• Association Between Decline in Slow Vital Capacity and Respiratory Insufficiency, Use of Assisted Ventilation, Tracheostomy, or Death in Patients With Amyotrophic Lateral Sclerosis

      Andrews, Jinsy A.; Meng, Lisa; Kulke, Sarah F.; Rudnicki, Stacy A.; Wolff, Andrew A.; Bozik, Michael E.; Malik, Fady I.; Shefner, Jeremy M.; Univ Arizona, Barrow Neurol Inst; Cytokinetics, Inc, South San Francisco, California; et al. (AMER MEDICAL ASSOC, 2018-01-01)
      IMPORTANCE The prognostic value of slow vital capacity (SVC) in relation to respiratory function decline and disease progression in patients with amyotrophic lateral sclerosis (ALS) is not well understood. OBJECTIVE To investigate the rate of decline in percentage predicted SVC and its association with respiratory-related clinical events and mortality in patients with ALS. DESIGN, SETTING, AND PARTICIPANTS This retrospective study included 893 placebo-treated patients from 2 large clinical trials (EMPOWER and BENEFIT-ALS, conducted from March 28, 2011, to November 1, 2012, and from October 23, 2012, to March 21, 2014, respectively) and an ALS trial database (PRO-ACT, containing studies completed between 1990 and 2010) to investigate the rate of decline in SVC. Data from the EMPOWER trial (which enrolled adults with possible, probable, or definite ALS; symptom onset within 24 months before screening; and upright SVC at least 65% of predicted value for age, height, and sex) were used to assess the relationship of SVC to respiratory-related clinical events; 456 patients randomized to placebo were used in this analysis. The 2 clinical trials included patients from North America, Australia, and Europe. MAIN OUTCOMES AND MEASURES Clinical events included the earlier of time to death or time to decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) respiratory subdomain, time to onset of respiratory insufficiency, time to tracheostomy, and all-cause mortality. RESULTS Among 893 placebo-treated patients with ALS, the mean (SD) patient age was 56.7 (11.2) years, and the mean (SD) SVC was 90.5%(17.1%) at baseline; 65.5%(585 of 893) were male, and 20.5%(183 of 893) had bulbar-onset ALS. In EMPOWER, average decline of SVC from baseline through 1.5-year follow-up was - 2.7 percentage points per month. Steeper declines were found in patients older than 65 years (-3.6 percentage points per month [P=.005 vs < 50 years and P=.007 vs 50-65 years) and in patients with an ALSFRS-R total score of 39 or less at baseline (-3.1 percentage points per month [P<.001 vs >39]). When the rate of decline of SVC was slower by 1.5 percentage points per month in the first 6 months, risk reductions for events after 6 months were 19% for decline in the ALSFRS-R respiratory subdomain or death after 6 months, 22% for first onset of respiratory insufficiency or death after 6 months, 23% for first occurrence of tracheostomy or death after 6 months, and 23% for death at any time after 6 months (P<.001 for all). CONCLUSIONS AND RELEVANCE The rate of decline in SVC is associated with meaningful clinical events in ALS, including respiratory failure, tracheostomy, or death, suggesting that it is an important indicator of clinical progression.
    • Association Between Hormone-Modulating Breast Cancer Therapies and Incidence of Neurodegenerative Outcomes for Women With Breast Cancer

      Branigan, Gregory L; Soto, Maira; Neumayer, Leigh; Rodgers, Kathleen; Brinton, Roberta Diaz; Univ Arizona, Ctr Innovat Brain Sci; Univ Arizona, Coll Med, Dept Pharmacol; Univ Arizona, MD PhD Training Program, Coll Med; Univ Arizona, Dept Surg, Coll Med; Univ Arizona, Dept Obstet & Gynecol, Coll Med; et al. (AMER MEDICAL ASSOC, 2020-03-02)
      Question Is hormone-modulating therapy associated with neurodegenerative disease in women with breast cancer? Findings In this cohort study of 57 & x202f;843 perimenopausal- to postmenopausal-aged women with breast cancer, exposure to hormone-modulating therapy (tamoxifen and aromatase inhibitors, especially exemestane) was associated with a significant decrease in the number of women who received a diagnosis of neurodegenerative disease, most specifically Alzheimer disease. Meaning With the increased life expectancy seen after treatment, therapy selection for breast cancer should include a careful discussion of the risks and benefits of each treatment option that may be associated with a reduced risk of neurodegenerative disease. Importance The association between exposure to hormone-modulating therapy (HMT) as breast cancer treatment and neurodegenerative disease (NDD) is unclear. Objective To determine whether HMT exposure is associated with the risk of NDD in women with breast cancer. Design, Setting, and Participants This retrospective cohort study used the Humana claims data set from January 1, 2007, to March 31, 2017. The Humana data set contains claims from private-payer and Medicare insurance data sets from across the United States with a population primarily residing in the Southeast. Patient claims records were surveyed for a diagnosis of NDD starting 1 year after breast cancer diagnosis for the duration of enrollment in the claims database. Participants were 57 & x202f;843 women aged 45 years or older with a diagnosis of breast cancer. Patients were required to be actively enrolled in Humana claims records for 6 months prior to and at least 3 years after the diagnosis of breast cancer. The analyses were conducted between January 1 and 15, 2020. Exposure Hormone-modulating therapy (selective estrogen receptor modulators, estrogen receptor antagonists, and aromatase inhibitors). Main Outcomes and Measures Patients receiving HMT for breast cancer treatment were identified. Survival analysis was used to determine the association between HMT exposure and diagnosis of NDD. A propensity score approach was used to minimize measured and unmeasured selection bias. Results Of the 326 & x202f;485 women with breast cancer in the Humana data set between 2007 and 2017, 57 & x202f;843 met the study criteria. Of these, 18 & x202f;126 (31.3%; mean [SD] age, 76.2 [7.0] years) received HMT, whereas 39 & x202f;717 (68.7%; mean [SD] age, 76.8 [7.0] years) did not receive HMT. Mean (SD) follow-up was 5.5 (1.8) years. In the propensity score-matched population, exposure to HMT was associated with a decrease in the number of women who received a diagnosis of NDD (2229 of 17 878 [12.5%] vs 2559 of 17 878 [14.3%]; relative risk, 0.89; 95% CI, 0.84-0.93; P < .001), Alzheimer disease (877 of 17 878 [4.9%] vs 1068 of 17 878 [6.0%]; relative risk, 0.82; 95% CI, 0.75-0.90; P < .001), and dementia (1862 of 17 878 [10.4%] vs 2116 of 17 878 [11.8%]; relative risk, 0.88; 95% CI, 0.83-0.93; P < .001). The number needed to treat was 62.51 for all NDDs, 93.61 for Alzheimer disease, and 69.56 for dementia. Conclusions and Relevance Among patients with breast cancer, tamoxifen and steroidal aromatase inhibitors were associated with a decrease in the number who received a diagnosis of NDD, specifically Alzheimer disease and dementia. This cohort study uses the Humana claims data set to examine whether exposure to hormone-modulating therapy is associated with the risk of neurodegenerative disease in women with breast cancer.
    • Association Between Noninvasive Fibrosis Markers and Postoperative Mortality After Hepatectomy for Hepatocellular Carcinoma

