Expanded validation of the EPIC bowel and urinary domains for use in women with gynecologic cancer undergoing postoperative radiotherapy.

OBJECTIVE: Women with endometrial or cervical cancer at risk for recurrence receive postoperative radiation therapy (RT). A patient reported outcomes (PRO) instrument to assess bowel and urinary toxicities is the Expanded Prostate Cancer Index Composite (EPIC), which has been validated in men with prostate cancer. As this instrument specifically measures bowel toxicity and the degree to which this is a problem, it was used in NRG Oncology/RTOG 1203 to compare intensity modulated RT (IMRT) to standard RT. This paper reports on the expanded validation of EPIC for use in women receiving pelvic RT. METHODS: In addition to the EPIC bowel domain, urinary toxicity (EPIC urinary domain), patient reported bowel toxicities (PRO-CTCAE) and quality of life (Functional Assessment of Cancer Therapy (FACT)) were completed before, during and after treatment. Sensitivity, reliability and concurrent validity were assessed. RESULTS: Mean bowel and urinary scores among 278 women enrolled were significantly worse during treatment and differed between groups. Acceptable to good reliability for bowel and urinary domain scores were obtained at all time points with the exception of one at baseline. Correlations between function and bother scores within the bowel and urinary domains were consistently stronger than those across domains. Correlations between bowel domain scores and PRO-CTCAE during treatment were stronger than those with the FACT. CONCLUSION: Correlations within and among the instruments indicate EPIC bowel and urinary domains are measuring conceptually discrete components of health. These EPIC domains are valid, reliable and sensitive instruments to measure PRO among women undergoing pelvic radiation.

Validation study of a pooled electronic healthcare database: the effect of obesity on the revision rate of total knee arthroplasty.

The objective of this study was to validate the use of a software platform (Explorys, Inc., Cleveland, OH) by determining whether the association observed between obesity and revision of total knee arthroplasty (TKA) was obtained within this database. Risk of revision in cohorts with a BMI > 30, as well as cohorts with a BMI between 30-35, 35-40 and >40 was compared to patients with a BMI between 18 and 30 (relative risk, RR). Risk in men versus women was examined. From this database, 70,070 patients were identified that had undergone a TKA. Risk of revision increased as a function of BMI; RR achieved significance in the following cohorts: all patients with a BMI > 30, all patients with a BMI > 40, men with a BMI > 30 and men with a BMI > 40. All other subgroups showed increased RR but did not reach significance. In obese patients, RR was greater in men than in women, and the effect was significant in all groups examined except patients with a BMI between 35 and 40. Data from this study contribute to the process of demonstrating the Explorys software platform is a valid and useful method to investigate associations across large populations.

Endometrial cancer survivors' assessment of the benefits of exercise.

OBJECTIVE: The majority of women who have had endometrial cancer remain at risk for obesity related diseases. The social cognitive theory was used to explore their beliefs about exercise to aid in the development of effective interventions. METHODS: Women who had been treated for Stage I endometrial cancer were asked about their level of exercise to determine if they had been exercising regularly for more than 6 months (exercisers vs non-exercisers). They were asked to rate the likelihood that exercise would result in various health outcomes (expectations) and to rate the importance of these outcomes (expectancies). Scores for how likely exercise would result in an outcome of importance were calculated. Height and weight were obtained from nurses for calculation of BMI. Statistics were conducted using SPSS v 15. RESULTS: There were 106 valid questionnaires (86% participation rate); 41% were exercisers. Mean BMI was significantly lower in exercisers (31.6 ± 1.2 vs. 37.3 ± 1.2, p=0.001); a significantly greater proportion reported not having diabetes, heart disease or hypertension (69.8% vs. 49.2%, p=0.035). Exercisers were significantly more likely to report that feeling better physically and emotionally versus reducing the risk of diseases were likely and important outcomes of exercise (18.2 ± 0.8 vs 15.0 ± 1.0, p=0.002). CONCLUSIONS: Exercisers identified outcomes of exercise that are more immediate and subjective as being important and likely outcomes of exercise. Focusing on these aspects of exercise (feeling better physically and emotionally) may aid in the development of effective interventions for non-exercisers.

