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Anne Lambert-Kerzner,1,2 Edward P Havranek,2,3 Mary E Plomondon,1,2 Katherine M Fagan,1 Marina S McCreight,1 Kelty B Fehling,1 David J Williams,2 Alison B Hamilton,4 Karen Albright,2 Patrick J Blatchford,2 Renee Mihalko-Corbitt,5 Chris L Bryson,6 Hayden B Bosworth,7 Miriam A Kirshner,7 Eric J Del Giacco,5 P Michael Ho1,2 1Department of Cardiology, Veterans Health Administration (VA) Eastern Colorado Health Care System, Denver, CO, 2School of Public Health or School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, 3Cardiology, Denver Health Medical Center, Denver, CO, 4Health Services Research, Veterans Health Administration (VA) Greater Los Angeles Healthcare System, Los Angeles, CA, 5Internal Medicine, John L. McClellan Memorial Veterans Hospital, Little Rock, AR, 6Health Services Research, Veterans Health Administration (VA) Puget Sound Health Care System, Seattle, WA, 7Health Services Research, Durham Veterans Affairs Medical Center, Durham, NC, USA Purpose: Poor adherence to cardioprotective medications after acute coronary syndrome (ACS) hospitalization is associated with increased risk of rehospitalization and mortality. Clinical trials of multifaceted interventions have improved medication adherence with varying results. Patients’ perspectives on interventions could help researchers interpret inconsistent outcomes. Identifying factors that patients believe would improve adherence might inform the design of future interventions and make them more parsimonious and sustainable. The objective of this study was to obtain patients’ perspectives on adherence to medical regimens after experiencing an ACS event and their participation in a medication adherence randomized control trial following their hospitalization. Patients and methods: Sixty-four in-depth interviews were conducted with ACS patients who participated in an efficacious, multifaceted, medication adherence randomized control trial. Interview transcripts were analyzed using the constant comparative approach. Results: Participants described their post-ACS event experiences and how they affected their adherence behaviors. Patients reported that adherence decisions were facilitated by mutually respectful and collaborative provider–patient treatment planning. Frequent interactions with providers and medication refill reminder calls supported improved adherence. Additional facilitators included having social support, adherence routines, and positive attitudes toward an ACS event. The majority of patients expressed that being active participants in health care decision-making contributed to their health. Conclusion: Our findings demonstrate that respectful collaborative communication can contribute to medication adherence after ACS hospitalization. These results suggest a potential role for training health-care providers, including pharmacists, social workers, registered nurses, etc, to elicit and acknowledge the patients’ views regarding medication treatment in order to improve adherence. Future research is needed with providers to understand how they elicit and acknowledge patients’ views, particularly in the face of nonadherence, and with patients to understand how to empower them to share their opinions with their providers. Keywords: cardiovascular disease, compliance, qualitative analysis, medications

The associations between objective measures of sleep duration and bone outcomes in older men are unknown. No consistent, significant association was identified between sleep duration and bone mineral density (BMD) in the current analysis. However, future research should determine if vitamin D status modifies this relationship.IntroductionPrior studies, predominantly in women, reported that long and short self-reported sleep duration are associated with lower BMD. Associations between actigraphy-determined sleep duration and BMD or bone turnover markers (BTMs) in older men are unknown.MethodsMen in The Osteoporotic Fractures in Men (MrOS) Study with wrist actigraphy and concurrent BMD assessment but without comorbidities affecting bone health were included. Sleep duration was considered as a continuous (N = 1926) and dichotomized variable where men were classified as getting the recommended (7-8 h/night; N = 478) or short (< 6 h/night; N = 577) sleep. The cross-sectional association between BMD, BTMs, and sleep duration was examined using a t test or linear regression, where appropriate, in unadjusted and adjusted models.ResultsThere were no clinically or statistically significant differences in BMD at the L-spine, total hip, or femoral neck between men getting the recommended vs. short sleep duration, using actigraphy or self-reported sleep duration (all p ≥ 0.07). When sleep duration was considered as a continuous variable, femoral neck BMD was higher in men with longer self-reported sleep duration (β = 0.006 ±0.003, p = 0.02), but this was not significant after further adjustment. In men with low 25OHD (< 20 ng/mL), longer actigraphy-determined sleep duration was associated with higher total hip BMD (β = 0.016 ± 0.008; p = 0.04). Sleep duration and BTMs were not associated.ConclusionSleep duration was not associated with hip or L-spine BMD or BTMs in older men. Future research should determine if vitamin D status or other factors modify this relationship.

Methodological limitations preclude determination of the association between sleep duration and bone mineral density (BMD) from existing literature. This was the first study to use objective sleep duration to determine its association with BMD. Nocturnal sleep duration, assessed objectively (actigraphy) or subjectively (questionnaire), was not independently associated with BMD in postmenopausal women.IntroductionBoth long and short self-reported sleep durations are associated with low bone mineral density (BMD) in men and women. The association between sleep duration measured by actigraphy and BMD in postmenopausal women is unknown.MethodsThe Study of Osteoporotic Fractures (SOF) ancillary sleep study was used to determine the association between sleep duration and BMD at the total hip and femoral neck in postmenopausal women ≥ 75 years old. Sleep duration was assessed by wrist actigraphy (average 4 nights) and questionnaire. BMD was compared between postmenopausal women with short (

BACKGROUND: High mortality rates after release from prison have been well-documented, particularly from overdose. However, little is known about the risk factors for death after release from prison. Therefore, the objective of this study was to determine the demographic and incarceration-related risk factors for all-cause, overdose and early mortality after release from prison. METHODS: We conducted a retrospective cohort study of inmates released from a state prison system from 1999 through 2003. The cohort included 30,237 who had a total of 38,809 releases from prison. Potential risk factors included gender, race/ethnicity, age, length of incarceration, and community supervision. Cox proportional hazards regression was used to determine risk factors for all-cause, overdose and early (within 30 days of release) death after release from prison. RESULTS: Age over 50 was associated with an increased risk for all-cause mortality (hazard ratio [HR] 2.67 for each decade increase, 95% confidence interval [CI] 2.23, 3.20) but not for overdose deaths or early deaths. Latinos were at decreased risk of death compared to Whites only for all-cause mortality (HR 0.61, 95% CI 0.42, 0.87). Increasing years of incarceration were associated with a decreased risk of all-cause mortality (HR 0.95, 95% CI 0.91, 0.99) and overdose deaths (HR 0.80, 95% CI 0.68, 0.95), but not early deaths. Gender and type of release were not significantly associated with all-cause, overdose or early deaths. CONCLUSIONS: Age, ethnicity and length of incarceration were associated with mortality after release from prison. Interventions to reduce mortality among former inmates are needed. [ABSTRACT FROM AUTHOR]

