify valid randomized controlled trials that compared psychosocial intervention with usual care. Hazard ratios (HRs) and their confidence intervals were pooled to estimate the strength of the treatment effect on survival time, and z‐tests were performed to assess possible heterogeneity of effect sizes associated with different patient and treatment characteristics. Results Twelve trials involving 2439 cancer patients that met screening criteria were included. The overall effect favored the treatment group with a HR of 0.71 (95% Cl 0.58‐0.88; P = 0.002). An effect size favoring treatment group was observed in studies sampling lower vs higher percentage of married patients’ (NNT = 4.3 vs NNT = 15.4), when Cognitive‐Behavioral Therapy was applied at early vs late cancer stage (NNT = 2.3 vs NNT = −28.6), and among patients’ older vs younger than 50 (NNT = 4.2 vs NNT = −20.5). Conclusions Psychosocial interventions may have an important effect on survival. Reviewed interventions appear to be more effective in unmarried patients, patients who are older, and those with an early cancer stage who attend CBT. Limitations of previous meta‐analysis are discussed.

Background: Little is known about the extent of alignment between hematopoietic stem cell transplant (HSCT) patients and their healthcare proxies with respect to advance care planning (ACP). Aim: To determine if a structured three-step process using the letter advance directive (LAD) could (1) allow for the differences in opinion between patient–proxy dyads to surface and (2) help bridge preexisting discordance about specific treatment choices. Design: Blinded to each other, the HSCT patient (LAD-1) and proxy (LAD-2) each completed the LAD (step 1). They unmasked, compared LAD-1 and LAD-2, and discussed their choices (step 2). They completed a final letter directive (LAD-3) by consensus (step 3). Settings/Participants: Convenience sample of eighty dyads (patient and proxy) at a regional HSCT referral center. Results: The mean patient–proxy concordance was 72.9% for the 12 questions in the LAD. Wanting to be pain free at the end of life was the statement with the most amount of agreement (88.75% in LAD-1, 91.25% in LAD-2, and 90% in LAD-3). Patient–proxy dyads had notable discordance related to specific treatments. The highest discordance was related to ventilator support (46.3% of patients refused it, while 58.8% of proxies refused on behalf of the patient). Overall, proxies were more likely than patients to opt in for dialyses and hospice care but more likely to opt out for cardiac resuscitation and sedation to palliate refractory symptoms. On open discussion, patient–proxy discordance mostly resolved in favor of the patient. Conclusions: The ACP process should allow for patient–proxy differences to surface, facilitate a discussion about the granular details with the goal of reaching consensus. Our three-step approach using the LAD is an effective way to identify areas of patient–proxy concordance and discordance about specific treatment preferences. A structured patient–proxy discussion using the LAD helped reconcile discordance and most often in favor of a patient's original wishes.

Deceptive practices by participants in clinical research are prevalent. It has been shown that as high as seventy-five percent of participants withheld information to avoid exclusion from studies. Self-reported adherence has been found to be largely inaccurate. Overcoming deception is a critical issue, since the safety of study participants, the integrity of research data and research resources are at risk. In this review article, we examine deception from the perspective of investigators conducting clinical trials; we describe the types (concealment, fabrication, drug holidays and collusion), prevalence, risks, and predictors of deception, and propose an approach to reduce the impact of deception, especially on adherence, in clinical trials.

Objective Smartphone applications (apps) for eating disorders are a promising approach to assist individuals who do not receive traditional treatment. This study examines usage characteristics, perceptions regarding the acceptability of a new self-help intervention developed for users with eating disorders, and associations between attitudes and use patterns. Methods 189 individuals pilot-tested a personalized app-based program, and 133 completed the required components of the pilot-test over an 8-day period. Of these, 64 individuals (49%) completed an exit survey pertaining to acceptability. Results Seventy percent of those who pilot-tested the app-based program completed the required components, i.e. a baseline review and then a 1-week assessment. Body mass index was associated with the total number of recorded meal logs. Study participants rated the app as highly suitable and acceptable, providing evidence of the feasibility and appropriateness of the program. Conclusion The app-based program demonstrated feasibility of deploying the app across user groups and high acceptability.

PURPOSE: This study tested a theory linking a marker of low serotonergic function to both depression and impulsivity in a sample of advanced breast cancer patients, among whom elevated depressive symptoms and difficulty regulating emotions are commonly reported. METHODS: A total of 95 patients provided blood samples for serotonin transporter polymorphic region of the gene (5-HTTLPR) and completed questionnaires that measured depressive symptoms and emotional impulsivity. RESULTS: Structural equation modeling revealed that the s allele of 5-HTTLPR was related to greater depressive symptoms (β = .20, p < .042) but only marginally to greater emotional impulsivity (β = .19, p < .068). Depressive symptoms and emotional impulsivity were positively related (β = .33, p < .003). Further tests explored possible mediation from genotype to one psychological variable via the other. Results suggest that depressive symptoms, particularly perceived interpersonal rejection, may be a pathway linking genotype to emotional impulsivity. CONCLUSIONS: Findings provide the first evidence that low serotonergic function contributes to both depression and impulsivity within a clinically meaningful sample. Furthermore, the link of s allele of 5-HTTLPR to emotional impulsivity was mediated by depressive symptoms, particularly perceptions of social rejection. Findings have implications for advanced breast cancer patients’ treatment decision.