The association between quality of life domains and overall survival in ovarian cancer patients during adjuvant chemotherapy: a Gynecologic Oncology Group Study.

PURPOSE: To explore the association between baseline quality of life (QOL) scores and overall survival (OS) in ovarian cancer patients receiving adjuvant chemotherapy. METHODS: Patients with stage III ovarian cancer on Gynecologic Oncology Group protocol #172 completed the Functional Assessment of Cancer Therapy-General (FACT-G) and were then randomly assigned to either intravenous (IV) or intraperitoneal (IP) chemotherapy. The FACT scale includes physical, functional, social, and emotional well-being domains (PWB, FWB, SWB, EWB). The PWB item, lack of energy, was used to assess the presence of fatigue. RESULTS: After adjusting for patient age, treatment assignment, and the presence of gross disease, PWB was associated with OS. Patients who reported baseline PWB scores in the lowest 25% (PWB score<15 points) relative to those who scored in the highest 25% (PWB score>24 points) had decreased OS (HR: 1.81; 95% CI: 1.2-2.72; p=0.005). Patients experienced death rates 20% lower for every mean item point increase in PWB (Hazard Ratio [HR]: 0.80; 95% CI: 0.68-0.93; p=0.005). Patients complaining of fatigue did not have an increased risk of death compared with those not feeling fatigued (HR: 1.21; 95% CI: 0.91-1.61; p=0.19). CONCLUSIONS: Poor physical well-being reported at baseline is associated with risk of death in patients undergoing adjuvant chemotherapy for advanced ovarian cancer. Identifying modifiable characteristics that are associated with survival offers the potential for providing support that may improve outcomes.

Emotion regulation predicts pain and functioning in children with juvenile idiopathic arthritis: an electronic diary study.

OBJECTIVES: This study utilized e-diaries to evaluate whether components of emotion regulation predict daily pain and function in children with juvenile idiopathic arthritis (JIA). METHODS: 43 children ages 8-17 years and their caregivers provided baseline reports of child emotion regulation. Children then completed thrice daily e-diary assessments of emotion, pain, and activity involvement for 28 days. E-diary ratings of negative and positive emotions were used to calculate emotion variability and to infer adaptive emotion modulation following periods of high or low emotion intensity. Hierarchical linear models were used to evaluate how emotion regulation related to pain and function. RESULTS: The attenuation of negative emotion following a period of high negative emotion predicted reduced pain; greater variability of negative emotion predicted higher pain and increased activity limitation. Indices of positive emotion regulation also significantly predicted pain. CONCLUSIONS: Components of emotion regulation as captured by e-diaries predict important health outcomes in children with JIA.

Robotic surgical skills: acquisition, maintenance, and degradation.

BACKGROUND AND OBJECTIVES: The degradation in robotic skills that occurs during periods of robotic surgical inactivity in newly trained surgeons was measured. The role of animate training in robotic skill was also assessed. METHODS: Robotically naive resident and attending surgeons underwent training with the da Vinci robot on needle passage (DN), rocking ring transfer peg board (RPB), and running suture pod tasks (SP). Errors were established to convert actual time to adjusted time. Participants were deemed "proficient" once their adjusted times were within 80% of those set by experienced surgeons through repeated trials. Participants did not use the robot except for repeating the tasks once at 4, 8, and 12 weeks (tests). Participants then underwent animate training and completed a final test within 7 days. RESULTS: Twenty-five attending and 29 resident surgeons enrolled; 3 withdrew. There were significant increases in time to complete each of the tasks, and in errors, by 4 weeks (Adjusted times: DN: 122.9 +/- 2.2 to 204.2 +/- 11.7, t = 6.9, P < .001; RPB: 262.4 +/- 2.5 to 364.7 +/- 8.0, t = 12.4, P < .001; SP: 91.4 +/- 1.4 to 169.9 +/- 6.8, t = 11.3, P < .001). Times decreased following animate training, but not to levels observed after proficiency training for the RPB and SP modules. CONCLUSIONS: Robotic surgical skills degrade significantly within 4 weeks of inactivity in newly trained surgeons. Animate training may provide different skills than those acquired in the dry lab.

