Two-stage stratified designs with survival outcomes and adjustment for misclassification in predictive biomarkers.

Biomarker stratified clinical trial designs are versatile tools to assess biomarker clinical utility and address its relationship with clinical endpoints. Due to imperfect assays and/or classification rules, biomarker status is prone to errors. To account for biomarker misclassification, we consider a two-stage stratified design for survival outcomes with an adjustment for misclassification in predictive biomarkers. Compared to continuous and/or binary outcomes, the test statistics for survival outcomes with an adjustment for biomarker misclassification is much more complicated and needs to take special care. We propose to use the information from the observed biomarker status strata to construct adjusted log-rank statistics for true biomarker status strata. These adjusted log-rank statistics are then used to develop sequential tests for the global (composite) hypothesis and component-wise hypothesis. We discuss the power analysis with the control of the type-I error rate by using the correlations between the adjusted log-rank statistics within and between the design stages. Our method is illustrated with examples of the recent successful development of immunotherapy in nonsmall-cell lung cancer.

Randomized trial promoting cancer genetic risk assessment when genetic counseling cost removed: 1-year follow-up.

PURPOSE: Cancer genetic risk assessment (CGRA) is recommended for women with ovarian and high-risk breast cancer. However, the underutilization of CGRA has long been documented, and cost has been a major barrier. In this randomized controlled trial, a tailored counseling and navigation (TCN) intervention significantly improved CGRA uptake at 6-month follow-up, compared with targeted print (TP) and usual care (UC). We aimed to examine the effect of removing genetic counseling costs on CGRA uptake by 12 months. METHODS: We recruited racially and geographically diverse women with breast and ovarian cancer from cancer registries in Colorado, New Jersey, and New Mexico. Participants assigned to TCN received telephone-based psychoeducation and navigation. After 6 months, the trial provided free genetic counseling to participants in all arms. RESULTS: At 12 months, more women in TCN obtained CGRA (26.6%) than those in TP (11.0%; odds ratio [OR] = 2.77, 95% confidence interval [CI] = 1.56 to 4.89) and UC (12.2%; OR = 2.46, 95% CI = 1.41 to 4.29). There were no significant differences in CGRA uptake between TP and UC. The Kaplan-Meier curve shows that the divergence of cumulative incidence slopes (TCN vs UC, TCN vs TP) appears primarily within the initial 6 months. CONCLUSION: TCN significantly increased CGRA uptake at the 12-month follow-up. Directly removing the costs of genetic counseling attenuated the effects of TCN, highlighting the critical enabling role played by cost coverage. Future policies and interventions should address multilevel cost-related barriers to expand patients' access to CGRA. TRIAL REGISTRATION: This trial was registered with the NIH clinical trial registry, clinicaltrials.gov, NCT03326713. https://clinicaltrials.gov/ct2/show/NCT03326713.

Adaptive Lung Radiation Therapy in the Era of Immunotherapy: A Single-Center Retrospective Study.

Purpose: Treatment for locally advanced non-small cell lung cancer consists of concurrent chemoradiation followed by immunotherapy. Though this combination has been shown to have a benefit in both progression-free survival and overall survival, treatment is often limited by the development of pneumonitis. One way to mitigate toxicity is through adaptive radiation therapy, which does not currently have a standardized implementation in clinical practice. Methods and Materials: A single-center retrospective review of patients with locally advanced stage III or oligometastatic stage IV non-small cell lung cancer who were treated with chemoradiation with concurrent or subsequent immunotherapy from 2015 to 2020 was performed. Patients were stratified based on having 1 or more offline adapted plan. The aim of this study was to evaluate the association between dose-volume histogram values and common toxicities experienced during this treatment, including pneumonitis and esophagitis. Results: Twenty-five patients were included in the final analysis: 10 with adapted plans (AP), and 15 with nonadapted plans (NAP). Mean age at onset was 74 years. The most common histology was adenocarcinoma (N = 13). Five patients experienced pneumonitis: 2 in AP and 3 in NAP. Mann-Whitney U test of gross tumor volume sizes between AP (346.2 ± 269.7 cm3) and NAP (153.1 ± 99.6 cm3) was significant (P = .019). Multiple linear regression analysis with adjustment for covariates of pneumonitis versus plan adaptation (P = .106) and esophagitis versus plan adaptation (P = .59) did not demonstrate a significant difference in toxicity between the adapted and nonadaptive patients. Conclusions: Despite similar toxicities in both groups, the gross tumor volume size in the AP was more than double compared with NAP, suggesting that adaptive techniques provide a method for patients with larger target volumes to be treated without an observed difference in pneumonitis rates. These results suggest adaptive radiation therapy may have a role in mitigating toxicity experience from chemoradiation and immunotherapy and warrants further investigation.