Background Eating disorders severely impact psychological, physical, and social functioning, and yet, the majority of individuals with eating disorders do not receive treatment. Mobile health apps have the potential to decrease access barriers to care and reach individuals who have been underserved by traditional treatment modalities. Objective The objective of this study was to evaluate the effectiveness of a tailored, fully automated self-help version of Recovery Record, an app developed for eating disorders management. We examined differences in eastin disorder symptom change in app users that were randomized to receive either a standard, cognitive behavioral therapy–based version of the app or a tailored version that included algorithmically determined clinical content aligned with baseline and evolving user eating disorder symptom profiles. Methods Participants were people with eating disorder symptoms who did not have access to traditional treatment options and were recruited via the open-access Recovery Record app to participate in this randomized controlled trial. We examined both continuous and categorical clinical improvement outcomes (measured with the self-report Eating Disorder Examination Questionnaire [EDE-Q]) in both intervention groups. Results Between December 2016 and August 2018, 3294 Recovery Record app users were recruited into the study, out of which 959 were considered engaged, completed follow-up assessments, and were included in the analyses. Both study groups achieved significant overall outcome improvement, with 61.6% (180/292) of the tailored group and 55.4% (158/285) of the standard group achieving a clinically meaningful change in the EDE-Q, on average. There were no statistically significant differences between randomized groups for continuous outcomes, but a pattern of improvement being greater in the tailored group was evident. The rate of remission on the EDE-Q at 8 weeks was significantly greater in the group receiving the tailored version (d=0.22; P≤.001). Conclusions This is the first report to compare the relative efficacy of two versions of a mobile app for eating disorders. The data suggest that underserved individuals with eating disorder symptoms may benefit clinically from a self-help app and that personalizing app content to specific clinical presentations may be more effective in promoting symptomatic remission on the EDE-Q than content that offers a generic approach. Trial Registration ClinicalTrials.gov NCT02503098; https://clinicaltrials.gov/ct2/show/NCT02503098.

The most pervasive and damaging myth in clinical research is that the smaller the p-value, the stronger the hypothesis. In reality, the p-value primarily reflects the quality of research design decisions. The most common proposal to avoid misleading conclusions from clinical research requires the appropriate use of effect sizes, but which effect size, used when and how, is an open question. A solution is proposed for perhaps the most common problem in clinical research, the comparison between two populations, for example, comparison of two treatments in a randomized clinical trial or comparison of high risk versus low risk individuals in an epidemiological study: the success rate difference or equivalently the number needed to treat/take (NNT).

BACKGROUND Eating disorders severely impact psychological, physical, and social functioning, and yet, the majority of individuals with eating disorders do not receive treatment. Mobile health apps have the potential to decrease access barriers to care and reach individuals who have been underserved by traditional treatment modalities. OBJECTIVE The objective of this study was to evaluate the effectiveness of a tailored, fully automated self-help version of Recovery Record, an app developed for eating disorders management. We examined differences in eastin disorder symptom change in app users that were randomized to receive either a standard, cognitive behavioral therapy–based version of the app or a tailored version that included algorithmically determined clinical content aligned with baseline and evolving user eating disorder symptom profiles. METHODS Participants were people with eating disorder symptoms who did not have access to traditional treatment options and were recruited via the open-access Recovery Record app to participate in this randomized controlled trial. We examined both continuous and categorical clinical improvement outcomes (measured with the self-report Eating Disorder Examination Questionnaire [EDE-Q]) in both intervention groups. RESULTS Between December 2016 and August 2018, 3294 Recovery Record app users were recruited into the study, out of which 959 were considered engaged, completed follow-up assessments, and were included in the analyses. Both study groups achieved significant overall outcome improvement, with 61.6% (180/292) of the tailored group and 55.4% (158/285) of the standard group achieving a clinically meaningful change in the EDE-Q, on average. There were no statistically significant differences between randomized groups for continuous outcomes, but a pattern of improvement being greater in the tailored group was evident. The rate of remission on the EDE-Q at 8 weeks was significantly greater in the group receiving the tailored version (d=0.22; P≤.001). CONCLUSIONS This is the first report to compare the relative efficacy of two versions of a mobile app for eating disorders. The data suggest that underserved individuals with eating disorder symptoms may benefit clinically from a self-help app and that personalizing app content to specific clinical presentations may be more effective in promoting symptomatic remission on the EDE-Q than content that offers a generic approach. CLINICALTRIAL ClinicalTrials.gov NCT02503098; https://clinicaltrials.gov/ct2/show/NCT02503098.

As aid-in-dying laws are gaining more public acceptance and support, it is important to understand diverse perceptions toward physician-assisted death (PAD). We compare attitudes of residents from California and Hawaii to identify variables that may predict attitudes toward PAD.A cross-sectional online survey of 1095 participants (a 75.8% survey completion rate) from California and 819 from Hawaii (a 78.4% survey completion rate). Data were collected between July through October 2015.Majority of study participants in California (72.5%) and Hawaii (76.5%) were supportive of PAD. Only 36.8% of participants in Hawaii and 34.8% of participants in California reported completing advance directives. To better understand which subgroups were most in favor of PAD, data were analyzed using both recursive partitioning and stepwise logistic regression. Older participants were more supportive of PAD in both states. Also, all ethnic groups were equally supportive of PAD. Completion of advance directives was not a significant predictor of attitudes toward PAD. Persons who reported that faith/religion/spirituality was less important to them were more likely to support PAD in both states. Thus, the major influences on the attitudes to PAD were religious/spiritual views and age, not ethnicity and gender. Even in the subgroups least supportive of PAD, the majority supported PAD.This study shows that in the ethnically diverse states of California and Hawaii, faith/religion/spirituality and age are major influencers of attitudes toward PAD and not ethnicity and gender. Even in the subgroups least supportive of PAD, the majority supports PAD.