      Maegawa, Felipe B; Shehorn, Lauren; Aziz, Hassan; Kettelle, John; Jie, Tun; Riall, Taylor S; Univ Arizona, Dept Surg (AMER MEDICAL ASSOC, 2019-01-18)
      IMPORTANCE The selection criteria for hepatectomy for hepatocellular carcinoma (HCC) is not well established. The role of noninvasive fibrosis markers in this setting is unknown in the US population. OBJECTIVE To evaluate whether aspartate aminotransferase-platelet ratio index (APRI) and fibrosis 4 (Fib4) values are associated with perioperative mortality and overall survival after hepatectomy for HCC. DESIGN, SETTING, AND PARTICIPANTS In a multicenter cohort study, Veterans Administration Corporate Data Warehouse was used to evaluate a retrospective cohort of 475 veterans who underwent hepatectomy for HCC between January 1, 2000, and December 31, 2012, in Veterans Administration hospitals. Data analysis occurred between September 30, 2016, and December 30, 2017. Logistic regression, survival analysis, and change in concordance index analysis were performed to evaluate the association between APRI and Fib4 values and mortality. EXPOSURES The cohort was stratified based on preoperative APRI and Fib4 values. Analysis was performed accounting for the validated and established predictors of outcome. MAIN OUTCOMES AND MEASURES Thirty-day mortality, 90-day mortality, and overall survival were the primary outcomes. An APRI value greater than 1.5 was considered high risk (cirrhosis), and an Fib4 value greater than 4.0 was considered high risk (advanced fibrosis). Portal hypertension (diagnosis of ascites or encephalopathy indicates presence of portal hypertension) and Child-Turcotte-Pugh (CTP) class (A indicates preserved liver function; B, mild to moderate liver dysfunction) served as 2 other measures of liver function. RESULTS A total of 475 patients with HCC underwent hepatectomy. The mean (SD) age was 65.6 (9.4) years; Model for End-Stage Liver Disease score, 8.9 (3.1); and body mass index, 28.1 (4.9) (calculated as weight in kilograms divided by height in meters squared). A total of 361 patients (76.0%) were men, 294 (61.9%) were white; 308 (64.8%) were hepatitis C positive, and 346 (72.8%) were categorized as CTP class A. The most common surgical procedure was partial lobectomy, with 321 (67.6%) procedures. The APRI value greater than 1.5 vs 1.5 or lower was associated with increased 30-day mortality (odds ratio [OR], 6.45; 95% CI, 2.80-14.80) and 90-day mortality (OR, 2.65; 95% CI, 1.35-5.22), as was Fib4 greater than 4.0 vs Fib4 4.0 or lower for 30-day mortality (OR, 5.41; 95% CI, 2.35-12.50) and 90-day mortality (OR, 2.74; 95% CI, 1.41-5.35). Survival analysis showed that overall survival was significantly different for APRI greater than 1.5 vs 1.5 or lower (mean survival time, 3.6 vs 5.4 years; log-rank P <.001) and Fib4 greater than 4.0 vs 4.0 or lower (mean survival time, 4.1 vs 5.3 years; log rank P =.01). Adjusted Cox proportional hazards regression analysis revealed that elevated APRI was significantly associated with worse survival (hazard ratio [HR], 1.13; 95% CI, 1.03-1.23) but Fib4 values were not (HR, 1.04; 95% CI, 0.99-1.09). Change in concordance index showed that APRI and Fib4 improved the ability of CTP class and portal hypertension to predict postoperative mortality. CONCLUSIONS AND RELEVANCE Elevated APRI and Fib4 values, which are noninvasive markers of fibrosis, were associated with higher perioperative mortality. The APRI was also associated with worse overall survival. Use of APRI and Fib4 measures improved the ability of established markers to predict postoperative mortality. These findings suggest incorporating APRI and Fib4 to the selection process for hepatectomy for HCC as predictors associated with mortalitymay be warranted.
    • Association Between Thyroid Disorders and Colorectal Cancer Risk in Adult Patients in Taiwan

      L’Heureux, Abby; Wieland, Daniel R.; Weng, Chien-Huan; Chen, Yi-Huei; Lin, Ching-Heng; Lin, Tseng-Hsi; Weng, Chien-Hsiang; Univ Arizona (AMER MEDICAL ASSOC, 2019-05-17)
      IMPORTANCE Thyroid hormones have been shown to affect several important pathways in cancer development, including colorectal cancer (CRC). Clinical studies examining the association between thyroid disorders and colorectal cancer have conflicting results and have predominantly involved white populations. OBJECTIVE To determine if a diagnosis of hyperthyroidism or hypothyroidism is associated with the risk of developing colorectal cancer in an East Asian population. DESIGN, SETTING, AND PARTICIPANTS This nationwide population-based case-control study was conducted from April 27, 2018, to November 8, 2018, using the Taiwanese National Health Insurance Research Database. Participants were adults (n = 139 426) either with a new diagnosis (between 2008 and 2013) of primary colorectal cancer without a history of cancer, or without cancer. Cases and controls were matched 11 by age, sex, and index date. Diagnosis of hyperthyroidism or hypothyroidism prior to the diagnosis of colorectal cancer (or the same index date in controls) was then determined. MAIN OUTCOMES AND MEASURES Risk differences in developing colorectal cancer among patients with a medical history of hyperthyroidism or hypothyroidism. RESULTS A total of 139 426 patients were included in the study, and 69 713 individuals made up each case and control group, which were both predominantly male (39 872 [57.2%]). The mean (SD) age for those with CRC was 65.8 (13.7) years and for those without CRC was 66.0 (13.6) years. Both hyperthyroidism (adjusted odds ratio [aOR], 0.77; 95% CI, 0.69-0.86; P < .001) and hypothyroidism (aOR, 0.78; 95% CI, 0.65-0.94; P = .008) were associated with a decreased risk of being diagnosed with colorectal cancer. An inverse association of rectal cancer was found among patients aged 50 years or older with a history of hypothyroidism despite treatment (aOR, 0.54; 95% CI, 0.39-0.74; P < .001). A history of hyperthyroidism in all age groups was associated with a lower risk of colon cancer (aOR, 0.74; 95% CI, 0.64-0.85; P < .001), with a stronger association seen among those younger than 50 years (aOR, 0.55; 95% CI, 0.36-0.85; P = .007). CONCLUSIONS AND RELEVANCE In this study, hypothyroidism appeared to be associated with a lower risk of rectal cancer, whereas hyperthyroidism appeared to be associated with a lower risk of colon cancer. Because of this, biochemical in vivo research and epidemiologic studies appear to be needed to further clarify the nature of these associations.
    • Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis

      Kidwell, Chelsea S; Univ Arizona, Dept Neurol (AMER MEDICAL ASSOC, 2019-04-01)
      IMPORTANCE Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. OBJECTIVE To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) epsilon 4 alleles, the most potent genetic risk factor for ICH. DESIGN, SETTING, AND PARTICIPANTS This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. MAIN OUTCOMES AND MEASURES Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. RESULTS In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE epsilon 4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE epsilon 4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity. CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
    • Association of Disease Recurrence With Survival Outcomes in Patients With Cutaneous Squamous Cell Carcinoma of the Head and Neck Treated With Multimodality Therapy