Telehealth Mindfulness-Oriented Recovery Enhancement vs Usual Care in Individuals With Opioid Use Disorder and Pain: A Randomized Clinical Trial.

Importance: Methadone treatment (MT) fails to address the emotion dysregulation, pain, and reward processing deficits that often drive opioid use disorder (OUD). New interventions are needed to address these factors. Objective: To evaluate the efficacy of MT as usual (usual care) vs telehealth Mindfulness-Oriented Recovery Enhancement (MORE) plus usual care among people with an OUD and pain. Design, Setting, and Participants: This study was a randomized clinical trial conducted from August 2020 to June 2022. Participants receiving MT for OUD and experiencing chronic pain were recruited at 5 clinics in New Jersey. Interventions: In usual care, participants received MT, including medication and counseling. Participants receiving MORE plus usual care attended 8 weekly, 2-hour telehealth groups that provided training in mindfulness, reappraisal, and savoring in addition to usual care. Main Outcomes and Measure: Primary outcomes were return to drug use and MT dropout over 16 weeks. Secondary outcomes were days of drug use, methadone adherence, pain, depression, and anxiety. Analyses were based on an intention-to-treat approach. Results: A total of 154 participants (mean [SD] age, 48.5 [11.8] years; 88 female [57%]) were included in the study. Participants receiving MORE plus usual care had significantly less return to drug use (hazard ratio [HR], 0.58; 95% CI, 0.37-0.90; P = .02) and MT dropout (HR, 0.41; 95% CI, 0.18-0.96; P = .04) than those receiving usual care only after adjusting for a priori-specified covariates (eg, methadone dose and recent drug use, at baseline). A total of 44 participants (57.1%) in usual care and 39 participants (50.6%) in MORE plus usual care returned to drug use. A total of 17 participants (22.1%) in usual care and 10 participants (13.0%) in MORE plus usual care dropped out of MT. In zero-inflated models, participants receiving MORE plus usual care had significantly fewer days of any drug use (ratio of means = 0.58; 95% CI, 0.53-0.63; P < .001) than those receiving usual care only through 16 weeks. A significantly greater percentage of participants receiving MORE plus usual care maintained methadone adherence (64 of 67 [95.5%]) at the 16-week follow-up than those receiving usual care only (56 of 67 [83.6%]; χ2 = 4.49; P = .04). MORE reduced depression scores and ecological momentary assessments of pain through the 16-week follow-up to a significantly greater extent than usual care (group × time F2,272 = 3.13; P = .05 and group × time F16,13000 = 6.44; P < .001, respectively). Within the MORE plus usual care group, EMA pain ratings decreased from a mean (SD) of 5.79 (0.29) at baseline to 5.17 (0.30) at week 16; for usual care only, pain decreased from 5.19 (0.28) at baseline to 4.96 (0.29) at week 16. Within the MORE plus usual care group, mean (SD) depression scores were 22.52 (1.32) at baseline and 18.98 (1.38) at 16 weeks. In the usual care-only group, mean (SD) depression scores were 22.65 (1.25) at baseline and 20.03 (1.27) at 16 weeks. Although anxiety scores increased in the usual care-only group and decreased in the MORE group, this difference between groups did not reach significance (group × time unadjusted F2,272 = 2.10; P= .12; Cohen d = .44; adjusted F2,268 = 2.33; P = .09). Within the MORE plus usual care group, mean (SD) anxiety scores were 25.5 (1.60) at baseline and 23.45 (1.73) at 16 weeks. In the usual care-only group, mean (SD) anxiety scores were 23.27 (1.75) at baseline and 24.07 (1.73) at 16 weeks. Conclusions and Relevance: This randomized clinical trial demonstrated that telehealth MORE was a feasible adjunct to MT with significant effects on drug use, pain, depression, treatment retention, and adherence. Trial Registration: ClinicalTrials.gov Identifier: NCT04491968.

Fixed and random effect selections in generalized linear mixed models.