Intensity-Modulated Radiation Therapy Reduces Patient-Reported Chronic Toxicity Compared With Conventional Pelvic Radiation Therapy: Updated Results of a Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The purpose of this update was to determine differences in patient-reported chronic toxicity and disease outcomes with intensity-modulated radiation therapy (IMRT) compared with conventional pelvic radiation. Patients with cervical and endometrial cancers who received postoperative pelvic radiation were randomly assigned to conventional radiation therapy (CRT) or IMRT. Toxicity and quality of life were assessed using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domains, and Functional Assessment of Cancer Therapy-General. Between 2012 and 2015, 279 eligible patients were enrolled to the study with a median follow-up of 37.8 months. There were no differences in overall survival (P = .53), disease-free survival (P = .21), or locoregional failure (P = .81). One year after RT, patients in the CRT arm experienced more high-level diarrhea frequency (5.8% IMRT v 15.1% CRT, P = .042) and a greater number had to take antidiarrheal medication two or more times a day (1.2% IMRT v 8.6% CRT, P = .036). At 3 years, women in the CRT arm reported a decline in urinary function, whereas the IMRT arm continued to improve (mean change in EPIC urinary score = 0.5, standard deviation = 13.0, IMRT v -6.0, standard deviation = 14.3, CRT, P = .005). In conclusion, IMRT reduces patient-reported chronic GI and urinary toxicity with no difference in treatment efficacy at 3 years.

Physical activity and gynecologic cancer survivorship.

Gynecologic oncology involves the study of preinvasive disease and cancers of the vulva, vagina, cervix, uterus, ovaries, and gestational trophoblastic disease. Endometrial cancer is the most common of the pelvic malignancies however, ovarian cancer is the most lethal. The other gynecologic cancers have not been studied in relation to physical activity (PA) and prognosis, and therefore are not included. Research addressing the relationship between PA and ovarian and endometrial cancer is sparse nevertheless, there are some emerging concepts. Studies suggest that overweight/obesity is associated with reduced survival from ovarian cancer, but the role that PA plays in these results, and whether survival can be altered by changes in body weight and/or PA following diagnosis is unknown. Limited research reveals that increased PA in older ovarian cancer patients is feasible and safe. The majority of endometrial cancer patients are overweight or obese. Obesity is associated with higher mortality, probably from cardiovascular disease and not cancer. Research reveals that increasing PA in overweight/obese endometrial cancers is feasible and successful. The effects of increased PA on recurrence or survival in gynecological cancers are not yet established, and randomized controlled trials are needed for definitive data.

Improvement in Patient-Reported Outcomes With Intensity-Modulated Radiotherapy (RT) Compared With Standard RT: A Report From the NRG Oncology RTOG 1203 Study.

PURPOSE: In oncology trials, the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) is the standard tool for reporting adverse events (AEs), but it may underreport symptoms experienced by patients. This analysis of the NRG Oncology RTOG 1203 compared symptom reporting by patients and clinicians during radiotherapy (RT). PATIENTS AND METHODS: Patients with cervical or endometrial cancer requiring postoperative RT were randomly assigned to standard 4-field RT or intensity-modulated RT (IMRT). Patients completed the 6-item patient-reported outcomes version of the CTCAE (PRO-CTCAE) for GI toxicity assessing abdominal pain, diarrhea, and fecal incontinence at various time points. Patients reported symptoms on a 5-point scale. Clinicians recorded these AEs as CTCAE grades 1 to 5. Clinician- and patient-reported AEs were compared using McNemar's test for rates > 0%. RESULTS: Of 278 eligible patients, 234 consented and completed the PRO-CTCAE. Patients reported high-grade abdominal pain 19.1% (P < .0001), high-grade diarrhea 38.5% (P < .0001), and fecal incontinence 6.8% more frequently than clinicians. Similar effects were seen between grade ≥ 1 CTCAE toxicity and any-grade patient-reported toxicity. Between-arm comparison of patient-reported high-grade AEs revealed that at 5 weeks of RT, patients who received IMRT experienced fewer GI AEs than patients who received 4-field pelvic RT with regard to frequency of diarrhea (18.2% difference; P = .01), frequency of fecal incontinence (8.2% difference; P = .01), and interference of fecal incontinence (8.5% difference; P = .04). CONCLUSION: Patient-reported AEs showed a reduction in symptoms with IMRT compared with standard RT, whereas clinician-reported AEs revealed no difference. Clinicians also underreported symptomatic GI AEs compared with patients. This suggests that patient-reported symptomatic AEs are important to assess in this disease setting.