      Sun, Lillian; Chin, Re-I; Gastman, Brian; Thorstad, Wade; Yom, Sue S; Reddy, Chandana A; Nussenbaum, Brian; Wang, Steven J; Knackstedt, Thomas; Vidimos, Allison T; et al. (AMER MEDICAL ASSOC, 2019-04-01)
      IMPORTANCE It has previously been demonstrated that immunosuppressed patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) treated with surgery and postoperative radiotherapy have significantly inferior disease-related outcomes compared with immunocompetent patients, but data on outcomes after disease recurrence are limited. OBJECTIVES To report survival outcomes in patients with cSCC-HN after disease recurrence after surgery and postoperative radiotherapy and to investigate the association of immune status with disease-related outcomes. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional study of 205 patients treated at the Cleveland Clinic, Washington University in St Louis, and the University of California, San Francisco, in which patients who underwent surgical resection and postoperative radiotherapy for primary or recurrent stage I to IV (nonmetastatic) cSCC-HN between January 1, 1995, and December 31, 2014, were identified. Patients with any disease recurrence, defined as local, regional, and/or distant failure, were included. Patients were categorized as immunosuppressed if they received a diagnosis of chronic hematologic malignant neoplasm or HIV or AIDS, or were treated with immunosuppressive therapy for organ transplantation 6 months or more before diagnosis. Statistical analysis was conducted from January 1, 1995, to December 31, 2015. MAIN OUTCOMES AND MEASURES Overall survival calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS Of the 205 patients in the original cohort, 72 patients (63 men and 9 women; median age, 71 years [range, 43-91 years]) developed disease recurrence after surgery and postoperative radiotherapy. Forty patients (55.6%) were immunosuppressed, and 32 patients (44.4%) were immunocompetent. Locoregional recurrence was the most common first pattern of failure for both groups (31 immunosuppressed patients [77.5%]; 21 immunocompetent patients [65.6%]). After any recurrence, 1-year overall survival was 43.2%(95% CI, 30.9%-55.4%), and median survival was 8.4 months. For patients for whom information on salvage treatment was available (n = 45), those not amenable to surgical salvage had significantly poorer median cumulative incidence of survival compared with those who were amenable to surgical salvage (4.7 months; 95% CI, 3.7-7.0 months vs 26.1 months; 95% CI, 6.6 months to not reached; P=.01), regardless of their immune status. CONCLUSIONS AND RELEVANCE Results of this study suggest that patients with cSCC-HN who experience disease recurrence after definitive treatment with surgery and postoperative radiotherapy have poor survival, irrespective of immune status. Survival rates are low for patients with recurrent disease that is not amenable to surgical salvage. The low rate of successful salvage underscores the importance of intensifying upfront treatment to prevent recurrence.
    • Association of Early Inhaled Nitric Oxide With the Survival of Preterm Neonates With Pulmonary Hypoplasia

      Ellsworth, Kevin R.; Ellsworth, Marc A.; Weaver, Amy L.; Mara, Kristin C.; Clark, Reese H.; Carey, William A.; Univ Arizona, Dept Child Hlth (AMER MEDICAL ASSOC, 2018-07)
      IMPORTANCE Pulmonary hypoplasia affects a very small percentage of preterm neonates, but its presence is associated with high rates of mortality. OBJECTIVE To determine whether treatment with inhaled nitric oxide during the first week of life was associated with improved in-hospital survival in a cohort of extremely preterm neonates with pulmonary hypoplasia. DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from the Pediatrix Medical Group's Clinical Data Warehouse, a data set containing information from more than 350 neonatal intensive care units in 35 US states and Puerto Rico. Since inhaled nitric oxide was not randomly prescribed, we used 1-to-1 propensity score matching to reduce the imbalance of measured covariates between the 2 treatment groups. The initial, unmatched cohort included singleton neonates who were born between 22 and 29 weeks' gestation, had a birth weight of 400 g or more, were diagnosed with pulmonary hypoplasia as a cause of their respiratory distress, remained free of major anomalies, and were discharged between January 1, 2000, and December 31, 2014. We defined exposure as the initiation of inhaled nitric oxide on day t in days 0 to 7 of the life of a neonate. Each exposed neonate was matched 1-to-1 to a neonate who had not initiated inhaled nitric oxide on a given day. MAIN OUTCOMES AND MEASURES The primary outcome was mortality defined as death prior to transfer or discharge home. Secondary outcomes were any-stage necrotizing enterocolitis, retinopathy of prematurity requiring treatment, chronic lung disease, and periventricular leukomalacia. RESULTS Among 92 635 neonates in our study sample, we identified 767 (0.8%) with pulmonary hypoplasia who met all study inclusion criteria, of whom 185 (0.2%) were exposed to inhaled nitric oxide. Among 151 matched pairs of exposed and unexposed neonates, we did not identify a significant association between inhaled nitric oxide use and mortality (hazard ratio [NM, 079; 95% CI, 0.57411). Subgroup analyses of neonates with and without persistent pulmonary hypertension (PPHN) likewise revealed no significant association between inhaled nitric oxide use and mortality (pulmonary hypoplasia with PPHN: HR, 0.67; 95% CI, 0.45-1.01; pulmonary hypoplasia without PPHN: HR, 1.11; 95% CI, 0.61-2.02), but these findings may have been influenced by ascertainment bias. CONCLUSIONS AND RELEVANCE Early treatment with inhaled nitric oxide is not associated with improved survival among extremely preterm neonates with pulmonary hypoplasia. Clinical trials are warranted to clarify the matter.
    • Association of Gender and Race With Allocation of Advanced Heart Failure Therapies

      Breathett, Khadijah; Yee, Erika; Pool, Natalie; Hebdon, Megan; Crist, Janice D.; Yee, Ryan H.; Knapp, Shannon M.; Solola, Sade; Luy, Luis; Herrera-Theut, Kathryn; et al. (AMER MEDICAL ASSOC, 2020-07)
      This qualitative study examines how patient race and gender are associated with clinician recommendations for allocation of advanced heart failure therapies. Importance Racial bias is associated with the allocation of advanced heart failure therapies, heart transplants, and ventricular assist devices. It is unknown whether gender and racial biases are associated with the allocation of advanced therapies among women. Objective To determine whether the intersection of patient gender and race is associated with the decision-making of clinicians during the allocation of advanced heart failure therapies. Design, Setting, and Participants In this qualitative study, 46 US clinicians attending a conference for an international heart transplant organization in April 2019 were interviewed on the allocation of advanced heart failure therapies. Participants were randomized to examine clinical vignettes that varied 1:1 by patient race (African American to white) and 20:3 by gender (women to men) to purposefully target vignettes of women patients to compare with a prior study of vignettes of men patients. Participants were interviewed about their decision-making process using the think-aloud technique and provided supplemental surveys. Interviews were analyzed using grounded theory methodology, and surveys were analyzed with Wilcoxon tests. Exposure Randomization to clinical vignettes. Main Outcomes and Measures Thematic differences in allocation of advanced therapies by patient race and gender. Results Among 46 participants (24 [52%] women, 20 [43%] racial minority), participants were randomized to the vignette of a white woman (20 participants [43%]), an African American woman (20 participants [43%]), a white man (3 participants [7%]), and an African American man (3 participants [7%]). Allocation differences centered on 5 themes. First, clinicians critiqued the appearance of the women more harshly than the men as part of their overall impressions. Second, the African American man was perceived as experiencing more severe illness than individuals from other racial and gender groups. Third, there was more concern regarding appropriateness of prior care of the African American woman compared with the white woman. Fourth, there were greater concerns about adequacy of social support for the women than for the men. Children were perceived as liabilities for women, particularly the African American woman. Family dynamics and finances were perceived to be greater concerns for the African American woman than for individuals in the other vignettes; spouses were deemed inadequate support for women. Last, participants recommended ventricular assist devices over transplantation for all racial and gender groups. Surveys revealed no statistically significant differences in allocation recommendations for African American and white women patients. Conclusions and Relevance This national study of health care professionals randomized to clinical vignettes that varied only by gender and race found evidence of gender and race bias in the decision-making process for offering advanced therapies for heart failure, particularly for African American women patients, who were judged more harshly by appearance and adequacy of social support. There was no associated between patient gender and race and final recommendations for allocation of advanced therapies. However, it is possible that bias may contribute to delayed allocation and ultimately inequity in the allocation of advanced therapies in a clinical setting. Question Is bias against a patient's gender and race associated with the allocation of advanced heart failure therapies? Findings In a qualitative study of 46 health care professionals, there was more bias against women compared with men when evaluating appearance and social support, particularly among African American women. Final recommendations were not different for groups defined by gender or race; all were offered ventricular assist devices rather than transplantation during interviews. Meaning Although gender and race were not associated with allocation of advanced heart failure therapies in this study, there was evidence of bias, which could contribute to delayed and lower allocation of advanced therapies to women.
    • Association of Light Physical Activity Measured by Accelerometry and Incidence of Coronary Heart Disease and Cardiovascular Disease in Older Women