Purpose: In this single-institution phase II investigator-initiated study, we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite-stable metastatic colorectal cancer (MSS mCRC)., Patients and Methods: Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate (ORR) in all patients combined (by Response Evaluation Criteria in Solid Tumors v1.1)., Results: Fifty patients received study drug treatment; 54% were male with a median age of 55 years (range, 31-79). The primary endpoint, ORR, was 12.0% [95% confidence interval (CI) 4.5%-24.3%], which was not statistically different than the historical control data of 5% (P = 0.038, exceeding prespecified threshold of 0.025). The disease control rate was 70.0% (95% CI, 55.4%-82.1%), the median progression-free survival 5.9 months (95% CI, 4.2-8.7 months), and the median overall survival 9.3 months (95% CI, 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%)., Conclusions: Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared with historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC., (©2024 The Authors; Published by the American Association for Cancer Research.)

Immune checkpoint inhibitors have been found to be effective in metastatic MSI-high colorectal cancers (CRC), however, have no efficacy in microsatellite stable (MSS) cancers, which comprise the majority of mCRC cases. Cabozantinib is a small molecule multi-tyrosine kinase inhibitor that is FDA approved in advanced renal cell, medullary thyroid, and hepatocellular carcinoma. Using Human Immune System (HIS) mice, we tested the ability of cabozantinib to prime MSS-CRC tumors to enhance the potency of immune checkpoint inhibitor nivolumab. In four independent experiments, we implanted distinct MSS-CRC patient-derived xenografts (PDXs) into the flanks of humanized BALB/c-Rag2 null Il2rγ null Sirpα NOD (BRGS) mice that had been engrafted with human hematopoietic stem cells at birth. For each PDX, HIS-mice cohorts were treated with vehicle, nivolumab, cabozantinib, or the combination. In three out of the four models, the combination had a lower tumor growth rate compared to vehicle or nivolumab-treated groups. Furthermore, interrogation of the HIS in immune organs and tumors by flow cytometry revealed increased Granzyme B+, TNFα+ and IFNγ+ CD4+ T cells among the human tumor infiltrating leukocytes (TIL) that correlated with reduced tumor growth in the combination-treated HIS-mice. Notably, slower growth correlated with increased expression of the CD4+ T cell ligand, HLA-DR, on the tumor cells themselves. Finally, the cabozantinib/nivolumab combination was tested in comparison to cobimetinib/atezolizumab. Although both combinations showed tumor growth inhibition, cabozantinib/nivolumab had enhanced cytotoxic IFNγ and TNFα+ T cells. This pre-clinical in vivo data warrants testing the combination in clinical trials for patients with MSS-CRC., Competing Interests: Exelixis supplied cabozantinib and funded this study, with TP as Principal Investigator, but had no role in study design, data collection, data analysis, data interpretation, or writing of the report. WM is the principal investigator of a phase II clinical trial of cabozantinib in patients with refractory metastatic colorectal cancer that is sponsored by Exelixis NCT03542877. AL is the principal investigator of a phase II clinical trial of cabozantinib in combination with nivolumab in metastatic colorectal cancer which is co-sponsored by Bristol Myers Squibb and Exelixis NCT04963283. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lang, Leal, Marín-Jiménez, Hartman, Shulman, Navarro, Lewis, Capasso, Bagby, Yacob, MacBeth, Freed, Eckhardt, Jordan, Blatchford, Pelanda, Lieu, Messersmith and Pitts.)

Purpose: Multi-tyrosine kinase inhibitors (TKI) have shown clinical activity in patients with metastatic colorectal cancer. Cabozantinib, a multi-TKI, exhibited potent antitumor activity superior to regorafenib in preclinical colorectal cancer patient-derived tumor xenograft models. This phase II study aimed to investigate cabozantinib, a multi-TKI, in patients with refractory, metastatic colorectal cancer (mCRC)., Experimental Design: A nonrandomized, two-stage, phase II clinical trial evaluating 12-week progression-free survival (PFS) was conducted in eight cancer centers across the United States between May 2018 and July 2020., Results: A total of 44 patients were enrolled between May 2018 and May 2019, 40 of which were response evaluable. Of the total 769 reported adverse events (AE), 93 (12%) were ≥ grade 3. Five grade 5 AEs were reported of which four were unrelated to study drug and one was reported as possibly related due to bowel perforation. Eighteen patients (45%) achieved 12-week PFS with stable disease or better (confidence interval, 0.29-0.62; P < 0.001). One patient (3%) had a partial response, and 27 other patients achieved stable disease as best response per RECISTv1.1. Median PFS was 3.0 months, and median overall survival was 8.3 months. Of the 18 patients who achieved 12-week PFS, 12 had left-sided primary tumors, 11 were RAS wild type, 11 were PIK3CA wild type, and 6 had previous regorafenib therapy. The 12-week PFS rate was higher in RAS wild-type tumors compared with RAS mutant tumors (0.61 vs. 0.32; P = 0.11)., Conclusions: This phase II study demonstrated clinical activity of cabozantinib in heavily pretreated, patients with refractory mCRC, and supports further investigation., Significance: Targeting angiogenesis through VEGF axis blockade provides incremental survival benefit in patients with mCRC. The hepatocyte growth factor/MET signal transduction pathway has been observed as a mechanism for acquired resistance. Dual inhibition of VEGF plus MET is an attractive therapeutic strategy. This phase II trial demonstrated clinical activity with cabozantinib, a multi-TKI targeting VEGFR2 and MET, in patients with refractory, mCRC., Competing Interests: E. Dotan reports grants from Iilly, Incyte, Relay, AstraZeneca, Zymeworks, Ipsen, Medimmune, NGM Biopharmaceuticals, Pfizer; personal fees from Incyte, Helsinn, Taiho, G1 therapeutics, Pfizer, Basilea, QED, and Boston Biomedical outside the submitted work. H.S. Hochster reports personal fees from Merck and TRIGR; personal fees and non-financial support from Processa outside the submitted work. S. Subramaniam reports personal fees from Exelixis outside the submitted work. P.J. Blatchford reports other from Exelixis during the conduct of the study. W.A. Messersmith reports other from Exelixis during the conduct of the study. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background: Endurance exercise can cause a decrease in serum ionized calcium (iCa) and increases in parathyroid hormone (PTH) and bone resorption, reflected by serum carboxy-terminal collagen crosslinks (CTX). We developed a calcium clamp to prevent the decrease in iCa during exercise, which attenuated increases in PTH and CTX during vigorous cycling in young men. The goal was to determine whether this occurs in older adults during brisk walking., Methods: Twelve older adults (6 men, 6 women) performed two identical 60-min treadmill walking bouts with Ca gluconate or half-normal saline infusion. Blood sampling for iCa, total calcium (tCa), phosphate (P), PTH, and CTX, occurred before, during, and for 4 h after exercise., Results: iCa decreased during exercise with the saline infusion (p = 0.04) and this provoked increases in PTH and CTX (both p < 0.01). The Ca clamp prevented the decrease in serum iCa during exercise and attenuated the PTH and CTX responses., Conclusions: Preventing the exercise-induced decrease in iCa markedly attenuated the increases in PTH and CTX. The cause of the decrease in iCa during exercise remains unclear, but the increases in PTH and CTX are likely counter-regulatory responses to defend serum iCa. This contention is supported by previous observations that the disruption of Ca homeostasis during exercise occurs regardless of training status. It will be important to establish whether this acute catabolic effect of exercise diminishes the potential chronic anabolic effects of exercise on bone., (Published by Elsevier Inc.)