Distress and quality of life characteristics associated with seeking surgical treatment for stress urinary incontinence.

BACKGROUND: Current research focuses on three variables in evaluating the impact of stress urinary incontinence (SUI) on daily living: severity of incontinence, distress or bother resulting from incontinence, and effect on health related quality of life (HRQoL). Understanding the impact of these variables is important as they are the driving force behind women seeking surgical treatment. Given the importance of HRQoL in determining need for treatment, as well as evaluating treatment success, this review provides an assessment of the degree to which HRQoL is impaired in women seeking surgical treatment. METHODS: PubMed searches for the terms "quality of life and distress and urinary incontinence" and "quality of life and bother and urinary incontinence" were performed with limits of English, human and female subjects through May 2008. All studies using validated instruments were included. No time limit was placed on the search. RESULTS: Of 178 articles retrieved, 21 met the inclusion criteria, and 17 reported methods of scoring. The studies used the Urogenital Distress Inventory (UDI) and the Incontinence Impact Questionnaire (IIQ). Wide ranges of mean and individual levels of severity of symptoms, UDI and IIQ scores were seen among women seeking surgical treatment. Fourteen studies reported baseline and post-surgical treatment distress and QoL data. Statistically significant improvements between baseline and post-surgical UDI and IIQ scores were reported in 12 studies. Reported cure rates ranged from 46% to 97%. Satisfaction with the procedure was reported in 4 studies and ranged from 84% to 91%. A minority of studies reported the relationship between reduction in symptoms and change in HRQoL. CONCLUSION: HRQoL is the main reason women seek surgical treatment for incontinence and surgical treatment leads to a significant improvement in mean HRQoL scores. Assessment of HRQoL has proved less useful in identifying why individual women seek treatment for incontinence. Preliminary work has begun to characterize the interaction between severity of symptoms, distress or bother resulting from these urinary symptoms, impact on HRQoL, and treatment seeking behavior, but further research is needed. Greater standardization in the reporting of results of distress or bother and HRQoL would allow for comparison across studies.

Obstetrics and gynaecology chief resident attitudes toward teaching junior residents under normal working conditions.

OBJECTIVES: This study aimed to identify factors that chief residents believe impact the teaching of junior residents under normal working conditions and the areas in which they believe education on the role of resident as teacher would be beneficial. METHODS: Obstetrics and gynaecology (O&G) chief residents were asked to rate the importance of teaching various skills, how often conflict situations arose, and to identify training that would be helpful through a national web-based survey. An e-mail was sent to coordinators of the Residency Review Committee (RRC) O&G residency programmes with a request that they forward the link to their chief residents three times from January through March 2006. RESULTS: Responses were received from 204 postgraduate Year 4 (PGY4) residents (18% of all PGY4 residents) from 133 programmes (54% of all residency programmes) and 33 states. Teaching junior residents how to prioritise patient care and obtain critical information in an emergent situation was considered very to extremely important by 97%. Conflict situations with junior residents were reported to occur between one and five times by 41-58%; an additional 26-28% reported that these situations occurred six or more times. Residents felt it would be helpful to extremely helpful to have training in resolving conflicts that involved patient care (48-59%), as well as in resolving conflict among junior residents, communicating effectively with them and becoming an effective leader (65-78%). CONCLUSIONS: The skills that chief residents considered most important to teach junior residents involved direct patient care. Chief residents would like training in how to resolve conflict with, and among, junior residents, and in how to become an effective leader.

Diagnosis of bacterial vaginosis in the pregnant patient in an acute care setting.