      LaCroix, Andrea Z; Bellettiere, John; Rillamas-Sun, Eileen; Di, Chongzhi; Evenson, Kelly R; Lewis, Cora E; Buchner, David M; Stefanick, Marcia L; Lee, I-Min; Rosenberg, Dori E; et al. (AMER MEDICAL ASSOC, 2019-03-15)
      IMPORTANCE To our knowledge, no studies have examined light physical activity (PA) measured by accelerometry and heart disease in older women. OBJECTIVE To investigate whether higher levels of light PA were associated with reduced risks of coronary heart disease (CHD) or cardiovascular disease (CVD) in older women. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of older women from baseline (March 2012 to April 2014) through February 28, 2017, for up to 4.91 years. The setting was community-dwelling participants from the Women's Health Initiative. Participants were ambulatory women with no history of myocardial infarction or stroke. EXPOSURES Data from accelerometers worn for a requested 7 days were used to measure light PA. MAIN OUTCOMES AND MEASURES Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% CIs for physician-adjudicated CHD and CVD events across light PA quartiles adjusting for possible confounders. Light PA was also analyzed as a continuous variable with and without adjustment for moderate to vigorous PA (MVPA). RESULTS Among 5861 women (mean [SD] age, 78.5 [6.7] years), 143 CHD events and 570 CVD events were observed. The HRs for CHD in the highest vs lowest quartiles of light PA were 0.42 (95% CI, 0.25-0.70; P for trend <. 001) adjusted for age and race/ethnicity and 0.58 (95% CI, 0.34-0.99; P for trend = .004) after additional adjustment for education, current smoking, alcohol consumption, physical functioning, comorbidity, and self-rated health. Corresponding HRs for CVD in the highest vs lowest quartiles of light PA were 0.63 (95% CI, 0.49-0.81; P for trend <. 001) and 0.78 (95% CI, 0.60-1.00; P for trend = .004). The HRs for a 1-hour/day increment in light PA after additional adjustment for MVPA were 0.86 (95% CI, 0.73-1.00; P for trend = .05) for CHD and 0.92 (95% CI, 0.85-0.99; P for trend = .03) for CVD. CONCLUSIONS AND RELEVANCE The present findings support the conclusion that all movement counts for the prevention of CHD and CVD in older women. Large, pragmatic randomized trials are needed to test whether increasing light PA among older women reduces cardiovascular risk.
    • Association of Physical Activity and Fracture Risk Among Postmenopausal Women

      LaMonte, Michael J; Wactawski-Wende, Jean; Larson, Joseph C; Mai, Xiaodan; Robbins, John A; LeBoff, Meryl S; Chen, Zhao; Jackson, Rebecca D; LaCroix, Andrea Z; Ockene, Judith K; et al. (AMER MEDICAL ASSOC, 2019-10-25)
      IMPORTANCE Physical activity is inversely associated with hip fracture risk in older women. However, the association of physical activity with fracture at other sites and the role of sedentary behavior remain unclear. OBJECTIVE To assess the associations of physical activity and sedentary behavior with fracture incidence among postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS The Women's Health Initiative prospective cohort study enrolled 77 206 postmenopausal women aged 50 to 79 years between October 1993 and December 1998 at 40 US clinical centers. Participants were observed for outcomes through September 2015, with data analysis conducted from June 2017 to August 2019. EXPOSURES Self-reported physical activity and sedentary time. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) and 95% CIs for total and site-specific fracture incidence. RESULTS During a mean (SD) follow-up period of 14.0 (5.2) years among 77 206 women (mean [SD] age, 63.4 [7.3] years; 66 072 [85.6%] white), 25 516 (33.1%) reported a first incident fracture. Total physical activity was inversely associated with the multivariable-adjusted risk of hip fracture (>17.7 metabolic equivalent [MET] h/wk vs none: HR, 0.82; 95% CI, 0.72-0.95; P for trend < .001). Inverse associations with hip fracture were also observed for walking (>7.5 MET h/wk vs none: HR, 0.88; 95% CI, 0.78-0.98; P for trend = .01), mild activity (HR, 0.82; 95% CI, 0.73-0.93; P for trend = .003), moderate to vigorous activity (HR, 0.88; 95% CI, 0.81-0.96; P for trend = .002), and yard work (HR, 0.90; 95% CI, 0.82-0.99; P for trend = .04). Total activity was positively associated with knee fracture (>17.7 MET h/wk vs none: HR, 1.26; 95% CI, 1.05-1.50; P for trend = .08). Mild activity was associated with lower risks of clinical vertebral fracture (HR, 0.87; 95% CI, 0.78-0.96; P for trend = .006) and total fractures (HR, 0.91; 95% CI, 0.87-0.94; P for trend < .001). Moderate to vigorous activity was positively associated with wrist or forearm fracture (HR, 1.09; 95% CI, 1.03-1.15; P for trend = .004). After controlling for covariates and total physical activity, sedentary time was positively associated with total fracture risk (>9.5 h/d vs <6.5 h/d: HR, 1.04; 95% CI, 1.01-1.07; P for trend = .01). When analyzed jointly, higher total activity mitigated some of the total fracture risk associated with sedentary behavior. Analysis of time-varying exposures resulted in somewhat stronger associations for total physical activity, whereas those for sedentary time were materially unchanged. CONCLUSIONS AND RELEVANCE In older ambulatory women, higher total physical activity was associated with lower total and hip fracture risk but higher knee fracture risk. Mild activity and walking were associated with lower hip fracture risk, a finding with important public health implications because these activities are common in older adults. The positive association between sedentary time and total fracture risk requires further investigation.
    • Association of Statewide Implementation of the Prehospital Traumatic Brain Injury Treatment Guidelines With Patient Survival Following Traumatic Brain Injury: The Excellence in Prehospital Injury Care (EPIC) Study