Background: Interventions targeting psychosocial factors may improve rehabilitation outcomes for prosthesis users after lower-limb amputation (LLA), but there is a need to identify targeted factors for minimizing disability., Objective: To identify psychosocial factors related to disability for prosthesis users after LLA in middle age or later., Design: Cross-sectional study., Setting: General community., Participants: Participants with LLA (N = 122) were included in this cross-sectional study if their most recent LLA was at least 1 year prior, they were ambulating independently with a prosthesis, and they were between 45 and 88 years old., Interventions: Not applicable., Main Outcome Measures: Disability, the primary outcome, was measured using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS). Candidate psychosocial variables included self-efficacy, social support, and motivation, measured using the Self-Efficacy of Managing Chronic Disease questionnaire (SEMCD), Multidimensional Scale of Perceived Social Support questionnaire (MSPSS), and modified contemplation ladder (mCL), respectively. The hypothesis was that greater self-efficacy, social support, and motivation would be associated with lower disability when controlling for covariates., Results: The covariate model, including etiology, age, sex, U.S. military veteran status, LLA characteristics, time since LLA, medical complexity, and perceived functional capacity, explained 66.1% of disability variability (WHODAS 2.0). Backward elimination of candidate psychosocial variables stopped after removal of motivation (P = .10), with self-efficacy (P < .001) and social support (P = .002) variables remaining in the final model. The final model fit was statistically improved (P < .001) and explained an additional 6.1% of disability variability when compared to the covariate model., Conclusions: Greater self-efficacy and social support are related to lower disability after LLA. Findings suggest there may be a role for interventions targeting increased physical function, self-efficacy, and social support for ambulatory prosthesis users after LLA in middle age or later, especially when complicated by multiple chronic conditions., (© 2020 American Academy of Physical Medicine and Rehabilitation.)

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2 null Il2rγ null SIRPα NOD (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of "responding" patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Marín-Jiménez, Capasso, Lewis, Bagby, Hartman, Shulman, Navarro, Yu, Rivard, Wang, Barkow, Geng, Kar, Yingst, Tufa, Dolan, Blatchford, Freed, Torres, Davila, Slansky, Pelanda, Eckhardt, Messersmith, Diamond, Lieu, Verneris, Wang, Kiseljak-Vassiliades, Pitts and Lang.)

Although all clinical trials are designed and monitored using more than one endpoint, methods are needed to assure that decision criteria are chosen to reflect the clinically relevant tradeoffs that assure the trial's scientific integrity. This article presents a framework for the design and monitoring clinical trials in a bivariate outcome space. The framework uses a rectangular hyperbola to define a bivariate null curve that divides outcome space into regions of benefit and lack of benefit. The curve is shown to be a flexible mapping of bivariate space that allows a continuous tradeoff between the two endpoints in a manner that captures many previous bivariate designs. The curve is extended to a distance function in bivariate space that allows different decisions in each of the four quadrants that comprise bivariate space. The distance function forms a statistic ( δ ); the distribution of its estimate is derived and used as a basis for trial design and group sequential monitoring plans in bivariate space. A recursive form of the bivariate group sequential density is used to evaluate and control operating characteristics for the proposed design. The bivariate designs are shown to meet or exceed the usual standards for size and power. The proposed design is illustrated in the ongoing NHLBI-sponsored Kids-DOTT multinational randomized controlled trial comparing shortened versus conventional anticoagulation for the treatment of venous thromboembolism in patients less than 21 years of age. The proposed methods are broadly applicable to a wide range of clinical settings and trial designs., (© 2020 John Wiley & Sons, Ltd.)