OBJECTIVE: To determine the accuracy of clinical criteria relative to Nugent's criteria for diagnosing bacterial vaginosis (BV) in the pregnant patient. METHODS: This prospective study was conducted in pregnant patients requiring a speculum examination in an ER triage system. Determination was made of vaginal pH, whiff test, clue cells and discharge for use with Amsel's criteria. Diagnosis of BV was made using Nugent's criteria. Data were analyzed with Student's t and chi square statistics. RESULTS: Samples by Nugent's criteria were positive for 32 women out of a sample size of 193 (16.6%). There were no significant differences in chief complaints between women with and without BV. Significantly more women with BV reported odor, but there were no other significant differences in symptoms between women with and without BV. Patients with BV were significantly less likely to have a white discharge. The whiff test was not reported in many cases, however, when a test was recorded, women with BV were significantly more likely to have a positive test. Approximately 50% of the women with BV had either >or=20% clue cells or pH>4.5; only 25% had both. Sensitivities of pH>4.5, pH >or= 4.5, >or=20% clue cells, whiff test and the combination of high pH and clue cells were low (22-81%). Specificities of individual and combined criteria ranged from 68 to 99%. The negative predictive power of pH<4.5 was 95%; 113 women had a pH less than 4.5 and of these women, 107 did not have BV. DISCUSSION: The negative predictive power of a pH<4.5 is very high, and the majority of women fell into this category. An algorithm for pregnant women could therefore be constructed that would call for pH to be tested. Women with a pH < 4.5 would not receive treatment or undergo further testing. The minority of women with a pH >or= 4.5 would then undergo testing with the Gram stain using Nugent's criteria.

Patient-Reported Toxicity During Pelvic Intensity-Modulated Radiation Therapy: NRG Oncology-RTOG 1203.

Purpose NRG Oncology/RTOG 1203 was designed to compare patient-reported acute toxicity and health-related quality of life during treatment with standard pelvic radiation or intensity-modulated radiation therapy (IMRT) in women with cervical and endometrial cancer. Methods Patients were randomly assigned to standard four-field radiation therapy (RT) or IMRT radiation treatment. The primary end point was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary end points included change in patient-reported urinary toxicity, change in GI toxicity measured with the Patient-Reported Outcome Common Terminology Criteria for Adverse Events, and quality of life measured with the Trial Outcome Index. Results From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group ( P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group ( P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group ( P = .06). At the end of RT, 51.9% of women who received standard RT and 33.7% who received IMRT reported frequent or almost constant diarrhea ( P = .01), and more patients who received standard RT were taking antidiarrheal medications four or more times daily (20.4% v 7.8%; P = .04). Conclusion Pelvic IMRT was associated with significantly less GI and urinary toxicity than standard RT from the patient's perspective.

Optimism predicting daily pain medication use in adolescents with sickle cell disease.

This study examined the influence of optimism on pain medication use in adolescents with sickle cell disease (n=27; 18 females, 9 males). Participants completed a baseline measure of optimism and an average of 100 daily-diary assessments of pain severity and medication use. Results indicated that adolescents who experienced more severe pain used more analgesic and opioid medications. Optimism was a significant moderator of the relation between pain and opioid-medication use. At medium and high levels of optimism, pain was positively related to opioid use, but at low levels of optimism, the same relation was not present, suggesting that more optimistic adolescents are better able to match their medication use to their pain severity. Future research should examine how other psychosocial factors might influence pain medication use in adolescents and adults who experience pain, and clinicians should take into account psychosocial factors when working with pain populations.

Baseline characteristics influencing quality of life in women undergoing gynecologic oncology surgery.