      Spaite, Daniel W; Bobrow, Bentley J; Keim, Samuel M; Barnhart, Bruce; Chikani, Vatsal; Gaither, Joshua B; Sherrill, Duane; Denninghoff, Kurt R; Mullins, Terry; Adelson, P David; et al. (AMER MEDICAL ASSOC, 2019-05-08)
      Importance Traumatic brain injury (TBI) is a massive public health problem. While evidence-based guidelines directing the prehospital treatment of TBI have been promulgated, to our knowledge, no studies have assessed their association with survival. Objective To evaluate the association of implementing the nationally vetted, evidence-based, prehospital treatment guidelines with outcomes in moderate, severe, and critical TBI. Design, Setting, and Participants The Excellence in Prehospital Injury Care (EPIC) Study included more than 130 emergency medical services systems/agencies throughout Arizona. This was a statewide, multisystem, intention-to-treat study using a before/after controlled design with patients with moderate to critically severe TBI (US Centers for Disease Control and Prevention Barell Matrix-Type 1 and/or Abbreviated Injury Scale Head region severity >= 3) transported to trauma centers between January 1, 2007, and June 30, 2015. Data were analyzed between October 25, 2017, and February 22, 2019. Interventions Implementation of the prehospital TBI guidelines emphasizing avoidance/treatment of hypoxia, prevention/correction of hyperventilation, and avoidance/treatment of hypotension. Main Outcomes and Measures Primary: survival to hospital discharge; secondary: survival to hospital admission. Results Of the included patients, the median age was 45 years, 14666 (67.1%) were men, 7181 (32.9%) were women; 16408 (75.1% ) were white, 1400 (6.4%) were Native American, 743 (3.4% ) were Black, 237 (1.1%) were Asian, and 2791 (12.8%) were other race/ethnicity. Of the included patients, 21852 met inclusion criteria for analysis (preimplementation phase [P1]: 15228; postimplementation [P3]: 6624). The primary analysis (P3 vs P1) revealed an adjusted odds ratio (aOR) of 1.06 (95% CI, 0.93-1.21; P = .40) for survival to hospital discharge. The aOR was 1.70 (95% CI, 1.38-2.09; P < .001) for survival to hospital admission. Among the severe injury cohorts (but not moderate or critical), guideline implementation was significantly associated with survival to discharge (Regional Severity Score-Head 3-4: aOR, 2.03; 95% CI, 1.52-2.72; P < .001; Injury Severity Score 16-24: aOR, 1.61; 95% CI, 1.07-2.48; P = .02). This was also true for survival to discharge among the severe, intubated subgroups (Regional Severity Score-Head 3-4: aOR, 3.14; 95% CI, 1.65-5.98; P < .001; Injury Severity Score 16-24: aOR, 3.28; 95% CI, 1.19-11.34; P = .02). Conclusions and Relevance Statewide implementation of the prehospital TBI guidelines was not associated with significant improvement in overall survival to hospital discharge (across the entire, combined moderate to critical injury spectrum). However, adjusted survival doubled among patients with severe TBI and tripled in the severe, intubated cohort. Furthermore, guideline implementation was significantly associated with survival to hospital admission. These findings support the widespread implementation of the prehospital TBI treatment guidelines.
    • Association of Time to Treatment With Short-term Outcomes for Pediatric Patients With Refractory Convulsive Status Epilepticus

      Gaínza-Lein, Marina; Sánchez Fernández, Iván; Jackson, Michele; Abend, Nicholas S.; Arya, Ravindra; Brenton, J. Nicholas; Carpenter, Jessica L.; Chapman, Kevin E.; Gaillard, William D.; Glauser, Tracy A.; et al. (AMER MEDICAL ASSOC, 2018-04)
      IMPORTANCE Treatment delay for seizures can lead to longer seizure duration. Whether treatment delay is associated with major adverse outcomes, such as death, remains unknown. OBJECTIVE To evaluate whether untimely first-line benzodiazepine treatment is associated with unfavorable short-term outcomes. DESIGN, SETTING, AND PARTICIPANTS This multicenter, observational, prospective cohort study included 218 pediatric patients admitted between June 1, 2011, and July 7, 2016, into the 11 tertiary hospitals in the United States within the Pediatric Status Epilepticus Research Group. Patients, ranging in age from 1 month to 21 years, with refractory convulsive status epilepticus (RCSE) that did not stop after the administration of at least 2 antiseizure medications were included. Patients were divided into 2 cohorts: those who received the first-line benzodiazepine treatment in less than 10 minutes and those who received it 10 or more minutes after seizure onset (untimely). Data were collected and analyzed from June 1, 2011, to July 7, 2016. MAIN OUTCOMES AND MEASURES The primary outcome was death during the related hospital admission. The secondary outcome was the need for continuous infusion for seizure termination. Multivariate analysis of mortality controlled for structural cause, febrile RCSE, age, and previous neurological history (including previous RCSE events). Use of continuous infusions was additionally adjusted for generalized RCSE, continuous RCSE, and 5 or more administrations of antiseizure medication. RESULTS A total of 218 patients were included, among whom 116 (53.2%) were male and the median (interquartile range) age was 4.0 (1.2-9.6) years. The RCSE started in the prehospital setting for 139 patients (63.8%). Seventy-four patients (33.9%) received their first-line benzodiazepine treatment in less than 10 minutes, and 144 (66.1%) received untimely first-line benzodiazepine treatment. Multivariate analysis showed that patients who received untimely first-line benzodiazepine treatment had higher odds of death (adjusted odds ratio [AOR], 11.0; 95% CI, 1.43 to infinity; P = .02), had greater odds of receiving continuous infusion (AOR, 1.8; 95% CI, 1.01-3.36; P = .047), had longer convulsive seizure duration (AOR, 2.6; 95% CI, 1.38-4.88; P = .003), and had more frequent hypotension (AOR 2.3; 95% CI, 1.16-4.63; P = .02). In addition, the timing of the first-line benzodiazepine treatment was correlated with the timing of the second-line (95% CI, 0.64-0.95; P < .001) and third-line antiseizure medications (95% CI, 0.25-0.78; P < .001). CONCLUSIONS AND RELEVANCE Among pediatric patients with RCSE, an untimely first-line benzodiazepine treatment is independently associated with a higher frequency of death, use of continuous infusions, longer convulsion duration, and more frequent hypotension. Results of this study raise the question as to whether poor outcomes could, in part, be prevented by earlier administration of treatment.
    • Benefits and Harms of Omalizumab Treatment in Adolescent and Adult Patients With Chronic Idiopathic (Spontaneous) Urticaria: A Meta-analysis of "Real-world" Evidence