Generalized linear mixed models are commonly used to describe relationships between correlated responses and covariates in medical research. In this paper, we propose a simple and easily implementable regularized estimation approach to select both fixed and random effects in generalized linear mixed model. Specifically, we propose to construct and optimize the objective functions using the confidence distributions of model parameters, as opposed to using the observed data likelihood functions, to perform effect selections. Two estimation methods are developed. The first one is to use the joint confidence distribution of model parameters to perform simultaneous fixed and random effect selections. The second method is to use the marginal confidence distributions of model parameters to perform the selections of fixed and random effects separately. With a proper choice of regularization parameters in the adaptive LASSO framework, we show the consistency and oracle properties of the proposed regularized estimators. Simulation studies have been conducted to assess the performance of the proposed estimators and demonstrate computational efficiency. Our method has also been applied to two longitudinal cancer studies to identify demographic and clinical factors associated with patient health outcomes after cancer therapies.

The Effects of a Parent-Focused Social Media Intervention on Child Sun Safety: Pilot and Feasibility Study.

BACKGROUND: Middle childhood (ages 8-12 years) is a critical period for forming behavioral habits and reducing the risk for the development of skin cancer later in life. During this time, children develop more autonomy and spend more unsupervised time away from their parents. Professional agencies recommend that all children engage in regular sun protection behaviors and avoid the sun during peak daytime hours. Unfortunately, in middle childhood, child sun protection often declines and UV radiation exposure increases. Effective parenting involves balancing ways to encourage the child's increasing independence while providing practical assistance to ensure sun protection is implemented. OBJECTIVE: The goal was to evaluate the feasibility, acceptability, and preliminary effects of Sun Safe Families, a Facebook group intervention for parents of children between 8 and 12 years of age. METHODS: The team developed Facebook messages targeting parent knowledge, normative influences, sun safety barriers, planning and goal setting, confidence in implementing sun safety, communication, forming habits, and managing sun safety in risky situations. A total of 92 parents were enrolled, and the groups ran for 6 weeks. Feasibility was measured by enrollment and retention rates. Acceptability was measured by engagement in the Facebook groups. Satisfaction was assessed by a treatment evaluation. At pre- and post-intervention, parents completed measures of child sun protection, UV radiation exposure, sunburn, sun safety knowledge, child risk, barriers, sun protection self-efficacy, planning, sun safe habits, norms for child sun safety, and communication about sun safety. RESULTS: Enrollment (64.3%, 92/143) and retention (94.6%, 87/92) were good. On average, participants viewed 67.6% (56.8/84) of posts, "liked" 16.4% (13.77/84) of posts, commented on 14.8% (12.43/84) of posts, and voted on 46% (6.4/14) of polls. Satisfaction was excellent. From pre- to post-intervention, there were significant increases in child sun protection, sun exposure, and sunburn (P<.01; moderate effect sizes), as well as statistically significant increases in planning and self-efficacy (P<.05) and family norms and parent communication (P<.01). CONCLUSIONS: This study demonstrated high survey retention, acceptability, and satisfaction with the intervention. There were promising preliminary effects on child sun protection behaviors and parent sun protection attitudes and communication with their child. Replication with a larger sample size and a comparison condition is warranted.

Leveraging the functionality of Research Electronic Data Capture (REDCap) to enhance data collection and quality in the Opioid Analgesic Reduction Study.

BACKGROUND: The Opioid Analgesic Reduction Study is a double-blind, prospective, clinical trial investigating analgesic effectiveness in the management of acute post-surgical pain after impacted third molar extraction across five clinical sites. Specifically, Opioid Analgesic Reduction Study examines a commonly prescribed opioid combination (hydrocodone/acetaminophen) against a non-opioid combination (ibuprofen/acetaminophen). The Opioid Analgesic Reduction Study employs a novel, electronic infrastructure, leveraging the functionality of its data management system, Research Electronic Data Capture, to not only serve as its data reservoir but also provide the framework for its quality management program. METHODS: Within the Opioid Analgesic Reduction Study, Research Electronic Data Capture is expanded into a multi-function management tool, serving as the hub for its clinical data management, project management and credentialing, materials management, and quality management. Research Electronic Data Capture effectively captures data, displays/tracks study progress, triggers follow-up, and supports quality management processes. RESULTS: At 72% study completion, over 12,000 subject data forms have been executed in Research Electronic Data Capture with minimal missing (0.15%) or incomplete or erroneous forms (0.06%). Five hundred, twenty-three queries were initiated to request clarifications and/or address missing data and data discrepancies. CONCLUSION: Research Electronic Data Capture is an effective digital health technology that can be maximized to contribute to the success of a clinical trial. The Research Electronic Data Capture infrastructure and enhanced functionality used in Opioid Analgesic Reduction Study provides the framework and the logic that ensures complete, accurate, data while guiding an effective, efficient workflow that can be followed by team members across sites. This enhanced data reliability and comprehensive quality management processes allow for better preparedness and readiness for clinical monitoring and regulatory reporting.