BACKGROUND: Quality of life (QoL) measurements are important in evaluating cancer treatment outcomes. Factors other than cancer and its treatment may have significant effects on QoL and affect assessment of treatments. Baseline data from longitudinal studies of women with endometrial or ovarian cancer or adnexal mass determined at surgery to be benign were analyzed to determine the degree to which QoL is affected by baseline differences in demographic variables and health. METHODS: This study examined the effect of independent variables on domains of the Functional Assessment of Cancer Therapy (FACT-G) pre-operatively in gynecologic oncology patients undergoing surgery for pelvic mass suspected to be malignant or endometrial cancer. Patients also completed the Short Form Medical Outcomes Survey (SF-36) questionnaire (a generic health questionnaire that measures physical and mental health). Independent variables were surgical diagnosis (ovarian or endometrial cancer, benign mass), age, body mass index (BMI), educational level, marital status, smoking status, physical (PCS) and mental (MCS) summary scores of the SF-36. Multiple regression analysis was used to determine the influence of these variables on FACT-G domain scores (physical, functional, social and emotional well-being). RESULTS: Data were collected on 157 women at their pre-operative visit (33 ovarian cancer, 45 endometrial cancer, 79 determined at surgery to be benign). Mean scores on the FACT-G subscales and SF-36 summary scores did not differ as a function of surgical diagnosis. PCS, MCS, age, and educational level were positively correlated with physical well-being, while increasing BMI was negatively correlated. Functional well-being was positively correlated with PCS and MCS and negatively correlated with BMI. Social well-being was positively correlated with MCS and negatively correlated with BMI and educational level. PCS, MCS and age were positively correlated with emotional well-being. Models that included PCS and MCS accounted for 30 to 44% of the variability in baseline physical, emotional, and functional well-being on the FACT-G. CONCLUSION: At the time of diagnosis and treatment, patients' QoL is affected by inherent characteristics. Assessment of treatment outcome should take into account the effect of these independent variables. As treatment options become more complex, these variables are likely to be of increasing importance in evaluating treatment effects on QoL.

Can sun protection knowledge change behavior in a resistant population?

The future skin cancer statistics for the youth of the United States are staggering. Traditional educational programs are currently the mainstay to foster sun protective awareness for this high-risk, sun-worshipping population. This study was designed to monitor high school students for both short-term and long-term changes in knowledge and attitude, as well as for any change in behavior, following a standard sun protection intervention. Our results demonstrated that although students had an increase in knowledge, it was insufficient to change their behavior.

Self-expansion as a mediator of relationship improvements in a mindfulness intervention.

In a recent randomized controlled trial, couples participating in a mindfulness-based relationship enhancement program demonstrated significant improvements in relationship satisfaction and relationship distress (Carson, Carson, Gil, & Baucom, 2004). Here we report on a multiple mediation analysis of these couples' improvements. Potential mediators included measures of couples' engagement in exciting self-expanding activities, couples' ability to accept one another's difficult characteristics, and individual partners' ability to relax. Results indicate that to a large extent, the mindfulness-related relationship improvements can be attributed to partners' sense that they were participating in exciting self-expanding activities together during the course of the intervention. The implications of these findings for future mindfulness research are discussed.

Use of Smartphones to Prospectively Evaluate Predictors and Outcomes of Caregiver Responses to Pain in Youth with Chronic Disease.

This study examined outcomes and predictors of different types of responses to child pain used by caregivers of youth with chronic disease. Sixty-six children and adolescents (ages 7-18) with juvenile idiopathic arthritis answered questions about pain, pain interference in activities, and mood on a smartphone three times per day for one month, while a caregiver contemporaneously answered questions about their own mood and use of protecting, monitoring, minimizing, or distracting responses to their child's pain. Multilevel models were used to evaluate (a) how a child's pain and pain interference changes after a caregiver uses different types of pain responses; (b) the extent to which caregiver responses to pain vary across days; and (c) whether variability in caregiver responses to pain is predicted by changes in child pain characteristics, child mood, and/or caregiver mood. Results showed that children's pain intensity and pain interference increased following moments when caregivers used more protective responses, whereas children's pain interference decreased following times when caregivers responded with minimizing responses. Caregiver pain responses varied considerably across days, with caregivers responding with more protecting and monitoring responses and fewer minimizing responses at moments when their child reported high levels of pain unpleasantness and pain interference. Caregivers also were found to respond with fewer protective responses at moments when they themselves were in a more positive mood. Implications for clinical recommendations and future studies are discussed.

Conceptualizing and testing random indirect effects and moderated mediation in multilevel models: new procedures and recommendations.

The authors propose new procedures for evaluating direct, indirect, and total effects in multilevel models when all relevant variables are measured at Level 1 and all effects are random. Formulas are provided for the mean and variance of the indirect and total effects and for the sampling variances of the average indirect and total effects. Simulations show that the estimates are unbiased under most conditions. Confidence intervals based on a normal approximation or a simulated sampling distribution perform well when the random effects are normally distributed but less so when they are nonnormally distributed. These methods are further developed to address hypotheses of moderated mediation in the multilevel context. An example demonstrates the feasibility and usefulness of the proposed methods.