Background: Lower-limb amputation (LLA) due to non-traumatic vascular etiology is linked to extremely low physical activity and high disability., Objective: To test the feasibility of a biobehavioral intervention designed to promote physical activity., Design: A randomized, single-blind feasibility trial with a crossover design., Setting: Veterans Administration Medical Center., Participants: Military veterans (age: 65.7 [7.8] years; mean [standard deviation]) with nontraumatic lower-limb amputation (LLA), randomized to two groups: GROUP1 (n = 16) and GROUP2 (n = 15). Both groups had similar baseline amputation characteristics (level of amputation and time since amputation)., Interventions: Twelve weekly, 30-minute telehealth sessions of physical activity behavior-change intervention, with GROUP1 participating in weeks 1-12 and GROUP2 in weeks 13-24. GROUP1 noncontact phase in weeks 13-24 and GROUP2 attention control telehealth phase in weeks 1-12., Main Outcome Measures: Feasibility (participant retention, dose goal attainment, intervention acceptability [Intrinsic Motivation Inventory [IMI] Interest and Enjoyment scale], safety) and signal of efficacy (free-living physical activity [accelerometer-based average daily step count], Late Life Function and Disability Index - Disability Scale [LLFDI-DS])., Results: Participant retention rate was high (90%), with three participants lost to follow-up during the intervention period. Dose goal attainment was low, with only 10% of participants achieving an a priori walking dose goal. Intervention was rated as acceptable, with mean IMI Interest and Enjoyment score (5.8) statistically higher than the null value of 5.0 (P = .002). There were no between-group differences in adverse event rates (falls: P = .19, lower extremity wounds: P = .60). There was no signal of efficacy for change in average daily step count (d = -0.15) or LLFDI-DS (d = -0.22 and 0.17 for frequency and limitations scales, respectively)., Conclusions: Telehealth delivered biobehavioral intervention resulted in acceptable participant retention, low dose goal attainment, high participant acceptability, and low safety risk, while having no signal of efficacy (physical activity, disability) for people with nontraumatic LLA., (© 2020 American Academy of Physical Medicine and Rehabilitation. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Purpose: Colorectal cancer (CRC) is the third most common cancer in the USA. The objective of this study was to compare quality of life (QoL) across long-term colorectal cancer survivors and unaffected matched controls while adjusting for comorbidities., Methods: The National Cancer Institute (NCI)-funded Colon Cancer Family Registry (CCFR) was used to randomly select and recruit CRC survivors (≥ 5 years from diagnosis) and matched controls for a cross-sectional survey. Nine geographically diverse sites in the USA from the CCFR participated in the study. Telephone interviews were conducted using computer-assisted methods to assess QoL., Results: A total of 403 cases and 401 controls were included in the final sample. Unadjusted comparison revealed no significant difference between CRC survivors and controls with respect to measures of fatigue, social, emotional, functional, and physical well-being. Multivariate logistic regression revealed that case status had a significant negative influence on colorectal cancer-specific QoL measures. Higher comorbidity indices had a significant negative influence on overall QoL regardless of case status., Conclusions: Quality of life among long-term CRC survivors is similar to control subjects, with the exception of worse CRC-specific QoL measures. Higher comorbidity indices were independently associated with poor QoL for both cases and controls., Implications for Cancer Survivors: Survivors and healthcare providers should be aware that long-term QoL is comparable to the general population; however, there is potential that digestive tract-specific issues may persist.

Regular exercise enhances endothelial function in older men, but not consistently in estrogen-deficient postmenopausal women. Estradiol treatment improves basal endothelial function and restores improvements in endothelial function (flow-mediated dilation, FMD) to aerobic exercise training in postmenopausal women; however, estradiol treatment is controversial. Resveratrol, an estrogen receptor ligand, enhances exercise training effects on cardiovascular function and nitric oxide (NO) release in animal models, but impairs exercise training effects in men. We conducted a randomized cross-over, double-blinded, placebo-controlled pilot study to determine whether acute (single dose) resveratrol (250-mg tablet) or estradiol (0.05 mg/day transdermal patch) treatment enhances FMD at rest and after a single bout of moderate-intensity aerobic exercise in healthy estrogen-deficient postmenopausal women ( n = 15, 58.1 ± 3.2 yr). FMD was measured before and after (30, 60, and 120 min) a 40-min bout of moderate-intensity treadmill exercise (60-75% peak heart rate) under the respective conditions (separated by 1-2 wk). FMD was higher ( P < 0.05) before exercise and at all post-exercise time points in the resveratrol and estradiol conditions compared to placebo. FMD was increased from baseline by 120 min postexercise in the estradiol condition ( P < 0.001), but not resveratrol or PL conditions. Consistent with our previous findings, estradiol also enhances endothelial function in response to acute endurance exercise. Although resveratrol improved basal FMD, there was no apparent enhancement of FMD to acute exercise and, therefore, may not act as an estradiol mimetic. NEW & NOTEWORTHY The benefits of endurance exercise training on endothelial function are diminished in estrogen-deficient postmenopausal women, but estradiol treatment appears to restore improvements in endothelial function in this group. We show that basal endothelial function is enhanced with both acute estradiol and resveratrol treatments in estrogen-deficient postmenopausal women, but endothelial function is only enhanced following acute endurance exercise with estradiol treatment.

Lung cancer chemoprevention, especially in high-risk former smokers, has great potential to reduce lung cancer incidence and mortality. Thiazolidinediones prevent lung cancer in preclinical studies, and diabetics receiving thiazolidinediones have lower lung cancer rates which led to our double-blind, randomized, phase II placebo-controlled trial of oral pioglitazone in high-risk current or former smokers with sputum cytologic atypia or known endobronchial dysplasia. Bronchoscopy was performed at study entry and after completing 6 months of treatment. Biopsies were histologically scored, and primary endpoint analysis tested worst biopsy scores (Max) between groups; Dysplasia index (DI) and average score (Avg) changes were secondary endpoints. Biopsies also received an inflammation score. The trial accrued 92 subjects (47 pioglitazone, 45 placebo), and 76 completed both bronchoscopies (39 pioglitazone, 37 placebo). Baseline dysplasia was significantly worse for current smokers, and 64% of subjects had mild or greater dysplasia at study entry. Subjects receiving pioglitazone did not exhibit improvement in bronchial dysplasia. Former smokers treated with pioglitazone exhibited a slight improvement in Max, while current smokers exhibited slight worsening. While statistically significant changes in Avg and DI were not observed in the treatment group, former smokers exhibited a slight decrease in both Avg and DI. Negligible Avg and DI changes occurred in current smokers. A trend toward decreased Ki-67 labeling index occurred in former smokers with baseline dysplasia receiving pioglitazone. While pioglitazone did not improve endobronchial histology in this high-risk cohort, specific lesions showed histologic improvement, and further study is needed to better characterize responsive dysplasia., (©2019 American Association for Cancer Research.)

Background: The same trauma that produces concussion may also produce neck injury. The signs of concussion and neck injury are similar, and symptoms after acceleration-deceleration trauma to the head-neck complex do not accurately discriminate between them. Research on the epidemiology of neck injury among sport-concussed youth is sparse., Purpose: The purpose of this study was to investigate the epidemiology of diagnosed neck injury in non-sport-related concussion (Non-SRC) versus sport-related concussion (SRC) in youth by age, sex, and sport., Study Design: Cross-sectional epidemiologic study., Methods: De-identified data from community-based electronic health records over 13 years were extracted to analyze rates and characteristics of neck injuries among non-SRCs and SRCs in youth aged five to 21. Neck injury diagnosis prevalence rates and odds ratios were calculated to estimate risk of neck injury among concussed youth, comparing non-SRCs to SRCs by age and sex., Results: Sixteen thousand, eight hundred eighty-five concussion records were extracted, of which 3,040 SRCs and 2,775 non-SRCs in youth aged five to 21 were identified by cross-filtering sport-related keywords (e.g., football, basketball, soccer, running, swimming, batting, horseback riding, skiing, etc.) with all ICD-9 and ICD-10 concussion codes. The prevalence of neck injuries diagnosed among SRCs (7.2%) was significantly different than the prevalence of neck injuries diagnosed among non-SRCs (12.1%, p < 0.000). Neck injury diagnoses were significantly more prevalent in females overall (p < 0.000) and among non-SRCs (p < 0.000). The prevalence of neck injury diagnoses was not significantly higher in concussed females versus concussed males with SRC (p = 0.164).Among youth aged five to 21 exposed to concussions, non-SRCs were more likely to be accompanied by a neck injury diagnosis than SRCs (OR 1.66; 95% CI 1.39 to 1.98; p < 0.000). Similarly, female-to-male neck injury proportion ratios were significantly higher in females in non-SRCs compared to SRCs (IPR 1.90, 95% CI 1.60 to 2.25, p < 0.000).Sports with highest prevalence of concussion differ from sports with highest prevalence of concussion-related neck injury in both sexes., Conclusions: The overall prevalence of diagnosed neck injuries in youth was higher in non-SRCs compared to SRCs (12.1 vs. 7.2%, p < 0.001), with the highest prevalence at age 14 in both sexes. The risk of neck injury diagnosis accompanying concussion was significantly higher in females compared to males (6.1% difference; p < 0.000)., (© 2019 by the Sports Physical Therapy Section.)