Identifying Mediators of Intervention Effects Within a Randomized Controlled Trial to Motivate Cancer Genetic Risk Assessment Among Breast and Ovarian Cancer Survivors.

BACKGROUND: A theory-guided Tailored Counseling and Navigation (TCN) intervention successfully increased cancer genetic risk assessment (CGRA) uptake among cancer survivors at increased risk of hereditary breast and ovarian cancer (HBOC). Understanding the pathways by which interventions motivate behavior change is important for identifying the intervention's active components. PURPOSE: We examined whether the TCN intervention exerted effects on CGRA uptake through hypothesized theoretical mediators. METHODS: Cancer survivors at elevated risk for HBOC were recruited from three statewide cancer registries and were randomly assigned to three arms: TCN (n = 212), Targeted Print (TP, n = 216), and Usual Care (UC, n = 213). Theoretical mediators from the Extended Parallel Process Model, Health Action Planning Approach, and Ottawa Decision Support Framework were assessed at baseline and 1-month follow-up; CGRA uptake was assessed at 6 months. Generalized structural equation modeling was used for mediation analysis. RESULTS: The TCN effects were most strongly mediated by behavioral intention alone (ß = 0.49 and 0.31) and by serial mediation through self-efficacy and intention (ß = 0.041 and 0.10) when compared with UC and TP, respectively. In addition, compared with UC, the TCN also increased CGRA through increased perceived susceptibility, knowledge of HBOC, and response efficacy. CONCLUSIONS: Risk communication and behavioral change interventions for hereditary cancer should stress a person's increased genetic risk and the potential benefits of genetic counseling and testing, as well as bolster efficacy beliefs by helping remove barriers to CGRA. System-level and policy interventions are needed to further expand access.

It is recommended that cancer survivors at increased risk for heredity seek cancer genetic risk assessment (CGRA), which includes cancer genetic counseling and genetic testing. A Tailored Counseling and Navigation (TCN) intervention successfully increased CGRA uptake among women with a history of cancer who enrolled in a randomized controlled trial. Understanding reasons for TCN's effectiveness can guide future interventions that use risk messages and behavior change techniques. We conducted mediation analyses, which enabled identification of the TCN's active components. Eligible breast and ovarian cancer survivors (n = 641) were recruited from three statewide cancer registries and were assigned to three groups: TCN, Targeted Print, and Usual Care. Mediator variables drawn from behavioral and risk communication theories were assessed at baseline and 1-month follow-up; CGRA uptake was assessed at 6 months. The strongest mediator was intention to obtain a CGRA, followed by self-efficacy, perceived risk, knowledge of hereditary breast and ovarian cancer, and perceived CGRA benefits. Risk communication and behavioral change interventions for hereditary cancer should stress a person's increased genetic risk and the potential benefits of genetic counseling and testing, as well as bolster efficacy beliefs by helping remove CGRA barriers. System-level and policy interventions are needed to further expand access.

Associations between risky alcohol use, disability, and problem-solving impairment among Veterans with Gulf War Illness: Secondary data analysis of a randomized clinical trial.

OBJECTIVE: Gulf War Illness (GWI) and alcohol use are both major sources of disability among Gulf War Veterans. The goal of this secondary data analysis was to examine associations between risky alcohol use, problem-solving impairment, and disability among Veterans in a randomized clinical trial of problem-solving treatment (PST) for GWI. We examined cross-sectional associations and conducted longitudinal analyses to test if alcohol use moderated treatment outcome of PST. METHODS: Participants were 268 United States military Veterans with GWI randomized to PST or a control intervention. Participants were assessed at four timepoints. Measures included the World Health Organization Disability Assessment Schedule 2.0 (WHO-DAS 2.0), Problem Solving Inventory (PSI), and Alcohol Use Disorders Identification Test-Concise (AUDIT-C). We conducted multivariate regression (cross-sectional) and mixed model analyses (longitudinal) with separate models for WHO-DAS 2.0 and PSI. All models included AUDIT-C and household income. This analysis was pre-registered on the Open Science Framework. RESULTS: Cross-sectional analyses revealed a significant negative association with small effect size between AUDIT-C and WHO-DAS 2.0 (p = 0.006; f2 = 0.05); worse disability was associated with less risky alcohol use. There was no evidence that risky alcohol use moderated effects of PST on disability or PSI. CONCLUSION: If replicated, the cross-sectional findings suggest high levels of disability may deter heavy drinking among Veterans with GWI. We did not find evidence that risky alcohol use moderated treatment outcome of PST for GWI. More research is needed to identify moderators of GWI interventions and to understand risky drinking among Veterans with complex health problems.