The study objective was to empirically identify barriers reported by multiethnic patients and families in receiving high-quality end-of-life care (EOLC).This cross-sectional, mixed-methods study in Burmese, English, Hindi, Mandarin, Tagalog, Spanish, and Vietnamese was held in multiethnic community centers in five California cities. Data were collected in 2013-2014. A snowball sampling technique was used to accrue 387 participants-261 women, 126 men, 133 Caucasian, 204 Asian Americans, 44 African Americans, and 6 Hispanic Americans. Measured were multiethnic patient-reported barriers to high-quality EOLC. A development cohort (72 participants) of responses was analyzed qualitatively using grounded theory to identify the six key barriers to high-quality EOLC. A new validation cohort (315 participants) of responses was transcribed, translated, and back-translated for verification. The codes were validated by analyses of responses from 50 randomly drawn subjects from the validation cohort. All the 315 validation cohort transcripts were coded for presence or absence of the six barriers.In the validation cohort, 60.6% reported barriers to receiving high-quality EOLC for persons in their culture/ethnicity. Primary patient-reported barriers were (1) finance/health insurance barriers, (2) doctor behaviors, (3) communication chasm between doctors and patients, (4) family beliefs/behaviors, (5) health system barriers, and (6) cultural/religious barriers. Age (χ(2) = 9.15, DF = 1, p = 0.003); gender (χ(2) = 6.605, DF = 1, p = 0.01); and marital status (χ(2) = 16.11 DF = 3, p = 0.001) were associated with reporting barriers; and women80 years were most likely to report barriers to receiving high-quality EOLC. Individual responses of reported barriers were analyzed and only the participant's level of education (Friedman statistic = 2.16, DF = 10, p = 0.02) significantly influenced choices.Multiethnic patients report that high-quality EOLC is important to them; but unfortunately, a majority state that they have encountered barriers to receiving such care. Efforts must be made to rapidly improve access to culturally competent EOLC for diverse populations.

Background: To provide preference-sensitive care, we propose that clinicians might routinely inquire about their patients' bucket-lists and discuss the impact (if any) of their medical treatments on their life goals. Methods: This cross-sectional, mixed methods online study explores the concept of the bucket list and seeks to identify common bucket list themes. Data were collected in 2015–2016 through an online survey, which was completed by a total of 3056 participants across the United States. Forty participants who had a bucket list were identified randomly and used as the development cohort: their responses were analyzed qualitatively using grounded theory methods to identify the six key bucket list themes. The responses of the remaining 3016 participants were used for the validation study. The codes identified from the development cohort were validated by analyses of responses from 50 randomly drawn subjects from the validation cohort. All the 3016 validation cohort transcripts were coded for presence or absence of each of the six bucket list themes. Results: Around 91.2% participants had a bucket list. Age and spirituality influence the patient's bucket-list. Participants who reported that faith/religion/spirituality was important to them were most likely (95%) to have a bucket list compared with those who reported it to be unimportant (68.2%), χ(2) = 37.67. Six primary themes identified were the desire to travel (78.5%), desire to accomplish a personal goal (78.3%), desire to achieve specific life milestones (51%), desire to spend quality time with friends and family (16.7%), desire to achieve financial stability (24.3%), and desire to do a daring activity (15%). Conclusions: The bucket list is a simple framework that can be used to engage patients about their healthcare decision making. Knowing a patient's bucket list can aid clinicians in relating each treatment option to its potential impact (if any) on the patient's life and life goals to promote informed decision making.

Aims: The prevalence of alcohol use disorders (AUDs) among hospitalized medically ill patients exceeds 40%. Most AUD patients experience uncomplicated alcohol withdrawal syndrome (AWS), requiring only supportive medical intervention, while complicated AWS occurs in up to 20% of cases (i.e. seizures, delirium tremens). We aimed to prospectively test and validate the Prediction of Alcohol Withdrawal Severity Scale (PAWSS), a new tool to identify patients at risk for developing complicated AWS, in medically ill hospitalized patients. Methods: We prospectively considered all subjects hospitalized to selected general medicine and surgery units over a 12-month period. Participants were assessed independently and blindly on a daily basis with PAWSS, Clinical Institute Withdrawal Assessment—Alcohol, Revised (CIWA-Ar) and clinical monitoring throughout their admission to determine the presence and severity of AWS. Results: Four hundred and three patients were enrolled in the study. Patients were grouped by PAWSS score: Group A (PAWSS < 4; considered at low risk for complicated AWS); Group B (PAWSS ≥ 4; considered at high risk for complicated AWS). The results of this study suggest that, using a PAWSS cutoff of 4, the tool’s sensitivity for identifying complicated AWS is 93.1% (95%CI[77.2, 99.2%]), specificity is 99.5% (95%CI[98.1, 99.9%]), positive predictive value is 93.1% and negative predictive value is 99.5%; and has excellent inter-rater reliability with Lin’s concordance coefficient of 0.963 (95% CI [0.936, 0.979]). Conclusion: PAWSS has excellent psychometric characteristics and predictive value among medically ill hospitalized patients, helping clinicians identify those at risk for complicated AWS and allowing for prevention and timely treatment of complicated AWS.

Although mobile technologies for eating disorders (EDs) are burgeoning, there is limited data about the clinical characteristics of individuals using specialized smartphone applications (apps) without accompanying traditional forms of treatment. This study evaluated whether the users of an ED app cluster in clinically meaningful groups. Participants were 1,280 app users (91.3% female; mean age 27) who reported not being in a weekly treatment for their ED. A hierarchical cluster analysis distinguished five groups of participants, all approximating DSM-5 ED categories. One cluster comprised of non-female, ethnically diverse users with Bulimia Nervosa features. Findings suggest that app users resemble known patient classifications.

BACKGROUND Several empirical investigations have attempted to characterize the effect of physical activity on cancer mortality, but these investigations have rarely focused on patients with advanced breast cancer. OBJECTIVE The current study examined the hypothesis that greater physical activity is associated with longer survival among women with advanced breast cancer. METHODS We conducted a secondary data analysis of a prospective study of 103 patients with stage IV (n = 100) or locally recurrent (n = 3) breast cancer involved in a group psychotherapy trial. Physical activity was assessed at baseline using the Seven-Day Physical Activity Recall questionnaire, and patients were followed until April 1, 2016, at which time 93 of 103 had died. RESULTS Greater physical activity level at baseline was significantly associated with longer subsequent survival time in a Cox proportional hazards model (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.84-0.97; P < .01). Engaging in 1 additional hour per day of moderate activity reduced the hazard of subsequent mortality by 23% (HR, 0.77; 95% CI, 0.65-0.92; P < .01). These results remained significant even after controlling for demographic, medical, cancer, depression, and cortisol variables (HR, 0.91; 95% CI, 0.84-0.99; P < .05). CONCLUSIONS Women with advanced breast cancer who engaged in physical activity for 1 or more hours per day at baseline had an increased likelihood of survival compared with those who exercised less than 1 hour per day. IMPLICATIONS FOR PRACTICE Nurses should consider recommending moderate physical activity for women with advanced breast cancer. Randomized trials of physical activity interventions for this population are needed.