Background: Physical activity remains low and nearly unchanged from preoperative levels following total knee arthroplasty (TKA), and this is thought to underlie long-term functional limitations, secondary health problems, and higher health care costs after TKA., Objective: Our objective is to determine whether a telehealth-based intervention could improve physical activity and functional outcomes after TKA., Design: The design is a 2-arm, parallel, assessor-blinded, randomized controlled trial with baseline, midintervention, postintervention, and 6-month follow-up assessments., Setting: The setting is one academic medical center and one Veterans Affairs health care system., Participants: One hundred US military veterans (aged 50-85 years) scheduled for unilateral TKA will participate in this study., Intervention: The telehealth-based intervention to change physical activity behavior will be delivered through 10 sessions each of 30 minutes over a 12-week period. Participants will be provided with a wearable physical activity monitor to receive feedback on step count and guide goal-setting. Control participants will receive telehealth-based education on nonbehavioral aspects of health for the same frequency and duration as the intervention group. For both groups, telehealth sessions will occur concurrently with standardized outpatient rehabilitation., Measurements: The primary outcome will be change in physical activity, assessed as daily step counts measured using an accelerometer-based sensor. Secondary outcomes will be measured using the Life-Space Assessment questionnaire and change in physical function (30-Second Chair-Stand Test, Timed "Up & Go" Test, Six-Minute Walk Test, Western Ontario and McMaster Universities Osteoarthritis Index, and Veterans RAND 12-Item Health Survey)., Limitations: Participant and interventionist blinding is not possible., Conclusions: This trial will assess the efficacy of a novel behavior-change intervention to improve physical activity and physical function in patients after TKA. Effective physical activity behavior change could provide clinicians with a technique to augment current practice and resolve poor physical activity outcomes, long-term health problems, and high costs following TKA.

The cardiovascular effects of testosterone (T) are controversial. Low T has been associated with accelerated vascular aging, characterized by large elastic artery stiffening (decreased compliance), intimal-medial thickening (IMT), and endothelial dysfunction. Endurance exercise improves vascular function, but resistance training may increase arterial stiffness. We sought to determine whether T supplementation improved markers of vascular aging in men with low-normal T and whether T supplementation prevented arterial stiffness with resistance exercise. We studied 160 community-dwelling older men (66 ± 5 yr) with low-normal baseline total T levels (200-350 ng/dl). Participants were randomized to transdermal T gel targeting either a lower (400-550 ng/dl) or higher (600-1,000 ng/dl) T range or to placebo gel and to either progressive resistance training (PRT) or to no exercise for 12 mo. Carotid artery stiffness (arterial compliance) and carotid IMT were measured at baseline, 6 mo, and 12 mo. Endothelial function (brachial artery flow-mediated dilation) was measured in a subset ( n = 86). Changes in carotid artery compliance, IMT, and endothelial function with either the lower or higher range of T supplementation were not different from placebo at 6 or 12 mo. There were no differences between PRT and no PRT groups, alone or with T supplementation, in changes in any of the vascular measures at either time point. Supplementation of T and PRT in older men with low-normal levels do not appear to improve or harm vascular function. NEW & NOTEWORTHY Increased promotion and prescription of testosterone (T) to aging men has raised concerns about potential adverse cardiovascular effects. We show that in older men with T levels in the low-normal range, 12 mo of T supplementation with or without resistance exercise did not improve or harm vascular function.

Purpose: Our goal was to evaluate the safety and toxicity of combining a PARP inhibitor, olaparib, with cetuximab and fractionated intensity-modulated radiotherapy for patients with locally advanced head and neck cancer and heavy smoking histories. Patients and Methods: Patients with ≥10 packs/year history of smoking were treated with olaparib at doses ranging from 25-200 mg orally twice daily beginning approximately 10 days prior to initiation of and with concurrent radiation (69.3 Gy in 33 fractions) using a time-to-event continual reassessment method model. Cetuximab was administered starting approximately 5 days prior to radiation per standard of care. Results: A total of 16 patients were entered onto the study, with 15 evaluable for acute toxicity. The most common treatment-related grade 3-4 side effects were radiation dermatitis and mucositis (38% and 69%, respectively). The MTD was determined to be 50 mg orally twice daily, but the recommended phase II dose was deemed to be 25 mg orally twice daily. At a median follow-up of 26 months, the actuarial median overall survival was 37 months, but was not reached for other endpoints. Two-year overall survival, progression-free survival, local control, and distant control rates were 72%, 63%, 72%, and 79%, respectively. Patients who continued to smoke during therapy experienced higher recurrence rates. MYC and KMT2A were identified as potential correlatives of response on gene amplification and mutational analysis. Conclusions: Olaparib at 25 mg orally twice daily with concurrent cetuximab and radiation was well tolerated with reduced dermatitis within the radiation field. Response rates were promising for this high-risk population. Clin Cancer Res; 24(20); 4949-59. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objective: The menopausal transition is associated with somatic symptoms and increased rates of depression, which can impair quality of life (QOL) and increase cardiovascular disease (CVD) risk. This period is also associated with accelerated vascular aging (arterial stiffening and endothelial dysfunction), an antecedent to CVD. This secondary analysis sought to explore associations between depression, menopausal symptoms and QOL, and vascular aging across menopause stages., Methods: Arterial stiffness (carotid artery compliance), endothelial function (brachial artery flow-mediated dilation [FMD]), menopausal symptoms (Menopausal Symptom List [MSL]), depression (Center for Epidemiologic Studies Depression Scale [CES-D]), and QOL (Utian QOL Scale [UQOL]) were measured in 138 women (19-70 years) classified as premenopausal (n = 41, 34 ± 8 years; mean ± SD), early (n = 25, 49 ± 3 years), or late perimenopausal (n = 26, 50 ± 4 years), or early (n = 22, 55 ± 4 years) or late postmenopausal (n = 24, 61 ± 5 years). Differences across menopause stages were determined using one-way analysis of variance; associations between vascular measures and MSL, CES-D, and UQOL were tested using Pearson's correlation analyses., Results: Menopausal symptoms, depression, and QOL worsened across menopause stages, particularly in late perimenopausal women. Vasosomatic symptom frequency, and general somatic symptom frequency and severity were inversely correlated with carotid artery compliance and FMD (r = -0.27 to -0.18, all P < 0.05). Only correlations with general somatic symptoms were significant after adjusting for multiple comparisons. Total QOL was positively correlated with carotid artery compliance (r = 0.23, P = 0.01). CES-D scores were not correlated with carotid artery compliance or FMD (r = -0.08, -0.03, P = 0.35)., Conclusions: Vascular dysfunction across the stages of menopause was associated with greater frequency and severity of menopausal symptoms, and lower QOL, but not depression. Mechanisms underlying these associations (eg, inflammation, oxidative stress) should be explored.