      Tharp, Michael D; Bernstein, Jonathan A; Kavati, Abhishek; Ortiz, Benjamin; MacDonald, Karen; Denhaerynck, Kris; Abraham, Ivo; Lee, Christopher S; Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci; Univ Arizona, Dept Family & Community Med, Coll Med (AMER MEDICAL ASSOC, 2018-11-14)
      IMPORTANCE Omalizumab is indicated for the management of chronic idiopathic urticaria (CIU) (also known as chronic spontaneous urticaria) in adolescents and adults with persistent hives not controlled with antihistamines. The effectiveness of omalizumab in the real-world management of CIU is largely unknown. OBJECTIVE To quantitatively synthesize what is known about the benefits and harms of omalizumab in the real-world clinical management of CIU regarding urticaria activity, treatment response, and adverse events. DATA SOURCES Published observational studies (January 1, 2006, to January 1, 2018) and scientific abstracts on the effectiveness of omalizumab in CIU were identified using PubMed, Embase, Web of Science, and Cochrane search engines; references were searched to identify additional studies. STUDY SELECTION Included studies were observational in design and included at least 1 outcome in common with other studies and at a concurrent time point of exposure to omalizumab. A total of 67 articles (35.2% of those screened) were included in the analysis. DATA EXTRACTION AND SYNTHESIS PRISMA and MOOSE guidelines were followed; independent selection and data extraction were completed by 2 observers. Random-effects meta-analyses were performed. MAIN OUTCOMES AND MEASURES Main outcomes were change in weekly Urticaria Activity Score (UAS7; range, 0-42), change in Urticaria Activity Score (UAS; range 0-6) (higher score indicating worse outcome in both scales), complete and partial response rates (percentages), and adverse event rate (percentage). RESULTS Omalizumab therapy was associated with an improvement in UAS7 scores (-25.6 points, 95% CI, -28.2 to -23.0; P < .001; 15 studies, 294 patients), an improvement in UAS scores (-4.7 points, 95% CI, -5.0 to -4.4, P < .001; 10 studies, 1158 patients), an average complete response rate of 72.2% (95% CI, 66.1%-78.3%; P<.001; 45 studies, 1158 patients) with an additional average partial response rate of 17.8% (95% CI, 11.7%-23.9%; P <.001; 37 studies, 908 patients), and an average adverse event rate of 4.0% (95% CI, 1.0%-7.0%; P<.001; any level of severity, 47 studies, 1314 patients). CONCLUSIONS AND RELEVANCE Benefits and safety of omalizumab in the real-world treatment of CIU meet or exceed results gleaned from clinical trials. These real-world data on omalizumab in CIU may help inform both clinical treatment expectations and policy decision making.
    • Binocular Interference vs Diplopia in Patients With Epiretinal Membrane

      Hatt, Sarah R; Leske, David A; Iezzi, Raymond; Holmes, Jonathan M; Univ Arizona, Dept Ophthalmol & Vis Sci (AMER MEDICAL ASSOC, 2020-09-10)
      This study evaluates associations with monocular eye closure in patients with epiretinal membrane and reports on binocular interference (closing 1 eye to improve visual quality). Importance Patients with epiretinal membrane (ERM) sometimes close 1 eye for improved vision, but associations have not been rigorously studied. Objective To evaluate associations with monocular eye closure in patients with ERM, and to report binocular interference (closing 1 eye to improve visual quality). Design, Setting, and Participants Retrospective medical record review of an adult strabismus clinic at a tertiary referral center. Patients with ERM referred from retina clinicians between June 2010 and October 2019 who completed the Adult Strabismus (AS)-20 questionnaire, including the question: "I cover or close one eye to see things better." Two groups were identified: (1) patients reporting eye closure sometimes or more, and (2) patients reporting no eye closure (as control patients). Main Outcomes and Measures Frequencies of (1) central-peripheral rivalry (CPR)-type diplopia (dragged fovea diplopia); (2) binocular interference (monocular eye closure but no diplopia or strabismus); and (3) other, associated with monocular eye closure. Visual acuity, metamorphopsia, aniseikonia, and AS-20 quality of life domain scores (self-perception, interactions, reading function, and general function) compared between binocular interference, CPR-type diplopia, and control patients. Results A total of 124 patients with ERM (58 of 124 were women [47%]; mean [SD] age, 70 [9] years) reported monocular eye closure. Associations were binocular interference in 36 (29%; 95% CI, 21%-38%), CPR-type diplopia in 34 (27%; 95% CI, 20%-36%), and other (primarily strabismus) in 54 (44%). Compared with control patients with ERM (n = 11), patients with ERM and binocular interference had worse quality of life on AS-20 reading function (95 vs 62; mean difference, 22 points; 95% CI, 7-27 points;P = .007) and general function (89 vs 68; mean difference, 23 points; 95% CI, 13-34 points;P = .01) domains. Compared with CPR-type diplopia, patients with binocular interference had poorer worst-eye visual acuity (median 0.50 vs 0.30 logMAR [20/63 vs 20/40]; mean difference, 0.13 logMAR; 95% CI, 0.00-0.25 logMAR [20/20 to 20/35];P = .03), and a larger interocular difference (0.46 vs 0.19 logMAR [20/58 vs 20/30]; mean difference, 0.15 logMAR; 95% CI, 0.03-0.28 logMAR [20/21 to 20/38];P = .004). Conclusions and Relevance Study findings suggest that binocular interference, manifesting as monocular eye closure (without diplopia or strabismus), is a distinct entity affecting quality of life in patients with epiretinal membrane. Question What features are associated with monocular eye closure in epiretinal membrane? Findings In this medical record review of patients with epiretinal membrane, monocular eye closure (sometimes or more; n = 124) was associated with binocular interference (reduced monocular vs binocular visual quality, no diplopia or strabismus) in 36 (29%), central-peripheral rivalry (CPR)-type diplopia in 34 (27%), and other (primarily strabismus) in 54 (44%). Patients with binocular interference were more likely to have reduced quality of life compared with epiretinal membrane patients who never close 1 eye. Meaning Study findings suggest binocular interference is a distinct entity and can be associated with epiretinal membrane.
    • Causes of Child and Youth Homelessness in Developed and Developing Countries

      Embleton, Lonnie; Lee, Hana; Gunn, Jayleen; Ayuku, David; Braitstein, Paula; Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Div Epidemiol & Biostat; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Biostatistics, Brown University, Providence, Rhode Island; Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson; Department of Behavioral Sciences, College of Health Sciences, Moi University, Eldoret, Kenya; et al. (AMER MEDICAL ASSOC, 2016-05-01)
    • Comparison of Coronary Artery Calcium Scores Between Patients With Psoriasis and Type 2 Diabetes