Simpler alternatives to traditional advance directives that are easy to understand and available in multiple formats and can be initiated by patients and families will help facilitate advance care planning. The goal of this study was to compare the acceptability of the letter advance directive (LAD) to the traditional advance directive (TAD) of the state of California.A web-based, randomized controlled trial was conducted, in which the participants were randomized to one of two types of advance directives (ADs): the LAD (intervention) or the TAD (control). Primary outcomes were participant ratings of the ease, value, and their level of comfort in the AD document they completed.A total of 400 participants completed the study, with 216 randomized to the LAD and 184 to the TAD by a computerized algorithm. Overall, participants preferred the LAD to the TAD (success rate difference [SRD] = 0.46, 95th percentile confidence interval [CI]: 0.36-0.56, p 0.001). The participants felt that, compared to the TAD, the LAD was easier to read and understand (SRD = 0.56, CI: 0.47-0.65, p 0.001); better reflected what matters most to them (SRD = 0.39, CI: 0.29-0.48, p 0.001); helped stimulate their thinking about the types of treatments they wanted at the end of life (SRD = 0.32, CI: 0.23-0.42, p 0.001); allowed them to describe how they made medical decisions in their family (SRD = 0.31, CI: 0.21-0.40, p 0.001); and could help their doctor(s) (SRD = 0.24, CI: 0.13-0.34, p 0.001) and their families (SRD = 0.19, CI: 0.08-0.28, p 0.001) understand their end-of-life treatment preferences.Patients reported the letter advance directive to be a better alternative to the traditional advance directive form.

Sleep disturbance is prevalent among women with metastatic breast cancer (MBC). Our study examined the relationship of depression and marital status to sleep assessed over three nights of polysomnography (PSG).Women with MBC (N=103) were recruited; they were predominately white (88.2%) and 57.8±7.7 years of age. Linear regression analyses assessed relationships among depression, marital status, and sleep parameters.Women with MBC who reported more depressive symptoms had lighter sleep (e.g., stage 1 sleep; P.05), less slow-wave sleep (SWS) (P.05), and less rapid eye movement (REM) sleep (P.05). Single women had less total sleep time (TST) (P.01), more wake after sleep onset (WASO) (P.05), worse sleep efficiency (SE) (P.05), lighter sleep (e.g., stage 1; P.05), and less REM sleep (P.05) than married women. Significant interactions indicated that depressed and single women had worse sleep quality than partnered women or those who were not depressed.Women with MBC and greater symptoms of depression had increased light sleep and reduced SWS and REM sleep, and single women had worse sleep quality and greater light sleep than married counterparts. Marriage was related to improved sleep for women with more depressive symptoms.

While a relationship between disruption of circadian rhythms and the progression of cancer has been hypothesized in field and epidemiologic studies, it has never been unequivocally demonstrated. We determined the circadian rhythm of cortisol and sleep in women with advanced breast cancer (ABC) under the conditions necessary to allow for the precise measurement of these variables. Women with ABC (n = 97) and age-matched controls (n = 24) took part in a 24-h intensive physiological monitoring study involving polysomnographic sleep measures and high-density plasma sampling. Sleep was scored using both standard clinical metrics and power spectral analysis. Three-harmonic regression analysis and functional data analysis were used to assess the 24-h and sleep-associated patterns of plasma cortisol, respectively. The circadian pattern of plasma cortisol as described by its timing, timing relative to sleep, or amplitude was indistinguishable between women with ABC and age-matched controls (p's > 0.11, t-tests). There was, however, an aberrant spike of cortisol during the sleep of a subset of women, during which there was an eightfold increase in the amount of objectively measured wake time (p

Clinicians working with cancer patients listen to them, observe their behavior, and monitor their physiology. How do we proceed when these indicators do not align? Under self-relevant stress, non-cancer repressors respond with high arousal but report low anxiety; the high-anxious report high anxiety but often have lower arousal. This study extends discrepancy research on repressors and the high-anxious to a metastatic breast cancer sample and examines physician rating of coping. Before and during a Trier Social Stress Test (TSST), we assessed affect, autonomic reactivity, and observers coded emotional expression from TSST videotapes. We compared non-extreme (N = 40), low-anxious (N = 16), high-anxious (N = 19), and repressors (N = 19). Despite reported low anxiety, repressors expressed significantly greater Tension or anxiety cues. Despite reported high anxiety, the high-anxious expressed significantly greater Hostile Affect rather than Tension. Physicians rated both groups as coping significantly better than others. Future research might productively study physician-patient interaction in these groups.