Background: Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in β-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral gamma secretase inhibitor, PF-03084014., Methods: PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated., Results: Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0-96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5-21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily., Conclusions: PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0-96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation.

Background: Optimal management of chronic medications for patients with life-limiting illness is uncertain. Medication deprescribing may improve outcomes in this population, but patient concerns regarding deprescribing are unclear., Objective: The aim of this study was to quantify the perceived benefits and concerns of statin discontinuation among patients with life-limiting illness., Design: Baseline data from a multicenter, pragmatic clinical trial of statin discontinuation were used., Setting/subjects: Cognitively intact participants with a life expectancy of 1-12 months receiving statin medications for primary or secondary prevention were enrolled., Measurements: Responses to a 9-item questionnaire addressing patient concerns about discontinuing statins were collected. We used Pearson chi-square tests to compare responses by primary life-limiting diagnosis (cancer, cardiovascular disease, other)., Results: Of 297 eligible participants, 58% had cancer, 8% had cardiovascular disease, and 30% other primary diagnoses. Mean (standard deviation) age was 72 (11) years. Fewer than 5% of participants expressed concern that statin deprescribing indicated physician abandonment. About one in five participants reported being told to take statins for the rest of their life (18%) or feeling that discontinuation represented prior wasted effort (18%). Many participants reported benefits of stopping statins, including spending less money on medications (63%), potentially stopping other medications (34%), and having a better quality of life (25%). More participants with cardiovascular disease as a primary diagnosis perceived that quality-of-life benefits related to statin discontinuation (52%) than participants with cancer (27%) or noncardiovascular disease diagnoses (27%) [p = 0.034]., Conclusion: Few participants expressed concerns about discontinuing statins; many perceived potential benefits. Cardiovascular disease patients perceived greater potential positive impact from statin discontinuation.

Objectives: To enhance understanding of the relationship between multimorbidity, symptom burden, and functional status in individuals with life-limiting illness., Design: Secondary analysis of baseline data from a randomized clinical trial conducted in the Palliative Care Research Cooperative Group. Group differences were tested using a t-test; multivariate regression analysis was used to determine the effect of multiple variables on functional status and symptom burden., Setting: Fifteen Palliative Care Research Cooperation sites., Participants: Adults who participated in a parent statin-discontinuation clinical trial were included in the analysis (N = 381). Inclusion criteria were diagnosis of a life-limiting illness, statin use for 3 months or longer, life expectancy longer than 1 month, and declining functional status., Measurements: Cancer diagnosis (solid organ and hematologic malignancies), multimorbidity (Charlson Comorbidity Index (CCI) score), symptom burden (Edmonton Symptom Assessment Scale (ESAS) score, number of symptoms with ESAS severity score >4), functional status (Australia-modified Karnofsky Performance Scale (AKPS))., Results: Fifty-one percent had a primary diagnosis of cancer; mean age 74.1 ± 11.6. Participants had multiple comorbid illnesses (CCI score 4.9 ± 2.8), multiple symptoms (ESAS score 27.2 ± 15.9), and poor functional status (AKPS = 53 ± 13). In univariate and multivariate analyses, multimorbidity was associated with greater symptom burden (4.2 vs 3.1 moderate or severe symptoms (t = -3.2, P = .002), 12% vs 6% with severe symptoms (t = -3.7, P < .001)), but cancer diagnosis was not. In univariate and multivariate analyses, higher symptom burden was associated with poorer functional status (F = 11.6, P < .001), but multimorbidity was not., Conclusion: Symptoms cannot be attributed solely to a diagnosis of cancer. The association between symptom burden and functional status underscores the importance of clinical attention to symptoms in individuals with multimorbidity., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Objectives: Among patients with T2N0M0 glottic larynx cancer undergoing definitive radiotherapy, recent retrospective and prospective data have suggested improved outcomes with altered fractionation over conventional fractionation (CFxn). We sought to characterize national fractionation patterns and to compare outcomes among them., Materials and Methods: We queried the National Cancer Database for T2N0M0 squamous cell carcinomas of the glottis diagnosed from 2004-2014 and managed with definitive radiotherapy. Dose-per-fraction and duration of radiotherapy were used to define cohorts undergoing CFxn, hypofractionation (HypoFxn), and hyperfractionation (HyperFxn). Logistic regression was performed to identify predictors of receiving altered fractionation. Cox regression and propensity-score matching (PSM) analyses were used to compare survival between schedules., Results: We abstracted 2 006 CFxn patients, 1 166 HypoFxn patients, and 161 HyperFxn patients. Fractionation patterns changed significantly from 2004 to 2014, with use of HyperFxn decreasing from 6.3% to 1.8% and use of HypoFxn increasing from 23.9% to 54.1% (p<0.001). Receipt of altered fractionation was independently associated with later year of diagnosis and higher facility volume. On Cox regression, both HypoFxn (hazard ratio [HR] for mortality 0.84, 95% confidence interval [95%CI] 0.73-0.97) and HyperFxn (HR 0.74, 95%CI 0.56-0.99) were associated with improved survival over CFxn. The survival advantage of each altered fractionation schedule over CFxn was redemonstrated on comparison of PSM groups., Conclusion: Increasing utilization of HypoFxn for T2N0M0 glottic cancer is driving national practice patterns away from CFxn. Our findings support the use of altered fractionation, particularly HypoFxn, for patients undergoing definitive radiotherapy, although HyperFxn remains understudied in a prospective fashion., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: People in prison may be at high risk for infectious diseases and have an elevated risk of death immediately after release compared with later; their risk of death is elevated for at least a decade after release. We compared rates, characteristics, and prison-related risk factors for infectious disease-related mortality among people released from prisons in Queensland, Australia, and Washington State, United States, regions with analogous available data., Methods: We analyzed data from retrospective cohort studies of people released from prison in Queensland (1997-2007, n=37,180) and Washington State (1999-2009, n=76,208) and linked identifiers from each cohort to its respective national death index. We estimated infectious disease-related mortality rates (deaths per person-years in community) and examined associations using Cox proportional hazard models., Results: The most frequent infectious disease-related underlying cause of death after release from prison was pneumonia (43%, 23/54 deaths) in the Australian cohort and viral hepatitis (40%, 69/171 deaths) in the U.S. cohort. The infectious disease-related mortality rate was significantly higher in the U.S. cohort than in the Australian cohort (51.2 vs. 26.5 deaths per 100,000 person-years; incidence rate ratio = 1.93, 95% confidence interval 1.42, 2.62). In both cohorts, increasing age was strongly associated with mortality from infectious diseases., Conclusion: Differences in the epidemiology of infectious disease-related mortality among people released from prison may reflect differences in patterns of community health service delivery in each region. These findings highlight the importance of preventing and treating hepatitis C and other infectious diseases during the transition from prison to the community.