Randomized controlled trial protocol of health coaching for veterans with complex chronic pain.

BACKGROUND: Pain predominant multisymptom illness (pain-CMI) refers to symptom-based conditions where pain is a primary symptom. There is initial evidence that health coaching may be efficacious in treating pain-CMI because it can be tailored to the veteran's goals and emphasizes long-term behavior change, which may indirectly impact the maintaining factors of pain-CMI (e.g., catastrophizing, poor pain control, and limited activity). This paper describes the study protocol and rationale of a randomized controlled trial that will compare the efficacy of remote-delivered health coaching in reducing disability and pain impairment for veterans with pain-CMI to remote-delivered supportive psychotherapy. METHODS: This randomized controlled trial will consist of two treatment arms: remote-delivered health coaching and remote-delivered supportive psychotherapy, the active control. Each treatment condition will consist of twelve, weekly one-on-one meetings with a study provider. In addition to the baseline assessment, participants will also complete 6-week (mid-treatment), 12-week (post-treatment), and 24-week (follow-up) assessments that consist of questionnaires that can be completed remotely. The primary aims for this study are to determine whether health coaching reduces disability and pain impairment as compared to supportive psychotherapy. We will also examine whether health coaching reduces physical symptoms, catastrophizing, limiting activity, and increasing pain control as compared to supportive psychotherapy. DISCUSSION: This study will contribute to the existing literature on pain-CMI and report the effectiveness of a novel, remote-delivered behavioral intervention.

Improving Uptake of Cancer Genetic Risk Assessment in a Remote Tailored Risk Communication and Navigation Intervention: Large Effect Size but Room to Grow.

PURPOSE: Cancer genetic risk assessment (CGRA) is recommended for women with ovarian cancer or high-risk breast cancer, yet fewer than 30% receive recommended genetic services, with the lowest rates among underserved populations. We hypothesized that compared with usual care (UC) and mailed targeted print (TP) education, CGRA uptake would be highest among women receiving a phone-based tailored risk counseling and navigation intervention (TCN). METHODS: In this three-arm randomized trial, women with ovarian or high-risk breast cancer were recruited from statewide cancer registries in Colorado, New Jersey, and New Mexico. Participants assigned to TP received a mailed educational brochure. Participants assigned to TCN received the mailed educational brochure, an initial phone-based psychoeducational session with a health coach, a follow-up letter, and a follow-up navigation phone call. RESULTS: Participants' average age was 61 years, 25.4% identified as Hispanic, 5.9% identified as non-Hispanic Black, and 17.5% lived in rural areas. At 6 months, more women in TCN received CGRA (18.7%) than those in TP (3%; odds ratio, 7.4; 95% CI, 3.0 to 18.3; P < .0001) or UC (2.5%; odds ratio, 8.9; 95% CI, 3.4 to 23.5; P < .0001). There were no significant differences in CGRA uptake between TP and UC. Commonly cited barriers to genetic counseling were lack of provider referral (33.7%) and cost (26.5%), whereas anticipated difficulty coping with test results (14.0%) and cost (41.2%) were barriers for genetic testing. CONCLUSION: TCN increased CGRA uptake in a group of geographically and ethnically diverse high-risk breast and ovarian cancer survivors. Remote personalized interventions that incorporate evidence-based health communication and behavior change strategies may increase CGRA among women recruited from statewide cancer registries.

Understanding cancer genetic risk assessment motivations in a remote tailored risk communication and navigation intervention randomized controlled trial.