Summary Background The surveillance and effector functions of the immune system are critically dependent on the appropriate distribution of immune cells in the body. An acute or short-term stress response induces a rapid and significant redistribution of immune cells among different body compartments. Stress-induced leukocyte redistribution may be a fundamental survival response that directs leukocyte subpopulations to specific target organs during stress, and significantly enhances the speed, efficacy and regulation of an immune response. Immune responses are generally enhanced in compartments (e.g., skin) that are enriched with leukocytes, and suppressed in compartments that are depleted of leukocytes during/following stress. The experiments described here were designed to elucidate the: (1) Time-course, trajectory, and subpopulation-specificity of stress-induced mobilization and trafficking of blood leukocytes. (2) Individual and combined actions of the principal stress hormones, norepinephrine (NE), epinephrine (EPI), and corticosterone (CORT), in mediating mobilization or trafficking of specific leukocyte subpopulations. (3) Effects of stress/stress hormones on adhesion molecule, L -selectin (CD62L), expression by each subpopulation to assess its adhesion/functional/maturation status. Methods Male Sprague Dawley rats were stressed (short-term restraint, 2–120 min), or adrenalectomized and injected with vehicle (VEH), NE, EPI, CORT, or their combinations, and blood was collected for measurement of hormones and flow cytometric quantification of leukocyte subpopulations. Results Acute stress induced an early increase/mobilization of neutrophils, lymphocytes, helper T cells (Th), cytolytic T cells (CTL), and B cells into the blood, followed by a decrease/trafficking of all cell types out of the blood, except neutrophil numbers that continued to increase. CD62L expression was increased on neutrophils, decreased on Th, CTL, and natural killer (NK) cells, and showed a biphasic decrease on monocytes & B cells, suggesting that CD62L is involved in mediating the redistribution effects of stress. Additionally, we observed significant differences in the direction, magnitude, and subpopulation specificity of the effects of each hormone: NE increased leukocyte numbers, most notably CD62L−/+ neutrophils and CD62L− B cells. EPI increased monocyte and neutrophil numbers, most notably CD62L−/+ neutrophils and CD62L− monocytes, but decreased lymphocyte numbers with CD62L−/+ CTL and CD62L+ B cells being especially sensitive. CORT decreased monocyte, lymphocyte, Th, CTL, and B cell numbers with CD62L− and CD62L+ cells being equally affected. Thus, naive (CD62L+) vs. memory (CD62L−) T cells, classical (CD62L+) vs. non-classical (CD62L−) monocytes, and similarly distinct functional subsets of other leukocyte populations are differentially mobilized into the blood and trafficked to tissues by stress hormones. Conclusion Stress hormones orchestrate a large-scale redistribution of immune cells in the body. NE and EPI mobilize immune cells into the bloodstream, and EPI and CORT induce traffic out of the blood possibly to tissue surveillance pathways, lymphoid tissues, and sites of ongoing or de novo immune activation. Immune cell subpopulations appear to show differential sensitivities and redistribution responses to each hormone depending on the type of leukocyte (neutrophil, monocyte or lymphocyte) and its maturation/functional characteristics (e.g., non-classical/resident or classical/inflammatory monocyte, naive or central/effector memory T cell). Thus, stress hormones could be administered simultaneously or sequentially to induce specific leukocyte subpopulations to be mobilized into the blood, or to traffic from blood to tissues. Stress- or stress hormone-mediated changes in immune cell distribution could be clinically harnessed to: (1) Direct leukocytes to sites of vaccination, wound healing, infection, or cancer and thereby enhance protective immunity. (2) Reduce leukocyte traffic to sites of inflammatory/autoimmune reactions. (3) Sequester immune cells in relatively protected compartments to minimize exposure to cytotoxic treatments like radiation or localized chemotherapy. (4) Measure biological resistance/sensitivity to stress hormones in vivo. In keeping with the guidelines for Richter Award manuscripts, in addition to original data we also present a model and synthesis of findings in the context of the literature on the effects of short-term stress on immune cell distribution and function.

To determine if improvement in mood would ameliorate autonomic dysregulation, HPA dysfunction, and typical risk factors and C-reactive protein in depressed patients with elevated cardiovascular disease risk (CVD), 48 depressed participants with elevated cardiovascular risk factors were randomized to a cognitive behavioral intervention (CBT) or a waiting list control (WLC) condition. Twenty non-depressed age and risk-matched controls were also recruited. Traditional risk factors (e.g., lipids, blood pressure) and C-reactive protein were assessed pre- and post-treatment six months later. Subjects also underwent a psychophysiological stress test while cardiovascular physiology was measured. Salivary cortisol was measured during the day and during the psychological stress test. At post-treatment, the CBT subjects were significantly less depressed than WLC subjects. There was no significant difference in change scores on any of the traditional risk factors or C-reactive protein, cortisol measures, or cardiovascular physiology, except for triglyceride levels and heart rate, which were significantly lower in treatment compared to control subjects. The normal controls exhibited no change in the variables measured during the same time. A significant improvement in mood may have little impact on most traditional or atypical risk factors, cortisol or cardiophysiology.

This study assessed whether high hypnotizability is associated with posttraumatic stress and depressive symptoms in a sample of 124 metastatic breast cancer patients. Hypnotic Induction Profile Scores were dichotomized into low and high categories; posttraumatic intrusion and avoidance symptoms were measured with the Impact of Events Scale (IES); hyperarousal symptoms with items from the Profile of Mood States; and depressive symptoms with the Center for Epidemiologic Studies–Depression Scale. High hypnotizability was significantly related to greater IES total, IES intrusion symptoms, and depressive symptoms. A logistic regression model showed that IES total predicts high hypnotizability after adjusting for depressive symptoms and hyperarousal. The authors relate these results to findings in other clinical populations and discuss implications for the psychosocial treatment of metastatic breast cancer.

This study evaluated the effectiveness of group psychotherapy in reducing levels of shame and guilt in adult survivors of childhood sexual abuse at risk for HIV, and whether such reductions would mediate the effects of treatment on posttraumatic stress disorder (PTSD) symptoms. One hundred sixty-six women were randomized into 3 conditions: a trauma-focused group, a present-focused group, and a waitlist group. Women received 6 months of treatment and were assessed at pretreatment (T1), immediately posttreatment (T2), and 6 months posttreatment (T3). Both treatment conditions resulted in reduced shame and guilt. The treatment effect on PTSD symptoms was mediated by changes in shame, but it was not associated with changes in guilt. These findings suggest that, when treating childhood sexual abuse survivors' PTSD, it is important to address the negative self-appraisals, such as shame, that commonly accompany such symptoms.