Background and Aims: While mortality rates after prison release are high, little is known about clinical risk factors for death. We sought to identify risk and protective factors for all-cause and accidental poisoning (overdose) death., Design: Nested case-control study of people released from prison., Setting: Washington State Department of Corrections, Washington, USA., Participants: Cases (699 all-cause deaths, of which 88 were among women, and 196 additional overdose deaths, of which 76 were among women) between 1999 and 2009 matched 1 : 1 to controls on sex, age and year of release using risk set sampling., Measurements: Prison medical charts were abstracted for clinical information. Independent associations between clinical characteristics and all-cause and overdose mortality were assessed using conditional logistic regression., Findings: Key independent risk factors for all-cause mortality included homelessness [odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.06, 2.23], injection drug use (OR = 1.54, 95% CI = 1.16, 2.06), tobacco use (OR = 1.51, 95% CI = 1.07, 2.13), cirrhosis (OR = 4.42, 95% CI = 1.63, 11.98) and psychiatric medications before release (OR = 2.38, 95% CI = 1.71, 3.30). Independent risk factors for overdose mortality included substance use disorder (OR = 2.33, 95% CI = 1.32, 4.11), injection drug use (OR = 2.43, 95% CI = 1.53, 3.86), panic disorder (OR = 3.87, 95% CI = 1.62, 9.21), psychiatric prescriptions before release (OR = 2.44, 95% CI = 1.55, 3.85) and problems with opiates/sedatives (OR = 2.81, 95% CI = 1.40, 5.63). Substance use disorder treatment during the index incarceration was protective for all-cause (OR = 0.67, 95% CI = 0.49, 0.91) and overdose (OR = 0.57, 95% CI = 0.36, 0.90) mortality., Conclusions: Injection drug use and substance use disorders are risk factors for death after release from prison. In-prison substance use disorder treatment services may reduce the risk.

Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient-derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1-targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes., (© 2015 UICC.)

Bronchial dysplasia (BD), a presumed precursor of pulmonary squamous cell carcinoma (SCC), rarely progresses to invasive cancer. A high-risk cohort at the University of Colorado provided an opportunity to directly sample airway epithelium at mapped sites on successive bronchoscopies. We have hypothesized that persistent dysplastic lesions showing a similar or higher level of dysplasia on follow-up biopsy, are associated with increased risk for the development of SCC. Endoscopic biopsies from 188 high-risk subjects were histologically classified according to the current WHO classification for BD using a numeric histology score ranging from 1 to 8 representing normal bronchial mucosa through invasive lung cancer. Differences in follow-up histology scores were compared between sites classified by clinical, histologic, and immunohistochemical variables. Subjects with a higher frequency of sites that persist or progress to high-grade dysplasia (≥37.5% persist/progress, N = 35 versus <37.5% persist/progress, N = 114) show a significant association with development of incident invasive SCC (adjusted HR, 7.84; 95% confidence interval, 1.56-39.39), and those with incident lung SCC have adjusted mean follow-up histology scores 1.55 U higher than in subjects without lung cancer. Current smoking, elevated Ki67 growth fraction, histologic features of angiogenic squamous dysplasia (ASD) and higher histology score in baseline biopsies are significantly associated with increased follow-up histology scores. These results show that persistent BD is associated with the development of invasive SCC. Furthermore, increased expression of Ki67, the presence of angiogenic change and degree of baseline atypia are associated with persistence of BD., (©2015 American Association for Cancer Research.)

Background: Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success., Methods: The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design., Results: No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%)., Conclusions: The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT., (© 2015 International Society on Thrombosis and Haemostasis.)

Importance: For patients with limited prognosis, some medication risks may outweigh the benefits, particularly when benefits take years to accrue; statins are one example. Data are lacking regarding the risks and benefits of discontinuing statin therapy for patients with limited life expectancy., Objective: To evaluate the safety, clinical, and cost impact of discontinuing statin medications for patients in the palliative care setting., Design, Setting, and Participants: This was a multicenter, parallel-group, unblinded, pragmatic clinical trial. Eligibility included adults with an estimated life expectancy of between 1 month and 1 year, statin therapy for 3 months or more for primary or secondary prevention of cardiovascular disease, recent deterioration in functional status, and no recent active cardiovascular disease. Participants were randomized to either discontinue or continue statin therapy and were monitored monthly for up to 1 year. The study was conducted from June 3, 2011, to May 2, 2013. All analyses were performed using an intent-to-treat approach., Interventions: Statin therapy was withdrawn from eligible patients who were randomized to the discontinuation group. Patients in the continuation group continued to receive statins., Main Outcomes and Measures: Outcomes included death within 60 days (primary outcome), survival, cardiovascular events, performance status, quality of life (QOL), symptoms, number of nonstatin medications, and cost savings., Results: A total of 381 patients were enrolled; 189 of these were randomized to discontinue statins, and 192 were randomized to continue therapy. Mean (SD) age was 74.1 (11.6) years, 22.0% of the participants were cognitively impaired, and 48.8% had cancer. The proportion of participants in the discontinuation vs continuation groups who died within 60 days was not significantly different (23.8% vs 20.3%; 90% CI, -3.5% to 10.5%; P=.36) and did not meet the noninferiority end point. Total QOL was better for the group discontinuing statin therapy (mean McGill QOL score, 7.11 vs 6.85; P=.04). Few participants experienced cardiovascular events (13 in the discontinuation group vs 11 in the continuation group). Mean cost savings were $3.37 per day and $716 per patient., Conclusions and Relevance: This pragmatic trial suggests that stopping statin medication therapy is safe and may be associated with benefits including improved QOL, use of fewer nonstatin medications, and a corresponding reduction in medication costs. Thoughtful patient-provider discussions regarding the uncertain benefit and potential decrement in QOL associated with statin continuation in this setting are warranted., Trial Registration: clinicaltrials.gov Identifier: NCT01415934.