Background: National guidelines recommend cancer genetic risk assessment (CGRA) (i.e. genetic counseling prior to genetic testing) for women at increased risk for hereditary breast and ovarian cancer (HBOC). Less than one-half of eligible women obtain CGRA, leaving thousands of women and their family members without access to potentially life-saving cancer prevention interventions. Purpose: The Genetic Risk Assessment for Cancer Education and Empowerment Project (GRACE) addressed this translational gap, testing the efficacy of a tailored counseling and navigation (TCN) intervention vs. a targeted print brochure vs. usual care on CGRA intentions. Selected behavioral variables were theorized to mediate CGRA intentions. Methods: Breast and ovarian cancer survivors meeting criteria for guideline-based CGRA were recruited from three state cancer registries (N = 654), completed a baseline survey, and were randomized. TCN and targeted print arms received the brochure; TCN also participated in a tailored, telephone-based decision coaching and navigation session grounded in the Extended Parallel Process Model and Ottawa Decision Support Framework. Participants completed a one-month assessment. Logistic regression was used to compare the rate of CGRA intentions. CGRA intentions and theorized mediator scores (continuous level variables) were calculated using mixed model analysis. Results: CGRA intentions increased for TCN (53.2%) vs. targeted print (26.7%) (OR = 3.129; 95% CI: 2.028, 4.827, p < .0001) and TCN vs. usual care (23.1%) (OR = 3.778, CI: 2.422, 5.894, p < .0001). Perceived risk (p = 0.023) and self-efficacy (p = 0.035) mediated CGRA intentions in TCN. Conclusions: Improvements in CGRA intentions and theorized mediators support the use of a tailored communication intervention among women at increased HBOC risk. (Clinicaltrials.gov: NCT03326713.)Trial registration: ClinicalTrials.gov identifier: NCT03326713.

Effect of Problem-solving Treatment on Self-reported Disability Among Veterans With Gulf War Illness: A Randomized Clinical Trial.

Importance: Few evidence-based treatments are available for Gulf War illness (GWI). Behavioral treatments that target factors known to maintain the disability from GWI, such as problem-solving impairment, may be beneficial. Problem-solving treatment (PST) targets problem-solving impairment and is an evidence-based treatment for other conditions. Objective: To examine the efficacy of PST to reduce disability, problem-solving impairment, and physical symptoms in GWI. Design, Setting, and Participants: This multicenter randomized clinical trial conducted in the US Department of Veterans Affairs compared PST with health education in a volunteer sample of 511 Gulf War veterans with GWI and disability (January 1, 2015, to September 1, 2019); outcomes were assessed at 12 weeks and 6 months. Statistical analysis was conducted between January 1, 2019, and December 31, 2020. Interventions: Problem-solving treatment taught skills to improve problem-solving. Health education provided didactic health information. Both were delivered by telephone weekly for 12 weeks. Main Outcomes and Measures: The primary outcome was reduction from baseline to 12 weeks in self-report of disability (World Health Organization Disability Assessment Schedule). Secondary outcomes were reductions in self-report of problem-solving impairment and objective problem-solving. Exploratory outcomes were reductions in pain, pain disability, and fatigue. Results: A total of 268 veterans (mean [SD] age, 52.9 [7.3] years; 88.4% male; 66.8% White) were randomized to PST (n = 135) or health education (n = 133). Most participants completed all 12 sessions of PST (114 of 135 [84.4%]) and health education (120 of 133 [90.2%]). No difference was found between groups in reductions in disability at the end of treatment. Results suggested that PST reduced problem-solving impairment (moderate effect, 0.42; P = .01) and disability at 6 months (moderate effect, 0.39; P = .06) compared with health education. Conclusions and Relevance: In this randomized clinical trial of the efficacy of PST for GWI, no difference was found between groups in reduction in disability at 12 weeks. Problem-solving treatment had high adherence and reduced problem-solving impairment and potentially reduced disability at 6 months compared with health education. These findings should be confirmed in future studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02161133.

Sex differences in Epworth Sleepiness Scale normalization with continuous positive airway pressure.