This study examined the effect of a cognitive behavior therapy (CBT) therapy intervention designed to reduce depression in older patients with elevated cardiovascular disease (CVD) risk. Forty-eight depressed patients with elevated CVD were randomized to a 16-week individual CBT intervention (n = 23) or a wait-list control (WLC) group (n = 25). Pre- and post-treatment measures of depression were obtained during office visits, and measures of positive and negative affect were obtained during laboratory psychological stress testing and at five points during the day. At post-treatment, the CBT subjects were significantly less depressed than WLC subjects on the Hamilton Depression Inventory (F = 52.8, P

BACKGROUND Psychosocial factors may significantly affect post-transplant outcomes. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) was developed as an assessment tool to enhance the pre-transplant psychosocial evaluation. METHODS We identified heart, lung, liver, or kidney transplant recipients assessed with the SIPAT pre-transplantation and transplanted between June 1, 2008, and July 31, 2011, at our institution. We analyzed prospectively accumulated psychosocial and medical outcomes at 1 year of follow-up. RESULTS 217 patients were identified and included in the analysis. The primary outcomes of organ failure and mortality occurred in 12 and 21 patients, respectively, and were not significantly associated with the pre-transplant SIPAT scores. On the other hand, SIPAT scores were significantly correlated with the probability of poor medical and psychosocial outcomes (secondary outcomes). In fact, higher SIPAT scores predicted higher rates of rejection episodes (Spearman ρ = 0.15, 95% 95% confidence interval [CI] = 0.02-0.28, p = .023), medical hospitalizations (ρ = 0.29, 95% CI = 0.16-0.41, p < .001), infection rates (p = .020), psychiatric decompensation (p = .005), and support system failure (area under the curve = 0.70, 95% CI = 0.60-0.79, p < .001). The relationship with nonadherence suggested a trend, but no statistical significance was observed (area under the curve = 0.60, 95% CI = 0.50-0.71, p = .058). CONCLUSIONS Study outcomes suggest that SIPAT is a promising pre-transplantation assessment tool that helps identify candidate's areas of psychosocial vulnerability and whose scores are associated with both psychosocial and medical outcomes after transplantation.

High levels of high-frequency heart rate variability (HF-HRV), related to parasympathetic-nervous-system functioning, have been associated with longer survival in patients with myocardial infarction and acute trauma and in patients undergoing palliative care. From animal studies linking higher vagal activity with better immune system functioning and reduced metastases, we hypothesized that higher HF-HRV would predict longer survival in patients with metastatic or recurrent breast cancer (MRBC).Eighty-seven patients with MRBC participated in a laboratory task including a 5-minute resting baseline electrocardiogram. HF-HRV was computed as the natural logarithm of the summed power spectral density of R-R intervals (0.15-0.50 Hz). In this secondary analysis of a study testing whether diurnal cortisol slope predicted survival, we tested the association between resting baseline HF-HRV on survival using Cox proportional hazards models.A total of 50 patients died during a median follow-up of 7.99 years. Higher baseline HF-HRV predicted significantly longer survival, with a hazard ratio of 0.75 (95% confidence interval = 0.60-0.92, p = .006). Visceral metastasis status and baseline heart rate were related to both HF-HRV and survival. However, a combination of HF-HRV and heart rate further improved survival prediction, with a hazard ratio of 0.64 (95% confidence interval = 0.48-0.85, p = .002).Vagal activity of patients with MRBC strongly predicted their survival, extending the known predictive window of HF-HRV in cancer beyond palliative care. Vagal activity can be altered by behavioral, pharmacological, and surgical interventions and may be a promising target for extending life expectancy in patients with metastasizing cancer.

Natural killer (NK) cells are a class of lymphocytes important in immune resistance to viral and other serious diseases. The cytotoxic function, or ‘killing activity’ of NK cells has become important in studies of the effects of stress and other psychosocial factors on physical health. Unfortunately, research on NK cell function has been plagued by discrepancies in the methods of interpreting NK cytotoxicity data. We briefly review some of the variations in measuring NK cell activity and present a new model for interpreting these results, introducing maximal target cell lysis (A) and the slope of the cytolytic curve (k) as parameters that attempt to make full use of the information and the statistical power in NK cell cytotoxicity data. Examples of these interpretation methods are presented using NK cytotoxicity data from a group of metastatic breast cancer patients. This approach will be useful in applications of NK cell measurement in psychoneuroimmunology research. Copyright © 2006 John Wiley & Sons, Ltd.

As medical care for cancer has become more specialized in diagnosis, treatment has become more technical and fragmented. In order to help cancer patients and their families, we developed a coordinated program called the Stanford Cancer Supportive Care Program (SCSCP) at the Center for Integrative Medicine at Stanford Hospital and Clinics. The Stanford Cancer Supportive Care Program was initiated in 1999 to provide support for cancer patients, addressing the need for improved physical and emotional well-being and quality of life. This paper is a program evaluation report. The number of patient visits grew from 421 in 1999 to 6319 in 2002. This paper describes the utilization of the SCSCP program as assessed by 398 patient visit evaluations during a 9-week period, January 2002 to March 2002. During this time we collected attendance records with demographic data and anonymous questionnaires evaluating each program. Patients were asked to evaluate how the program helped them regarding increase of energy, reduction in stress, restful sleep, pain reduction, sense of hopefulness, and empowerment. Over 90% of the patients using the SCSCP felt there was benefit to the program. Programs were chosen based on a needs assessment by oncologists, nurse managers, social workers, and patients. Massage, yoga, and qigong classes had the highest number of participants. Qualitative data showed benefit for each program offered. This evaluation of a free cancer supportive care program initiated in a hospital outpatient setting provides initial evidence of patient satisfaction and improvement in quality of life.

The contribution of social support and social networks to risk of neural tube defects (NTDs) has not been explored, despite evidence that various aspects of the social environment contribute to their etiology. Using data from a population-based case-control study of deliveries occurring in California from 1989 to 1991, this study investigates whether social networks, as measured by the presence and frequency of various types of social contacts, are associated with NTD risk. In-person interviews were conducted with 538 (88% of eligible) mothers of NTD cases and with mothers of 539 non-malformed controls (88%) on average 5 months from the term delivery date. Unadjusted results indicate that women who reported having close friends, close relatives, or monthly contacts with close friends or relatives had 30-70% lower risks of having NTD-affected pregnancies, relative to women reporting 'none' to any of these measures. Only the presence of close friends was associated with reduced NTD risk after adjustment for other aspects of the social network and several potential covariates. This study is the first to investigate the association between social networks and risk of NTDs. Stronger inferences await replication and extension of these results.