      Mansouri, Bobbak; Kivelevitch, Dario; Natarajan, Balaji; Joshi, Aditya A.; Ryan, Caitriona; Benjegerdes, Katie; Schussler, Jeffrey M.; Rader, Daniel J.; Reilly, Muredach P.; Menter, Alan; et al. (AMER MEDICAL ASSOC, 2016-11-01)
      IMPORTANCE Psoriasis is associated with an increased risk of cardiovascular diseases. Subclinical atherosclerosis in patients with psoriasis has not been compared with other conditions associated with increased cardiovascular risk and more rigorous cardiovascular disease screening, such as type 2 diabetes. OBJECTIVE To assess the burden of asymptomatic coronary atherosclerosis measured by coronary artery calcium score in patients with moderate to severe psoriasis compared with patients with type 2 diabetes and healthy controls. DESIGN, SETTING, AND PARTICIPANTS Three single-center, cross-sectional studies were performed in patients recruited from specialty outpatient clinics with moderate to severe psoriasis without type 2 diabetes (recruited from November 1, 2013, through April 31, 2015), patients with type 2 diabetes without psoriasis or other inflammatory diseases (recruited from July 1, 2009, through June 20, 2011), and age-and sex-matched healthy controls without psoriasis, type 2 diabetes, or other inflammatory diseases (recruited from July 1, 2009, through June 20, 2011). EXPOSURES Psoriasis, type 2 diabetes, and healthy control effect on coronary artery calcium score. MAIN OUTCOMES AND MEASURES Coronary artery calcium measured by Agatston score. RESULTS A total of 387 individuals participated in the study. Mean (SD) age was 51 (7.7), 52 (8.0), and 52 (8.0) years in the psoriasis, type 2 diabetes, and healthy control cohorts, respectively. There were 64 men (49.6%) in each group, and most patients were white (119 [ 92.2%], 123 [ 95.3%], and 128 [ 99.2%] in the psoriasis, type 2 diabetes, and healthy control cohorts, respectively). Patients with psoriasis had low cardiovascular risk measured by the Framingham Risk Score but had a high prevalence of cardiovascular and cardiometabolic risk factors, similar to patients with type 2 diabetes. In a fully adjusted model, psoriasis was associated with coronary artery calcium (Tobit regression ratio, 0.89; P < .001) similar to the association in type 2 diabetes (Tobit regression ratio, 0.79; P = .04). Likelihood ratio testing revealed incremental value for psoriasis in a fully adjusted model (chi(2) = 4.48, P = .03) in predicting coronary artery calcium. Psoriasis was independently associated with the presence of any coronary artery calcium (odds ratio, 2.35; 95% CI, 1.12-4.94) in fully adjusted models, whereas the association of coronary artery calcium with type 2 diabetes was no longer significant after adding body mass index to the model (odds ratio, 2.18; 95% CI, 0.75-6.35). CONCLUSIONS AND RELEVANCE Patients with psoriasis have increased coronary artery calcium by mean total Agatston scores, similar to that of patients with type 2 diabetes, suggesting that patients with psoriasis harbor high rates of subclinical atherosclerosis beyond adjustment for body mass index. Major educational efforts for patients and physicians should be undertaken to reduce the burden of cardiovascular disease in patients with psoriasis.
    • Core Outcome Set for Actinic Keratosis Clinical Trials

      Reynolds, Kelly A; Schlessinger, Daniel I; Vasic, Jelena; Iyengar, Sanjana; Qaseem, Yaqoob; Behshad, Ramona; DeHoratius, Danielle M; Denes, Pablo; Drucker, Aaron M; Dzubow, Leonard M; et al. (AMER MEDICAL ASSOC, 2020-01-15)
      Question What are the most important outcomes to report in clinical trials on actinic keratosis? Findings In this survey study including physician and patient stakeholders (33 in round 1 and 29 in round 2), a consensus was reached regarding a core set of 6 of 137 outcomes and domains of actinic keratosis: complete clearance of actinic keratoses, percentage of actinic keratoses cleared, severity of adverse events, patient perspective on effectiveness, patient-reported future treatment preference, and rate of recurrence. Meaning In studies of treatment of actinic keratosis, the recommended core outcomes should be reported as a minimum to facilitate comparison of results across studies. This survey study assesses the most important outcomes to report in clinical trials on actinic keratosis based on Delphi surveys completed by physician and patient stakeholders. Importance Although various treatments have been found in clinical trials to be effective in treating actinic keratosis (AK), researchers often report different outcomes. Heterogeneous outcome reporting precludes the comparison of results across studies and impedes the synthesis of treatment effectiveness in systematic reviews. Objective To establish an international core outcome set for all clinical studies on AK treatment using systematic literature review and a Delphi consensus process. Evidence Review Survey study with a formal consensus process. The keywords actinic keratosis and treatment were searched in PubMed, Embase, CINAHL, and the Cochrane Library to identify English-language studies investigating AK treatments published between January 1, 1980, and July 13, 2015. Physician and patient stakeholders were nominated to participate in Delphi surveys by the Measurement of Priority Outcome Variables in Dermatologic Surgery Steering Committee members. All participants from the first round were invited to participate in the second round. Outcomes reported in randomized controlled clinical trials on AK treatment were rated via web-based e-Delphi consensus surveys. Stakeholders were asked to assess the relative importance of each outcome in 2 Delphi survey rounds. Outcomes were provisionally included, pending the final consensus conference, if at least 70% of patient or physician stakeholders rated the outcome as critically important in 1 or both Delphi rounds and the outcome received a mean score of 7.5 from either stakeholder group. Data analysis was performed from November 5, 2018, to February 27, 2019. Findings A total of 516 outcomes were identified by reviewing the literature and surveying key stakeholder groups. After deduplication and combination of similar outcomes, 137 of the 516 outcomes were included in the Delphi surveys. Twenty-one physicians and 12 patients participated in round 1 of the eDelphi survey, with 17 physicians (81%) retained and 12 patients (100%) retained in round 2. Of the 137 candidate outcomes, 9 met a priori Delphi consensus criteria, and 6 were included in the final outcomes set after a consensus meeting: complete clearance of AKs, percentage of AKs cleared, severity of adverse events, patient perspective on effectiveness, patient-reported future treatment preference, and recurrence rate. It was recommended that treatment response be assessed at 2 to 4 months and recurrence at 6 to 12 months, with the AK rate of progression to cutaneous squamous cell carcinoma reported whenever long-term follow-up was possible. Conclusions and Relevance Consensus was reached regarding a core outcome set for AK trials. Further research may help determine the specific outcome measures used to assess each of these outcomes.
    • Economic Evaluation of Talimogene Laherparepvec Plus Ipilimumab Combination Therapy vs Ipilimumab Monotherapy in Patients With Advanced Unresectable Melanoma

      Almutairi, Abdulaali R; Alkhatib, Nimer S; Oh, Mok; Curiel-Lewandrowski, Clara; Babiker, Hani M; Cranmer, Lee D; McBride, Ali; Abraham, Ivo; Univ Arizona, Coll Pharm, Ctr Hlth Outcomes & PharmacoEcon Res; Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci; et al. (AMER MEDICAL ASSOC, 2019-01-01)
      IMPORTANCE. A phase 2 trial comparing talimogene laherparepvec plus ipilimumab vs ipilimumab monotherapy in patients with advanced unresectable melanoma found no differential benefit in progression-free survival (PFS) but noted objective response rates (ORRs) of 38.8% (38 of 98 patients) vs 18.0% (18 of 100 patients), respectively. OBJECTIVE To perform an economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy. DESIGN, SETTING, AND PARTICIPANTS For PFS, cost-effectiveness and cost-utility analyses using a 2-state Markov model (PFS vs progression or death) was performed. For ORRs, cost-effectiveness analysis of the incremental cost of 1 additional patient achieving objective response was performed. In this setting based on a US payer perspective (2017 US dollars), participants were patients with advanced unresectable melanoma. MAIN OUTCOMES AND MEASURES The PFS life-years and PF5 quality-adjusted life-years were determined, and the associated incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs) were estimated. Also estimated was the ICER per 1 additional patient (out of 100 treated patients) achieving objective response. Base-case analyses were validated by sensitivity analyses. RESULTS In PFS analyses, the cost of talimogene laherparepvec plus ipilimumab ($494 983) exceeded the cost of ipilimumab monotherapy ($132 950) by $362 033. The ICER was $2 129 606 per PFS life-years, and the ICUR was $2 262 706 per PFS quality-adjusted life-year gained. Probabilistic sensitivity analyses yielded an ICER of $1 481 208 per PFS life-year gained and an ICUR of $1 683 191 per PFS quality-adjusted life-year gained. In 1-way sensitivity analyses, the PFS hazard ratio and the utility of response were the most influential parameters. Talimogene laherparepvec plus ipilimumab has a 50% likelihood of being cost-effective at a willingness-to-pay threshold of $1 683 191 per PFS quality-adjusted life-year gained. In ORR analyses, talimogene laherparepvec plus ipilimumab ($474 904) vs ipilimumab alone ($132 810), a $342 094 difference, yielded an ICER of $1 629 019 per additional patient achieving objective response. In subgroup analyses by disease stage and BRAF(V600E) mutation status, ICERs ranged from $1 069 044 to $17 104 700 per 1 additional patient achieving objective response. CONCLUSIONS AND RELEVANCE The cost to gain 1 additional progression-free quality-adjusted life-year, 1 additional progression-free life-year, or to have 1 additional patient attain objective response is about $1.6 million. This amount may be beyond what payers typically are willing to pay. Combination therapy of talimogene laherparepvec plus ipilimumab does not offer an economically beneficial treatment option relative to ipilimumab monotherapy at the population level. This should not preclude treatment for individual patients for whom this regimen may be indicated.
    • Effect of a Positive Psychological Intervention on Pain and Functional Difficulty Among Adults With Osteoarthritis