STUDY OBJECTIVES: Continuous positive airway pressure (CPAP) improves sleepiness in patients with obstructive sleep apnea, but some patients remain sleepy. The objective of this study was to identify determinants that are associated with improvements in self-reported sleepiness in patients with obstructive sleep apnea on CPAP therapy. METHODS: A retrospective cohort study was performed in a clinic-based population to determine which variables contributed to the improvement in the Epworth Sleepiness Scale (ESS) in patients on CPAP therapy for OSA, stratified by baseline ESS score (< 11 or ≥ 11). Variables associated with ESS scores normalizing with CPAP were also assessed. RESULTS: Patients with a baseline high ESS score showed greater improvements in the ESS with CPAP. When looking at interactions between baseline ESS classification and changes in ESS, we found that a higher apnea-hypopnea index was only associated with improvement in the ESS among patients with a high baseline ESS. Other assessed factors or covariates were not significantly different. When looking at ESS normalization, we found that female sex and lower body mass index were associated with a lower likelihood of ESS normalization. The difference in the rate of ESS normalization between females and males was higher with more days on CPAP. CONCLUSIONS: Of all the assessed factors and covariates, only the apnea-hypopnea index was associated with the change in the ESS differently in patients with a high or normal baseline ESS score. ESS normalization rates were lower in females than in males, and this disparity was amplified by more days on CPAP. CITATION: Scharf MT, Zhang P, Walker NA, et al. Sex differences in Epworth Sleepiness Scale normalization with continuous positive airway pressure. J Clin Sleep Med. 2022;18(9):2273-2279.

Changing Trends in the Proportional Incidence and Five-year Net Survival of Screened and Non-screened Breast Cancers among Women During 1995-2011 in England.

Background and objectives: Uptake of breast cancer screening has been decreasing in England since 2007. However, the associated factors are unclear. On the other hand, survival among breast cancer patients have recently increased. We conducted a quasi-experimental analysis to test whether the trend-change in proportional incidence of non-screened cancers coincided with that in five-year net-survival. Methods: We extracted population-based proportional incidence and age-standardized five-year net-survival data from Public Health England that included English women with invasive breast cancer diagnosed during 1995-2011 (linked to death certificates, followed through 2016). Piece-wise log-linear models with change-point/joinpoint were used to estimate temporal trends. Results: Among 254,063 women in England with invasive breast cancer diagnosed during 1995-2011, there was downward-to-upward trend-change in proportional incidence of non-screened breast cancers (annual percent change [APC]=5.6 after 2007 versus APC=-3.5 before 2007, p<0.001) in diagnosis-year 2007, when a steeper upward-trend in age-standardized five-year net survival started (APC=5.7 after 2007/2008 versus APC=0.3 before 2007/2008, p<0.001). Net-survival difference of screened versus non-screened cancers also significantly narrowed (18% in 2007/2008 versus 5% in 2011). Similar associations were found in all strata of race, cancer stage, grade, and histology, except in Black patients or patients with stage I, stage III, or grade I cancer. Conclusions: There was a downward-to-upward trend-change in proportional incidence of non-screened breast cancers in 2007 that coincided with a steeper upward-trend in age-standardized five-year net survival among English women in 2007. Survival benefits of breast cancer screening decreased during 2007-2011. The data support reduction of breast cancer screening in some patients, but future validation studies are warranted.

Effect of the COVID-19 pandemic on surgical oncology practice-Results of an SSO survey.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic significantly affected healthcare delivery, shifting focus away from nonurgent care. The aim of this study was to examine the impact of the pandemic on the practice of surgical oncology. METHODS: A web-based survey of questions about changes in practice during the COVID-19 pandemic was approved by the Society of Surgical Oncology (SSO) Research and Executive Committees and sent by SSO to its members. RESULTS: A total of 121 SSO members completed the survey, 77.7% (94/121) of whom were based in the United States. Breast surgeons were more likely than their peers to refer patients to neoadjuvant therapy (p = 0.000171). Head and neck surgeons were more likely to refer patients to definitive nonoperative treatment (p = 0.044), while melanoma surgeons were less likely to do so (p = 0.029). In all, 79.2% (95/120) of respondents are currently using telemedicine. US surgeons were more likely to use telemedicine (p = 0.004). Surgeons believed telemedicine is useful for long-term/surveillance visits (70.2%, 80/114) but inappropriate (50.4%, 57/113) for new patient visits. CONCLUSION: COVID-19 pandemic resulted in increased use of neoadjuvant therapy, delays in operative procedures, and increased use of telemedicine. Telemedicine is perceived to be most efficacious for long-term/surveillance visits or postoperative visits.

The Opioid Analgesic Reduction Study (OARS)-a comparison of opioid vs. non-opioid combination analgesics for management of post-surgical pain: a double-blind randomized clinical trial.

BACKGROUND: Everyday people die unnecessarily from opioid overdose-related addiction. Dentists are among the leading prescribers of opioid analgesics. Opioid-seeking behaviors have been linked to receipt of initial opioid prescriptions following the common dental procedure of third molar extraction. With each opioid prescription, a patient's risk for opioid misuse or abuse increases. With an estimated 56 million tablets of 5 mg hydrocodone annually prescribed after third molar extractions in the USA, 3.5 million young adults may be unnecessarily exposed to opioids by dentists who are inadvertently increasing their patient's risk for addiction. METHODS: A double-blind, stratified randomized, multi-center clinical trial has been designed to evaluate whether a combination of over-the-counter non-opioid-containing analgesics is not inferior to the most prescribed opioid analgesic. The impacted 3rd molar extraction model is being used due to the predictable severity of the post-operative pain and generalizability of results. Within each site/clinic and gender type (male/female), patients are randomized to receive either OPIOID (hydrocodone/acetaminophen 5/300 mg) or NON-OPIOID (ibuprofen/acetaminophen 400/500 mg). Outcome data include pain levels, adverse events, overall patient satisfaction, ability to sleep, and ability to perform daily functions. To develop clinical guidelines and a clinical decision-making tool, pain management, extraction difficulty, and the number of tablets taken are being collected, enabling an experimental decision-making tool to be developed. DISCUSSION: The proposed methods address the shortcomings of other analgesic studies. Although prior studies have tested short-term effects of single doses of pain medications, patients and their dentists are interested in managing pain for the entire post-operative period, not just the first 12 h. After surgery, patients expect to be able to perform normal daily functions without feeling nauseous or dizzy and they desire a restful sleep at night. Parents of young people are concerned with the risks of opioid use and misuse, related either to treatments received or to subsequent use of leftover pills. Upon successful completion of this clinical trial, dentists, patients, and their families will be better able to make informed decisions regarding post-operative pain management. TRIAL REGISTRATION: ClinicalTrials.gov NCT04452344 . Registered on June 20, 2020.

Family type and cognitive function in older Chinese Americans: acculturation as a moderator.

OBJECTIVES: Acculturation to the mainstream culture and the settlement contexts could shape cognitive function of older immigrants. Guided by ecological theory, this study examines the interaction effect between individual acculturation and ecology of family on cognitive function among older Chinese Americans. METHODS: Data were derived from the Population Study of Chinese Elderly in Chicago (n = 3,019). Family types included tight-knit (high solidarity and low conflicts), unobligated-ambivalent (high solidarity and conflicts), commanding-conflicted (low solidarity and high conflicts), and detached (low solidarity and low conflicts). Acculturation was measured via language ability, media use, and ethnic social relations. Cognitive function was evaluated by global cognition, episodic memory, working memory, processing speed, and mini-mental state examination. Multiple regression analyses and interaction terms were used. RESULTS: Older adults in the commanding-conflicted type had the lowest cognitive function. After controlling confounding variables, higher levels of acculturation (b = 0.009, SE = 0.003, p < .01) were associated with higher levels of global cognition. Acculturation buffered the negative impact of having a commanding-conflicted relationship with children on global cognition (b = 0.070, SE = 0.016, p < .001). Language ability, media use, and ethnic social relations played a unique role in the relationships between family types and cognitive domains. CONCLUSION: Acculturation to the dominant culture is identified as a cultural asset for cognitive function in older Chinese Americans. Social services could protect cognitive function of older immigrants in the commanding-conflicted type through enhancing cultural participation. Future research could test how affective and cognitive aspects of acculturation affect health.

Multivariate survival analysis in big data: A divide-and-combine approach.

Multivariate failure time data are frequently analyzed using the marginal proportional hazards models and the frailty models. When the sample size is extraordinarily large, using either approach could face computational challenges. In this paper, we focus on the marginal model approach and propose a divide-and-combine method to analyze large-scale multivariate failure time data. Our method is motivated by the Myocardial Infarction Data Acquisition System (MIDAS), a New Jersey statewide database that includes 73,725,160 admissions to nonfederal hospitals and emergency rooms (ERs) from 1995 to 2017. We propose to randomly divide the full data into multiple subsets and propose a weighted method to combine these estimators obtained from individual subsets using three weights. Under mild conditions, we show that the combined estimator is asymptotically equivalent to the estimator obtained from the full data as if the data were analyzed all at once. In addition, to screen out risk factors with weak signals, we propose to perform the regularized estimation on the combined estimator using its combined confidence distribution. Theoretical properties, such as consistency, oracle properties, and asymptotic equivalence between the divide-and-combine approach and the full data approach are studied. Performance of the proposed method is investigated using simulation studies. Our method is applied to the MIDAS data to identify risk factors related to multivariate cardiovascular-related health outcomes.