Women who consume folic acid in early pregnancy reduced their risks for delivering offspring with neural tube defects (NTDs). The underlying process by which folic acid facilitated this risk reduction is unknown. Investigating genetic variation that influences cellular absorption, transport, and metabolism of folate will help fill this data gap. We focused our studies on a candidate gene that is involved in folate transport, the reduced folate carrier 1 (RFC1). Using data from a California population–based case control interview study (1989–1991 birth cohorts), we investigated whether spina bifida risk was influenced by an interaction between a polymorphism of infant RFC1 at nucleotide 80 (A80G) and maternal periconceptional use of vitamins containing folic acid. Allelic variants of RFC1 were determined by genotyping 133 live-born spina bifida case infants and 188 control infants. The percentages of case infants with the A80/A80, G80/G80, and G80/A80 genotypes were 27.2%, 28.0%, and 44.7%, respectively. The percentages of control infants were similar: 26.1%, 29.3%, and 44.7%. Odds ratios of 1.0 (95% confidence interval 0.5–2.0) for the G80/G80 genotype and 1.1 (0.6–2.0) for the G80/A80 genotype were observed relative to the A80/A80 genotype. Among mothers who did not use vitamins, spina bifida risk was 2.4 (0.8–6.9) for infants with genotype G80/G80 compared to those with A80/A80 genotype. Among mothers who did use vitamins, the risk was 0.5 (0.1–3.1) for infants with the G80/G80 genotype. Although this study did not find an increased spina bifida risk for infants who were heterozygous or homozygous for RFC1 A80G, it did reveal modest evidence for a gene-nutrient interaction between infant homozygosity for the RFC1 G80/G80 genotype and maternal periconceptional intake of vitamins containing folic acid on the risk of spina bifida. © 2002 Wiley-Liss, Inc.

Objective: Owing to its association with known risk factors for neural tube defects (NTDs) and its impact on physiologic processes relevant to fetal development, physical activity was identified as a potential risk factor for NTD-affected pregnancy. Methods: Using data from a population-based case-control study of deliveries occurring in California from 1989 to 1991, we estimated the potential risk of having an NTD-affected pregnancy associated with variation in maternal physical activity. In-person interviews were conducted with 538 (88% of eligible) mothers of NTD cases and with mothers of 539 (88%) nonmalformed controls on average 5 months from the term delivery date. An index reflecting reported frequency and exertion level for six activity groups (e.g., jogging and running) was used to summarize each woman's physical activity level in the periconceptional period. Results: Unadjusted analyses indicated that compared to women considered inactive by this index, physically active women had 30–50% lower risk for NTD-affected pregnancies. After adjustment for several potential confounders and an evaluation of potential effect modification, results suggested that the association was restricted to women who did not take multivitamin/mineral supplements during the periconceptional period. Excluding mothers with reported medical problems did not substantially alter findings. Conclusions: This study suggests that the benefits of physical activity may extend to reduction of NTD risk among certain subgroups of women.

Objective Though most patients wish to discuss end-of-life (EOL) issues, doctors are reluctant to conduct end-of-life conversations. Little is known about the barriers doctors face in conducting effective EOL conversations with diverse patients. This mixed methods study was undertaken to empirically identify barriers faced by doctors (if any) in conducting effective EOL conversations with diverse patients and to determine if the doctors’ age, gender, ethnicity and medical sub-specialty influenced the barriers reported. Design Mixed-methods study of multi-specialty doctors caring for diverse, seriously ill patients in two large academic medical centers at the end of the training; data were collected from 2010 to 2012. Outcomes Doctor-reported barriers to EOL conversations with diverse patients. Results 1040 of 1234 potential subjects (84.3%) participated. 29 participants were designated as the development cohort for coding and grounded theory analyses to identify primary barriers. The codes were validated by analyses of responses from 50 randomly drawn subjects from the validation cohort (n= 996 doctors). Qualitative responses from the validation cohort were coded and analyzed using quantitative methods. Only 0.01 % doctors reported no barriers to conducting EOL conversations with patients. 99.99% doctors reported barriers with 85.7% finding it very challenging to conduct EOL conversations with all patients and especially so with patients whose ethnicity was different than their own. Asian-American doctors reported the most struggles (91.3%), followed by African Americans (85.3%), Caucasians (83.5%) and Hispanic Americans (79.3%) in conducting EOL conversations with their patients. The biggest doctor-reported barriers to effective EOL conversations are (i) language and medical interpretation issues, (ii) patient/family religio-spiritual beliefs about death and dying, (iii) doctors’ ignorance of patients’ cultural beliefs, values and practices, (iv) patient/family's cultural differences in truth handling and decision making, (v) patients’ limited health literacy and (vi) patients’ mistrust of doctors and the health care system. The doctors' ethnicity (Chi-Square = 12.77, DF = 4, p = 0.0125) and medical subspecialty (Chi-Square = 19.33, DF = 10, p =0.036) influenced their reported barriers. Friedman’s test used to examine participants relative ranking of the barriers across sub-groups identified significant differences by age group (F statistic = 303.5, DF = 5, p < 0.0001) and medical sub-specialty (F statistic =163.7, DF = 5, p < 0.0001). Conclusions and Relevance Doctors report struggles with conducting effective EOL conversations with all patients and especially with those whose ethnicity is different from their own. It is vital to identify strategies to mitigate barriers doctors encounter in conducting effective EOL conversations with seriously ill patients and their families.

Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

BACKGROUND Poor sleep, prevalent among cancer survivors, is associated with disrupted hormonal circadian rhythms and poor quality of life. Using a prospective research design, this study aimed to clarify the relationship between objective measures of sleep efficiency and sleep disruption with survival among women with advanced breast cancer. METHOD We examined sleep quality and duration via wrist-worn actigraphy and sleep diaries for 3 days among 97 women in whom advanced breast cancer was diagnosed (age = 54.6 ± 9.8 years). Sleep efficiency was operationalized using actigraphy as the ratio of total sleep time to total sleep time plus wake after sleep onset. RESULTS As hypothesized, better sleep efficiency was found to predict a significant reduction in overall mortality (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.94-0.98; P < 0.001) at median 6 y follow-up. This relationship remained significant (HR, 0.94; 95% CI, 0.91-0.97; P < 0.001) even after adjusting for other known prognostic factors (age, estrogen receptor status, cancer treatment, metastatic spread, cortisol levels, and depression). Secondary hypotheses were also supported (after adjusting for baseline prognostic factors) showing that less wake after sleep onset (HR, 0.41; 95% CI, 0.25-0.67; P < 0.001), fewer wake episodes, (HR, 0.93; 95% CI, 0.88-0.98; P = 0.007); and shorter wake episode duration (HR, 0.29; 95% CI, 0.14-0.58; P < 0.001) also contributed to reductions in overall mortality. CONCLUSIONS These findings show that better sleep efficiency and less sleep disruption are significant independent prognostic factors in women with advanced breast cancer. Further research is needed to determine whether treating sleep disruption with cognitive behavioral and/or pharmacologic therapy could improve survival in women with advanced breast cancer.

Many studies have investigated whether chemical exposures early in pregnancy increase risks to women of delivering offspring with congenital anomalies. We investigated whether periconceptional exposures to chemicals in combination increased risks to women of having neural tube defect (NTD)-affected pregnancies. Women were asked about occupational tasks performed during the periconceptional period. These tasks were assigned by an industrial hygienist to a priori defined exposure categories. The exposure categories included 74 chemical groups. Two population-based case control studies were analyzed. Information on tasks was obtained from mothers of 538 NTD cases and their 539 controls in one study, and mothers of 265 NTD cases and 481 controls from another study. We used data from the first study to identify clues. Specifically, we estimated NTD risks for maternal occupational exposures to all possible pairs, triplets, and quadruplets of 74 chemical groups. Chemical combinations revealing elevated NTD risks in these “clue generation” analyses were then investigated in the second population-based case-control study for their contribution to risk of NTDs. We computed odds ratios for each of the total 192,374 possible comparisons and identified all combinations that produced odds ratios of 5 or more. A 5-fold elevated risk criterion revealed 53 combinations. These 53 reflected various combinations of exposures exclusive to 12 of 74 chemical groups. Analyses of data from the second study did not identify odds ratios of 2.0 or greater for maternal exposures to the 12 chemical groups that resulted in 5-fold elevated risks in the first study. Despite the use of a labor-intensive method to categorize exposures, we were unable to substantiate clues associated with combined chemical exposures identified in one large case-control study as NTD risk factors in a second case-control study.

Introduction: The ‘diurnal slope' of salivary cortisol has been used as a measure of stress and circadian function in a variety of reports with several detailing its association with cancer progression. The relationship of this slope, typically a negative value from high morning concentrations to low evening concentrations, to the underlying daily variation in total plasma cortisol throughout the 24-hour cycle, however, has never been reported. Methods: To examine the relationship between the diurnal salivary cortisol slope and the underlying pattern of plasma cortisol in individuals with cancer, we examined a cohort of women with advanced breast cancer (n = 97) who had saliva and plasma collected during a modified 24-hour, constant posture protocol. Results: We found that the steepness of the diurnal slope of salivary cortisol was correlated with the amplitude of plasma cortisol rhythm when the slope was calculated from samples taken at wake + 30 min and 9 PM (r = -0.29, p > 0.05). Other variants of salivary slope calculations were not significantly correlated with the amplitude of the plasma cortisol rhythm. Diurnal salivary cortisol slope steepness was not correlated with the time between habitual waking and the computed circadian peak of cortisol, but there was a correlation between diurnal slope steepness and the time between habitual waking and the time of the awakening spike of morning cortisol (r values Conclusion: It therefore appears that in women with advanced breast cancer, diurnal salivary cortisol slope primarily represents aspects of the cortisol awakening response in relation to evening levels more than the circadian rhythm of total plasma cortisol.

Disruption of circadian rhythms, which frequently occurs during night shift work, may be associated with cancer progression. The effect of chronotype (preference for behaviors such as sleep, work, or exercise to occur at particular times of day, with an associated difference in circadian physiology) and alignment of bedtime (preferred vs. habitual), however, have not yet been studied in the context of cancer progression in women with breast cancer. Chronotype and alignment of actual bedtime with preferred chronotype were examined using the Morningness-Eveningness Scale (MEQ) and sleep-wake log among 85 women with metastatic breast cancer. Their association with disease-free interval (DFI) was retrospectively examined using the Cox proportional hazards model. Median DFI was 81.9 months for women with aligned bedtimes ("going to bed at preferred bedtime") (n = 72), and 46.9 months for women with misaligned bedtimes ("going to bed later or earlier than the preferred bedtime") (n = 13) (log rank p = 0.001). In a multivariate Cox proportional hazard model, after controlling for other significant predictors of DFI, including chronotype (morning type/longer DFI; HR = 0.539, 95% CI = 0.320-0.906, p = 0.021), estrogen receptor (ER) status at initial diagnosis (negative/shorter DFI; HR = 2.169, 95% CI = 1.124-4.187, p = 0.028) and level of natural-killer cell count (lower levels/shorter DFI; HR = 1.641, 95% CI = 1.000-2.695, p = 0.050), misaligned bedtimes was associated with shorter DFI, compared to aligned bedtimes (HR = 3.180, 95% CI = 1.327-7.616, p = 0.018). Our data indicate that a misalignment of bedtime on a daily basis, an indication of circadian disruption, is associated with more rapid breast cancer progression as measured by DFI. Considering the limitations of small sample size and study design, a prospective study with a larger sample is necessary to explore their causal relationship and underlying mechanisms.