      Hausmann, Leslie R. M.; Youk, Ada; Kwoh, C. Kent; Gallagher, Rollin M.; Weiner, Debra K.; Vina, Ernest R.; Obrosky, D. Scott; Mauro, Genna T.; McInnes, Shauna; Ibrahim, Said A.; et al. (AMER MEDICAL ASSOC, 2018-09)
      IMPORTANCE Positive psychological interventions for improving health have received increasing attention recently. Evidence on the impact of such interventions on pain, and racial disparities in pain, is limited. OBJECTIVE To assess the effects of a positive psychological intervention on pain and functional difficulty in veterans with knee osteoarthritis. DESIGN, SETTING, AND PARTICIPANTS The Staying Positive With Arthritis Study is a large, double-blinded randomized clinical trial powered to detect race differences in self-reported pain in response to a positive psychological intervention compared with a neutral control intervention. Data were collected from 2 urban Veterans Affairs medical centers. Participants included non-Hispanic white and non-Hispanic African American patients aged 50 years or older with a diagnosis of osteoarthritis. Mailings were sent to 5111 patients meeting these criteria, of whom 839 were fully screened, 488 were eligible, and 360 were randomized. Enrollment lasted from July 8, 2015, to February 1, 2017, with follow-up through September 6, 2017. INTERVENTIONS The intervention comprised a 6-week series of evidence-based activities to build positive psychological skills (eg, gratitude and kindness). The control program comprised similarly structured neutral activities. Programs were delivered via workbook and weekly telephone calls with interventionists. MAIN OUTCOMES AND MEASURES The primary outcomes were self-reported pain and functional difficulty measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; range 0-100). Secondary outcomes included affect balance and life satisfaction. RESULTS The sample included 180 non-Hispanic white patients and 180 non-Hispanic African American patients (mean [SD] age, 64.2 [8.8] years; 76.4% were male). Mean (SD) baseline scores for WOMAC pain and functional difficulty were 48.8 (17.6) and 46.8 (18.1). respectively. Although both decreased significantly over time (pain: chi(2)(3) = 49.50. P < .001; functional difficulty: chi(2)(3) = 22.11, P < .001), differences were small and did not vary by treatment group or race. Exploratory analyses suggested that the intervention had counter-intuitive effects on secondary outcomes. CONCLUSIONS AND RELEVANCE The results of this randomized clinical trial do not support the use of positive psychological interventions as a stand-alone treatment for pain among white or African American veterans with knee osteoarthritis. Adaptations are needed to identify intervention components that resonate with this population, and the additive effect of incorporating positive psychological interventions into more comprehensive pain treatment regimens should be considered.
    • Effect of a Virtual Patient Navigation Program on Behavioral Health Admissions in the Emergency Department: A Randomized Clinical Trial

      Roberge, Jason; McWilliams, Andrew; Zhao, Jing; Anderson, William E; Hetherington, Timothy; Zazzaro, Christine; Hardin, Elisabeth; Barrett, Amy; Castro, Manuel; Balfour, Margaret E; et al. (AMER MEDICAL ASSOC, 2020-01-29)
      This randomized clinical trial assesses whether the availability of a 45-day behavioral health-virtual patient navigation program decreases hospitalization among adult patients presenting to the emergency department with a behavioral health crisis or need. Importance The number of patients presenting to emergency departments (EDs) for psychiatric care continues to increase. Psychiatrists often make a conservative recommendation to admit patients because robust outpatient services for close follow-up are lacking. Objective To assess whether the availability of a 45-day behavioral health-virtual patient navigation program decreases hospitalization among patients presenting to the ED with a behavioral health crisis or need. Design, Setting, and Participants This randomized clinical trial enrolled 637 patients who presented to 6 EDs spanning urban and suburban locations within a large integrated health care system in North Carolina from June 12, 2017, through February 14, 2018; patients were followed up for up to 45 days. Eligible patients were aged 18 years or older, with a behavioral health crisis and a completed telepsychiatric ED consultation. The availability of the behavioral health-virtual patient navigation intervention was randomly allocated to specific days (Monday through Friday from 7 am to 7 pm) so that, in a 2-week block, there were 5 intervention days and 5 usual care days; 323 patients presented on days when the program was offered, and 314 presented on usual care days. Data analysis was performed from March 7 through June 13, 2018, using an intention-to-treat approach. Interventions The behavioral health-virtual patient navigation program included video contact with a patient while in the ED and telephonic outreach 24 to 72 hours after discharge and then at least weekly for up to 45 days. Main Outcomes and Measures The primary outcome was the conversion of an ED encounter to hospital admission. Secondary outcomes included 45-day follow-up encounters with a self-harm diagnosis and postdischarge acute care use. Results Among 637 participants, 358 (56.2%) were men, and the mean (SD) age was 39.7 (16.6) years. The conversion rates were 55.1% (178 of 323) in the intervention group vs 63.1% (198 of 314) in the usual care group (odds ratio, 0.74; 95% CI, 0.54-1.02; P = .06). The percentage of patient encounters with follow-up encounters having a self-harm diagnosis was significantly lower in the intervention group compared with the usual care group (36.8% [119 of 323] vs 45.5% [143 of 314]; P = .03). Conclusions and Relevance Although the primary result did not reach statistical significance, there is a strong signal of potential positive benefit in an area that lacks evidence, suggesting that there should be additional investment and inquiry into virtual behavioral health programs. Question Does offering virtual patient navigation reduce admission rates for patients presenting to the emergency department with a behavioral health crisis? Findings In this randomized clinical trial, there were fewer admissions on days when the navigation program was available (55.1%) vs on days with usual care (63.1%), although the difference was not statistically significant. Significantly fewer patients who used the navigation program had a follow-up encounter involving a self-harm diagnosis within 45 days compared with patients who received usual care (36.8% vs 45.5%). Meaning Although the primary result did not reach statistical significance, there is a strong signal of potential positive benefit in an area that lacks evidence, suggesting that there should be additional investment and inquiry into this area.