Purpose: The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA)., Methods: A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses., Results: Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25 %) of 12 evaluable patients achieved stable disease. The 6-month survival rate was 27.8 % (95 % CI 9.7-53.5). The median OS was 4.1 months (95 % CI 2.7-5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3-1.6 months). Pharmacokinetic properties of RO4929097 in patients (n = 5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration., Conclusions: RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.

The authors aimed to evaluate age-related differences in inflammation biomarkers during the first 72 h of hospitalization for sepsis. This was a secondary analysis of a prospective observational cohort of adult patients (n = 855) from 10 urban academic emergency departments with confirmed infection and two or more systemic inflammatory response syndrome criteria. Six inflammation-related biomarkers were analyzed-chemokine (CC-motif) ligand-23, C-reactive protein, interleukin-1 receptor antagonist, neutrophil gelatinase-associated lipocalin (NGAL), peptidoglycan recognition protein, and tumor necrosis factor receptor-1a (TNFR-1a)-measured at presentation and 3, 6, 12, 24, 48, or 72 h later. The median age was 56 (interquartile range, 43 - 72) years, and sepsis severity was 38% sepsis, 16% severe sepsis without shock, and 46% septic shock; the overall 30-day mortality was 12%. Older age was associated with higher sepsis severity: 41% of subjects aged 18 to 34 years had severe sepsis or septic shock compared with 71% for those aged 65 years or older (P < 0.001). In longitudinal models adjusting for demographics, comorbidities, and infection source, older age was associated with higher baseline values for chemokine (CC-motif) ligand-23, interleukin-1 receptor antagonist, NGAL, and TNFR-1a (all P < 0.05). However, older adults had higher mean values during the entire 72-h period only for NGAL and TNFR-1a and higher final 72-h values only for TNFR-1a. Adjustment or stratification by sepsis severity did not change the age-inflammation associations. Although older adults had higher levels of inflammation at presentation and an increased incidence of severe sepsis and septic shock, these age-related differences in inflammation largely resolved during the first 72 h of hospitalization.

Background: Among former prisoners, a high rate of death has been documented in the early postrelease period, particularly from drug-related causes. Little is known about risk factors and trends in postrelease mortality in the past decade, especially given general population increases in overdose deaths from pharmaceutical opioids., Objective: To determine postrelease mortality between 1999 and 2009; cause-specific mortality rates; and whether sex, calendar year, and custody factors were risk factors for all-cause, overdose, and opioid-related deaths., Design: Cohort study., Setting: Prison system of the Washington State Department of Corrections., Participants: 76 208 persons released from prison., Measurements: Identities were linked probabilistically to the National Death Index to identify deaths and causes of death, and mortality rates were calculated. Cox proportional hazards regression estimated the effect of age, sex, race or ethnicity, whether the incarceration resulted from a violation of terms of the person's community supervision, length of incarceration, release type, and calendar year on the hazard ratio (HR) for death., Results: The all-cause mortality rate was 737 per 100 000 person-years (95% CI, 708 to 766) (n = 2462 deaths). Opioids were involved in 14.8% of all deaths. Overdose was the leading cause of death (167 per 100 000 person-years [CI, 153 to 181]), and overdose deaths in former prisoners accounted for 8.3% of the overdose deaths among persons aged 15 to 84 years in Washington from 2000 to 2009. Women were at increased risk for overdose (HR, 1.38 [CI, 1.12 to 1.69]) and opioid-related deaths (HR, 1.39 [CI, 1.09 to 1.79])., Limitation: The study was done in only 1 state., Conclusion: Innovation is needed to reduce the risk for overdose among former prisoners., Primary Funding Source: National Institute on Drug Abuse and the Robert Wood Johnson Foundation., Competing Interests: Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-0979.

Introduction: Little is known about how the development of a new chronic health condition affects management of existing chronic conditions over time. New conditions might worsen management of existing conditions because of competing demands or improve management of existing conditions because of increased engagement with heath care. We assessed the effect of incident stage 0, 1, 2 or 3 breast, colon or prostate cancer; incident depression; or an exacerbation of chronic pulmonary disease on control of type 2 diabetes (DM2)., Methods: We conducted a longitudinal, historical cohort study within an integrated, not-for-profit HMO. Of a cohort of persons with diagnoses of DM2 between 1998 and 2008, 582, 2,959 and 2,332 developed incident cancer, depression or pulmonary disease exacerbation, respectively. We assessed change in hemoglobin A1c (A1c) as a function of the occurrence of the incident comorbidity in each subcohort for a period of 1 to 5 years after the occurrence of the incident comorbidity. Secondary outcomes were systolic blood pressure (SBP) and low density lipoprotein (LDL) levels. Multivariate linear regression was adjusted for demographics, morbidity level, BMI, numbers of primary and specialty visits, and continuity of primary care. Latent class analyses assessed post-comorbidity outcome trajectories. All time-varying covariates were calculated for a 24-month pre-diagnosis period and 0 to 24- and 24 to 60-month post-diagnosis periods., Results: For each condition, A1c did not change significantly from before to after the incident comorbidity. This was confirmed by latent class growth curve analyses that grouped patients by their A1c trajectories. SBP and LDL were also not significantly changed pre- and post-diagnosis of the incident comorbidities., Discussion: Although incident comorbidities inevitably will affect patients' and clinicians' care priorities, we did not observe changes in these particular outcomes. Additional investigation of interactions between diseases will inform changes in care that benefit complex patient populations.

There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer.