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Supplementary Figure 1 from Development of a Multiplex Quantitative PCR Signature to Predict Progression in Non–Muscle-Invasive Bladder Cancer

Supplementary Methods, Figures 1-7 from Development of a Multiplex Quantitative PCR Signature to Predict Progression in Non–Muscle-Invasive Bladder Cancer

In bladder cancer, clinical grade and stage fail to capture outcome. We developed a clinically applicable quantitative PCR (QPCR) gene signature to predict progression in non–muscle-invasive bladder cancer. Comparative metaprofiling of 12 DNA microarray data sets (comprising 631 samples and 241,298 probe sets) identified 96 genes, which showed differential expression in seven clinical outcome categories, or were identified as outliers, historic markers, or housekeeping genes. QPCR was done to determine mRNA expression from 96 bladder tumors. Fifty-seven genes differentiated T2 from non-T2 tumors (P < 0.05). Principal components analysis and Cox regression models were used to predict probability of T2 progression for non-T2 patients, placing them into high- and low-risk groups based on their gene expression. At 2 years, high-risk patients exhibited greater T2 progression (45% for high-risk patients versus 12% for low-risk patients; P = 0.003, log-rank test). This difference remained significant within T1 tumors (61% for high-risk patients versus 22% for low-risk patients; P = 0.02) and Ta tumors (29% for high-risk patients versus 0% for low-risk patients; P = 0.03). The best multivariate Cox model included stage and gender, and this signature provided predictive improvement over both (P = 0.002, likelihood ratio test). Immunohistochemistry was done for two genes in the signature not previously described in bladder cancer, ACTN1 and CDC25B, corroborating their up-regulation at the protein level with disease progression. Thus, we identified a 57-gene QPCR panel to help predict progression of non–muscle-invasive bladder cancers and delineate a systematic, generalizable approach to converting microarray data into a multiplex assay for cancer progression. [Cancer Res 2009;69(9):3810–8]

Supplementary Figure 2 from Development of a Multiplex Quantitative PCR Signature to Predict Progression in Non–Muscle-Invasive Bladder Cancer

Evidence-based treatments for chronic low back pain (cLBP) typically work well in only a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients. Our central hypothesis is that an interventional response phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based treatments for cLBP. Thus, we will conduct a randomized controlled Sequential, Multiple Assessment, Randomized Trial (SMART) design study in cLBP with the following three aims. Aim 1: Perform an interventional response phenotyping study in a cohort of cLBP patients (n = 400), who will receive a sequence of interventions known to be effective in cLBP. For 4 weeks, all cLBP participants will receive a web-based pain self-management program as part of a run-in period, then individuals who report no or minimal improvement will be randomized to: a) mindfulness-based stress reduction, b) physical therapy and exercise, c) acupressure self-management, and d) duloxetine. After 8 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 8 weeks. Using those data, we will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically derived measures, can predict differential responsiveness to the treatments. In Aim 3, a subset of participants will receive deeper phenotyping (n = 160), to identify new experimental measures that predict differential responsiveness to the treatments, as well as to infer mechanisms of action. Deep phenotyping will include functional neuroimaging, quantitative sensory testing, measures of inflammation, and measures of autonomic tone.

Background Black men in the United States have markedly higher rates of prostate cancer than the general population. National guidelines for prostate-specific antigen (PSA) screening do not provide clear guidance for this high-risk population. The purpose of this study is to estimate the benefit and harm of intensified PSA screening in Black men. Methods Two microsimulation models of prostate cancer calibrated to incidence from the Surveillance, Epidemiology, and End Results program among Black men project the impact of different screening strategies (varying screening intervals, starting and stopping ages, and biopsy utilization following an abnormal PSA) on disease-specific mortality and overdiagnosis. Each strategy induces a mean lead time (MLT) for detected cases. A longer MLT reduces mortality according to estimates combining the US and European prostate cancer screening trials but increases overdiagnosis. Results Under historical population screening, Black men had similar MLT to men of all races and similar mortality reduction (range between models = 21%-24% vs 20%-24%) but a higher frequency of overdiagnosis (75-86 vs 58-60 per 1000 men). Screening Black men aged 40-84 years annually would increase both mortality reduction (29%-31%) and overdiagnosis (112-129 per 1000). Restricting screening to ages 45-69 years would still achieve substantial mortality reduction (26%-29%) with lower overdiagnosis (51-61 per 1000). Increasing biopsy utilization to 100% of abnormal tests would further reduce mortality but substantially increase overdiagnosis. Conclusions Annual screening in Black men is expected to reduce mortality more than that estimated under historical screening. Limiting screening to men younger than 70 years is expected to help reduce overdiagnosis.

IMPORTANCE Benign paroxysmal positional vertigo of the posterior canal (PC-BPPV) is a common disorder that is diagnosed using the Dix-Hallpike test (DHT) and treated with the canalith repositioning maneuver (CRM). Patients often seek out information about BPPV self-management, but studies to develop and evaluate patient-centered instructional resources are limited. OBJECTIVE To develop and preliminarily evaluate a patient-oriented PC-BPPV self-management instructional video. METHODS We assembled a multidisciplinary team and used an iterative process to develop a theory-based instructional video for self-performing the DHT and CRM. We recruited individuals searching online for information about dizziness to complete a survey and review the video. Patients rated the video by scoring seven questions that measure behavioral intent to perform the DHT or CRM (attitudes/acceptability, perceived self-efficacy, and social norms) using a 10-point scale (higher scores = more favorable ratings). A multilevel linear regression model was used to determine the association of age, sex, race, and education with video ratings. RESULTS Of the 771 participants who completed the survey, 124 (16%) also reviewed and evaluated the PC-BPPV instructional video. The video review participants were typically more than or equal to 55 years old (70%; 93/124), women (70%; 87/124), and White (70%; 88/124). These participants also generally reported acute-subacute and moderate-to-severe dizziness, and 60% (75/124) reported typical BPPV triggers. The median scores for the seven questions about attitudes/acceptability, self-efficacy, and social norms on the PC-BPPV instructional video were all more than or equal to 9 out of 10 with interquartile ratios that ranged from 7 to 9 at the 25th percentile to 10 at the 75th percentile. Female sex was the only demographic variable associated with higher video ratings (coefficient, 1.21, 95% CI 0.60-1.83). CONCLUSION This study found that participants rated the PC-BPPV self-management video favorably on measures that contribute to behavioral intent to perform the DHT or CRM. The findings provide support that the video is appropriate to use in future studies that evaluate patient self-performance accuracy and outcomes.

Dynamic prediction methods incorporate longitudinal biomarker information to produce updated, more accurate predictions of conditional survival probability. There are two approaches for obtaining dynamic predictions: (1) a joint model of the longitudinal marker and survival process, and (2) an approximate approach that specifies a model for a specific component of the joint distribution. In the case of a binary marker, an illness-death model is an example of a joint modeling approach that is unified and produces consistent predictions. However, previous literature has shown that approximate approaches, such as landmarking, with additional flexibility can have good predictive performance. One such approach proposes using a Gaussian copula to model the joint distribution of conditional continuous marker and survival distributions. It has the advantage of specifying established, flexible models for the marginals for which goodness-of-fit can be assessed, and has easy estimation that can be implemented in standard software. In this article, we provide a Gaussian copula approach for dynamic prediction to accommodate a binary marker using a continuous latent variable formulation. We compare the predictive performance of this approach to joint modeling and landmarking using simulations and demonstrate its use for obtaining dynamic predictions in an application to a prostate cancer study.

Background Surgical patients are vulnerable to opioid dependency and related risks. Clinical-translational data suggest that caffeine may enhance postoperative analgesia. This trial tested the hypothesis that intraoperative caffeine would reduce postoperative opioid consumption. The secondary objective was to assess whether caffeine improves neuropsychological recovery postoperatively. Methods This was a single-center, randomized, placebo-controlled trial. Participants, clinicians, research teams, and data analysts were all blinded to the intervention. Adult (≥18 years old) surgical patients (n = 65) presenting for laparoscopic colorectal and gastrointestinal surgery were randomized to an intravenous caffeine citrate infusion (200 mg) or dextrose 5% in water (40 mL) during surgical closure. The primary outcome was cumulative opioid consumption through postoperative day 3. Secondary outcomes included subjective pain reporting, observer-reported pain, delirium, Trail Making Test performance, depression and anxiety screens, and affect scores. Adverse events were reported, and hemodynamic profiles were also compared between the groups. Results Sixty patients were included in the final analysis, with 30 randomized to each group. The median (interquartile range) cumulative opioid consumption (oral morphine equivalents, milligrams) was 77 mg (33-182 mg) for caffeine and 51 mg (15-117 mg) for placebo (estimated difference, 55 mg; 95% confidence interval [CI], -9 to 118; P = .092). After post hoc adjustment for baseline imbalances, caffeine was associated with increased opioid consumption (87 mg; 95% CI, 26-148; P = .005). There were otherwise no differences in prespecified pain or neuropsychological outcomes between the groups. No major adverse events were reported in relation to caffeine, and no major hemodynamic perturbations were observed with caffeine administration. Conclusions Caffeine appears unlikely to reduce early postoperative opioid consumption. Caffeine otherwise appears well tolerated during anesthetic emergence.

395 Background: Understanding contemporary radiation therapy outcomes for prostate cancer (i.e., metastasis, death) is important for shared decision-making and setting expectations for patients and providers. Unfortunately, long-term outcome estimates are often derived from meta-analyses of outdated prospective clinical trials or population-based data lacking reliable clinical details (e.g., incident metastatic disease). For these reasons, we used a recently validated, natural language processing algorithm to identify incident metastatic prostate cancer within the electronic medical records of men treated with radiation therapy for localized prostate cancer in order to conduct an innovative and contemporary population-based survival outcomes study. Methods: We used national administrative, cancer registry, and electronic health record data for patients undergoing definitive radiation therapy with or without concurrent androgen deprivation therapy (ADT) within the Veterans Health Administration from 2005 to 2015. We used National Death Index data through 2019 for overall and prostate cancer-specific survival, and identified the date of incident metastatic prostate cancer using a validated natural language processing algorithm. We estimated metastasis-free, prostate cancer-specific, and overall survival using Kaplan-Meier methods. Results: We identified 41,876 patients treated with definitive radiation therapy for prostate cancer from 2005 through 2015, and followed them for over 8 years (follow up, median, 8.7 years, age at diagnosis, median, 65 years). Most patients had intermediate (42%) and high risk (33%) disease, with nearly half treated with ADT as part of initial therapy (44%). Unadjusted 10-year metastasis-free survival was 96%, 92%, and 80% for low, intermediate, and high risk disease. Similarly, unadjusted 10-year prostate cancer-specific survival was 98%, 97%, and 90% for low, intermediate, and high risk disease. Unadjusted overall survival was lower across disease risk categories at 77%, 71%, and 62% for low, intermediate, and high risk disease. Conclusions: These data provide population-based benchmarks for clinically relevant endpoints, including metastasis-free survival, among patients with low, intermediate, and high risk prostate cancer undergoing radiation therapy using contemporary techniques. The survival rates for high risk disease, in particular, compare favorably with historical outcomes.

Background The Timing Of Androgen Deprivation (TOAD) trial found an overall survival benefit for immediate vs delayed androgen deprivation therapy (ADT) for prostate-specific antigen (PSA)–relapsed or noncurable prostate cancer. However, broad eligibility criteria allowed entry of a heterogeneous participant group, including those with prior ADT exposure, raising concerns about subsequent androgen sensitivity. For these reasons, we completed previously specified subgroup analyses to assess if prior ADT was associated with ADT timing efficacy after PSA relapse. Methods We examined TOAD trial patient-level data for participants with PSA relapse after local therapy. We performed Kaplan-Meier analyses for overall survival stratified by prior ADT and randomized treatment arm (immediate or delayed ADT). We compared group characteristics using Mann-Whitney U and Fisher exact tests. All hypothesis tests were 2-sided. Results We identified 261 patients with PSA relapse, 125 of whom received prior ADT. Patients with prior ADT had higher PSA at presentation (12.1 vs 9.0 ng/mL; P Conclusions The survival benefit demonstrated in the TOAD trial may be driven by patients who received ADT prior to trial entry. We provide possible explanations for this finding with implications for treatment of PSA-relapsed prostate cancer and future study planning.

Summary A dynamic treatment regimen (DTR) is a sequence of decision rules that can alter treatments or doses based on outcomes from prior treatment. In the case of two lines of treatment, a DTR specifies first-line treatment, and second-line treatment for responders and treatment for non-responders to the first-line treatment. A sequential, multiple assignment, randomized trial (SMART) is one such type of trial that has been designed to assess DTRs. The primary goal of our project is to identify the treatments, covariates, and their interactions result in the best overall survival rate. Many previously proposed methods to analyze data with survival outcomes from a SMART use inverse probability weighting and provide non-parametric estimation of survival rates, but no other information. Other methods have been proposed to identify and estimate the optimal DTR, but inference issues were seldom addressed. We apply a joint modeling approach to provide unbiased survival estimates as a mechanism to quantify baseline and time-varying covariate effects, treatment effects, and their interactions within regimens. The issue of multiple comparisons at specific time points is addressed using multiple comparisons with the best method.

Background Studies conducted in Swedish populations have shown that men with lowest prostate-specific antigen (PSA) levels at ages 44–50 years and 60 years have very low risk of future distant metastasis or death from prostate cancer. This study investigates benefits and harms of screening strategies stratified by PSA levels. Methods PSA levels and diagnosis patterns from two microsimulation models of prostate cancer progression, detection, and mortality were compared against results of the Malmö Preventive Project, which stored serum and tracked subsequent prostate cancer diagnoses for 25 years. The models predicted the harms (tests and overdiagnoses) and benefits (lives saved and life-years gained) of PSA-stratified screening strategies compared with biennial screening from age 45 years to age 69 years. Results Compared with biennial screening for ages 45–69 years, lengthening screening intervals for men with PSA less than 1.0 ng/mL at age 45 years led to 46.8–47.0% fewer tests (range between models), 0.9–2.1% fewer overdiagnoses, and 3.1–3.8% fewer lives saved. Stopping screening when PSA was less than 1.0 ng/mL at age 60 years and older led to 12.8–16.0% fewer tests, 5.0–24.0% fewer overdiagnoses, and 5.0–13.1% fewer lives saved. Differences in model results can be partially explained by differences in assumptions about the link between PSA growth and the risk of disease progression. Conclusion Relative to a biennial screening strategy, PSA-stratified screening strategies investigated in this study substantially reduced the testing burden and modestly reduced overdiagnosis while preserving most lives saved. Further research is needed to clarify the link between PSA growth and disease progression.

Objective Many studies suggest a strong familial component to fibromyalgia (FM). However, those studies have nearly all been confined to individuals with primary FM, i.e., FM without any other accompanying disorder. The current 2011 and 2016 criteria for diagnosing FM construct a score using a combination of the number of painful body sites and the severity of somatic symptoms (FM score). This study was undertaken to estimate the genetic heritability of the FM score across sex and age groups to identify subgroups of individuals with greater heritability, which may help in the design of future genetic studies. Methods We collected data on 26,749 individuals of European ancestry undergoing elective surgery at the University of Michigan (Michigan Genomics Initiative study). We estimated the single-nucleotide polymorphism-based heritability of FM score by age and sex categories using genome-wide association study data and a linear mixed-effects model. Results Overall, the FM score had an estimated heritability of 13.9% (SE 2.9%) (P = 1.6 × 10-7 ). Estimated FM score heritability was highest in individuals ≤50 years of age (23.5%; SE 7.9%) (P = 3.0 ×10-4 ) and lowest in individuals >60 years of age (7.5%; SE 8.1%) (P = 0.41). These patterns remained the same when we analyzed FM as a case-control phenotype. Even though women had an ~30% higher average FM score than men across age categories, FM score heritability did not differ significantly by sex. Conclusion Younger individuals appear to have a much stronger genetic component to the FM score than older individuals. Older individuals may be more likely to have what was previously called "secondary FM." Regardless of the cause, these results have implications for future genetic studies of FM and associated conditions.

Summary Dynamic prediction uses patient information collected during follow-up to produce individualized survival predictions at given time points beyond treatment or diagnosis. This allows clinicians to obtain updated predictions of a patient’s prognosis that can be used in making personalized treatment decisions. Two commonly used approaches for dynamic prediction are landmarking and joint modeling. Landmarking does not constitute a comprehensive probability model, and joint modeling often requires strong distributional assumptions and computationally intensive methods for estimation. We introduce an alternative approximate approach for dynamic prediction that aims to overcome the limitations of both methods while achieving good predictive performance. We separately specify the marker and failure time distributions conditional on surviving up to a prediction time of interest and use standard variable selection and goodness-of-fit techniques to identify the best-fitting models. Taking advantage of its analytic tractability and easy two-stage estimation, we use a Gaussian copula to link the marginal distributions smoothly at each prediction time with an association function. With simulation studies, we examine the proposed method’s performance. We illustrate its use for dynamic prediction in an application to predicting death for heart valve transplant patients using longitudinal left ventricular mass index information.

INTRODUCTION AND OBJECTIVE:The TOAD trial (Lancet Oncology 2016) found an overall survival benefit for immediate compared to delayed androgen deprivation therapy (ADT) for PSA-relapsed or non-curab...

Rationale and Objectives The journal impact factor (JIF) is often used to assess the prestige of scientific journals. Citations from original articles and reviews as well as citations from noncitable items contribute to the numerator in these calculations. However, since noncitable articles are not included in the denominator, the JIF may be skewed by the types of articles and not accurately reflect the prestige of the journal. The purpose of our study was to develop an alternative and complementary metric by which journals may be assessed. This “adjusted citation rate metric” is based on citations that originate only from citable items in the journal. Material and Methods We tabulated the number of citations and citable items for original articles from the Web of Science Core Collection for 5 consecutive years (2010–2014) for 20 general radiology journals. The adjusted citation rates (CR) per original article and reviews were calculated using only citations that originated from citable items. Results The adjusted CR in 2015 was similar to the JIF in 14 of the 20 journals, higher in four journals, and lower in two journals. Using this system, Radiology, Investigative Radiology, and European Radiology remained first, second, and third respectively among journals published in the field of general radiology. To allow for equal distribution of original articles vs reviews among general radiology journals, we calculated the adjusted CR where the standard distribution of original articles is 50%. Conclusion Adjusted citation rate is an objective index for assessing journal impact that can serve as an alternative and complementary metric with which to measure the journal impact.

5090 Background: Accurate survival estimates after prostatectomy are critical for patient counseling, treatment decisions, and trial design. Prior prostate cancer natural history studies may not reflect contemporary outcomes and often lack key endpoints (e.g. incident metastases). For these reasons, we explored population-based recurrence and survival following radical prostatectomy. Methods: We conducted a retrospective study of men with localized prostate cancer treated with radical prostatectomy from 2005-2015 with follow up through 2019 in the Veterans Health Administration. We excluded men with adjuvant radiation or hormonal therapy and defined biochemical recurrence (BCR) as a PSA ≥0.2 ng/mL. We used a validated natural language processing encoded dataset to identify incident metastatic disease. We then estimated actuarial time from surgery to BCR, BCR to metastatic disease, and metastatic disease to death using Kaplan-Meier methods. Results: Of 22,033 men post-prostatectomy, 5,963 (27%) developed BCR, with 5- and 10-year BCR estimates of 21% and 29% (Table). Of 5,963 men with BCR, 678 (11%) developed metastasis, with 5- and 10-year metastasis-free survival from time of BCR of 91% and 77%. Of these 678 men with metastases, 235 died (35%), with 5- and 10-year overall survival of 61% and 47%. Median actuarial overall survival from incident metastatic disease was 8.8 years. Conclusions: On average, we found a man undergoing radical prostatectomy for localized prostate cancer can expect about a 1 in 4 chance of biochemical recurrence. Of men with BCR, we identified a 1 in 10 chance of developing metastases, surviving nearly 9 years after incident metastasis. Both metastasis-free survival after biochemical recurrence and overall survival after developing metastasis appear to have lengthened consistent with a long natural history after prostate cancer surgery. Novel advanced prostate cancer treatments may help explain these findings, though their optimal use warrants further study especially as advanced imaging techniques to characterize recurrence increase. [Table: see text]

Recent studies show decreasing prostate-specific antigen utilization and increasing incidence of metastatic prostate cancer in the United States after national recommendations against screening in 2012. Yet, whether the increasing incidence of metastatic prostate cancer is consistent in magnitude with the expected impact of decreased screening is unknown. We compared observed incidence of metastatic prostate cancer from the Surveillance, Epidemiology, and End Results program and published effects of continued historical screening and discontinued screening starting in 2013 projected by 2 models of disease natural history, screening, and diagnosis. The observed rate of new metastatic prostate cancer cases in 2017 was 44%-60% of the projected increase under discontinued screening relative to continued screening. Thus, the observed increase in incident metastatic prostate cancer is consistent with the expected impact of reduced screening. Although this comparison does not establish a causal relationship, it highlights the plausible role of decreased screening in the observed trend.

In this paper we consider the generalized self-consistency approach to maximum likelihood estimation (MLE). The idea is to represent a given likelihood as a marginal one based on artificial missing data. The computational advantage is sought in the likelihood simplification at the complete-data level. Semiparametric survival models and models for categorical data are used as an example. Justifications for the approach are outlined when the model at the complete-data level is not a legitimate probability model or if it does not exist at all.

Adrenal vein sampling (AVS) is required to distinguish unilateral from bilateral aldosterone sources in primary aldosteronism (PA), and cortisol is used for AVS data interpretation, but cortisol has several pitfalls. In this study, we present the utility of several other steroids in PA subtyping, both during AVS, as well as in peripheral serum. We included patients with PA who underwent AVS at University of Michigan between 2012 and 2018. We used mass spectrometry to simultaneously quantify 17 steroids in adrenal veins (AV) and periphery, both at baseline and after cosyntropin administration. PA was classified as unilateral or bilateral based on a lateralization index ≥ or P

Background Chronic pelvic pain is a debilitating problem that afflicts 15% to 20% of women in the United States. Although more than 200,000 hysterectomies are performed annually for the treatment of chronic pelvic pain, previous studies indicate that 1 in 4 women undergo the discomfort and morbidity of hysterectomy without the relief of pain. The factors that predict treatment failure remain poorly characterized. Objective To describe the incidence of persistent pelvic pain 6 months following hysterectomy in women with chronic pelvic pain and determine whether a simple, self-reported measure of central sensitization is associated with a greater risk of persistent pelvic pain following hysterectomy. Study Design We conducted a prospective, observational cohort study of women undergoing hysterectomy at an academic tertiary care center for a benign indication. Patients with preoperative chronic pelvic pain, defined as average pelvic pain ≥3 on a 0 to 10 numeric rating scale for >3 months before hysterectomy, were included in this analysis. The patients completed validated assessments of pain, anxiety, depression, and centralized pain (using the 2011 Fibromyalgia Survey Criteria, 0–31 points) preoperatively and 6 months after hysterectomy. The demographic information, surgical history, intraoperative findings, and surgical pathology were abstracted from the electronic medical records. Multivariate logistic regression was used to identify the independent predictors of persistent pelvic pain 6 months following hysterectomy, defined as Results Among 176 participants with pelvic pain before hysterectomy, 126 (71.6%) were retained at 6 months, and 15 (11.9%) reported persistent pelvic pain. There was no difference in age (P=.46), race (P=.55), average pain severity during menses (P=.68), average overall pelvic pain (P=.10), or pain duration (P=.80) in those with and without persistent pelvic pain. Whereas intraoperative findings of endometriosis (P=.05) and uterine fibroids (P=.03) were associated with a higher incidence of persistent pain on univariate analysis, the surgical route (P=.46), pelvic adhesions (0.51), uterine weight (P=.66), and adenomyosis on histopathology (P=.27) were not related to the risk of persistent pain. Higher preoperative centralized pain scores (P=.01) but not depression (P=.64) or anxiety (P=.45) were more common in women with persistent pelvic pain. Multivariate logistic regression adjusting for age, preoperative pain severity, anxiety, depression, and operative findings of endometriosis and fibroids indicated that every 1-point increase in centralized pain before hysterectomy was associated with a 27% increase in the odds of persistent pelvic pain (odds ratio, 1.27; 95% confidence interval, 1.03–1.57) 6 months after surgery. Conclusion Although the majority of women with chronic pelvic pain report considerable improvement in pain following hysterectomy, higher degrees of centralized pain before hysterectomy is a robust predictor of persistent pelvic pain.

Background The European Randomized Study of Screening for Prostate Cancer (ERSPC) demonstrated that prostate-specific antigen (PSA) screening significantly reduced prostate cancer mortality (rate ratio, 0.79; 95% confidence interval, 0.69-0.91). The US Prostate, Lung, Colorectal, and Ovarian (PLCO) trial indicated no such reduction but had a wide 95% CI (rate ratio for prostate cancer mortality, 1.09; 95% CI, 0.87-1.36). Standard meta-analyses are unable to account for key differences between the trials that can impact the estimated effects of screening and the trials' point estimates. Methods The authors calibrated 2 microsimulation models to individual-level incidence and mortality data from 238,936 men participating in the ERSPC and PLCO trials. A cure parameter for the underlying efficacy of screening was estimated by the models separately for each trial. The authors changed step-by-step major known differences in trial settings, including enrollment and attendance patterns, screening intervals, PSA thresholds, biopsy receipt, control arm contamination, and primary treatment, to reflect a more ideal protocol situation and differences between the trials. Results Using the cure parameter estimated for the ERSPC, the models projected 19% to 21% and 6% to 8%, respectively, prostate cancer mortality reductions in the ERSPC and PLCO settings. Using this cure parameter, the models projected a reduction of 37% to 43% under annual screening with 100% attendance and biopsy compliance and no contamination. The cure parameter estimated for the PLCO trial was 0. Conclusions The observed cancer mortality reduction in screening trials appears to be highly sensitive to trial protocol and practice settings. Accounting for these differences, the efficacy of PSA screening in the PLCO setting is not necessarily inconsistent with ERSPC results. Cancer 2018;124:1197-206. © 2017 American Cancer Society.

Objective To quantify physician prescribing patterns and patient opioid use in the 2 weeks after hysterectomy at an academic institution and to determine whether patient factors predict postsurgical opioid use and pain recovery. Methods We conducted a prospective quality initiative study by recruiting all English-speaking patients undergoing hysterectomy for benign, nonobstetric indications at a university hospital between August 2015 and December 2015, excluding those with major medical morbidities or substance abuse. Before hysterectomy, patients completed the Fibromyalgia Survey, a validated measure of centralized pain. After hysterectomy, opioid use (converted to oral morphine equivalents) and pain scores (0-10 numeric rating scale) were collected by a daily diary and a structured telephone interview 14 days after surgery. Primary outcomes were total opioid prescribed and consumed in the 2 weeks after hysterectomy. Secondary outcomes included daily opioid use and daily pain severity for 14 days after hysterectomy. Results Of 103 eligible patients, 102 (99%) agreed to participate, including 44 (43.1%) laparoscopic, 42 (41.2%) vaginal, and 16 (15.7%) abdominal hysterectomies. Telephone surveys were completed on 89 (87%) participants; diaries were returned from 60 (59%) participants. Diary nonresponders had different baseline characteristics than nonresponders. Median amount of opioid prescribed was 200 oral morphine equivalents (interquartile range 150-250). Patients reported using approximately half of the opioids prescribed with a median excess of 110 morphine equivalents (interquartile range 40-150). The best fit model of total opioid consumption identified preoperative Fibromyalgia Survey Score, overall body pain, preoperative opioid use, prior endometriosis, abdominal hysterectomy (compared with laparoscopic), and uterine weight as significant predictors. Highest tertile of Fibromyalgia Survey Score was associated with greater daily opioid consumption (13.9 [95% CI 3.0-24.8] greater oral morphine equivalents at baseline, P=.02). Conclusion Gynecologists at a large academic medical center prescribe twice the amount of opioids than the average patient uses after hysterectomy. A personalized approach to prescribing opioids for postoperative pain should be considered.

3032 Background: Earlier detection of cancer could lead to improved outcomes. Non-invasive biomarkers are integral for early detection, and protein and DNA-based assays have been previously described for this purpose. Evaluation of highly expressed circulating RNA would improve upon existing methods by allowing for quantitation, however RNA expression in plasma is low. Circular RNA (circRNA) is formed by alternative backsplicing and provide resistance to exoribonclease-mediated degradation. Therefore, circRNA is more stable in plasma and could potentially be more easily detected non-invasively. Here, we report results from a novel assay that identifies and quantitates expression of circRNA in cancer plasma. Methods: Cancer-specific circRNA targets were identified by analyzing differential expression and abundance based on capture RNA sequencing in tissues. CircRNA-specific probes were designed and validated by stable expression with RNAse R incubation. Expression of selected circRNA isoforms were measured using a quantitative PCR-based assay. For breast cancer specimens, plasma was collected from a cohort of 36 patients and 12 normal female controls without known cancer diagnosis. Expression was determined by normalizing signal to two averaged universally expressed circRNAs. Differential expression for each target was determined for cancer vs. normal and stratified based on ER and HER2 positivity as well as stage. Results: Normalized expression of seven proposed breast cancer-specific circRNA targets was determined for all patients in the cohort. All targets demonstrated resistance to RNAse R-mediated degradation in breast cancer cell lines. In the breast cancer cohort, CircTRPS1 expression was higher in cancer plasma than normal, trending toward significance. Expression of circTRPS1 was significantly more common in ER-negative than ER-positive breast cancer (p = 0.02). CircPDHX expression was elevated in normal plasma compared to cancer and relatively higher in ER-positive than ER-negative cancer (p = 0.05). Median expression in plasma was elevated in cancer specimens compared to normal for CircVAV3, circDNAH14, and circCDYL. CircERBB2 expression was also relatively higher in HER2-positive cancer when compared to other targets. Higher expression significantly positively correlated with metastatic disease for circERBB2 (p = 0.01) and circCDYL (p = 0.005) and negatively correlated with metastasis for circWDR78 (p = 0.02). Conclusions: CircRNA are promising biomarkers for early non-invasive detection of cancer. We identified seven circRNA biomarkers in breast cancer plasma which correlated with clinical characteristics. Three circRNAs were significantly prognostic for metastatic breast cancer. Identification of additional cancer-specific targets and multiplexing markers is underway. This assay is generalizable to other cancers, and similar studies in prostate and bladder cancer are in progress.

BACKGROUND: Black men in the United States have substantially higher prostate cancer incidence rates than the general population. The extent to which this incidence disparity is because prostate cancer is more prevalent, more aggressive, and/or more frequently diagnosed in black men is unknown. METHODS: The authors estimated 3 independently developed models of prostate cancer natural history in black men and in the general population using an updated reconstruction of prostate-specific antigen screening, based on the National Health Interview Survey in 2005 and on prostate cancer incidence data from the Surveillance, Epidemiology, and End Results program during 1975 through 2000. By using the estimated models, the natural history of prostate cancer was compared between black men and the general population. RESULTS: The models projected that from 30% to 43% (range across models) of black men develop preclinical prostate cancer by age 85 years, a risk that is (relatively) 28% to 56% higher than that in the general population. Among men who had preclinical disease onset, black men had a similar risk of diagnosis (range, 35%-49%) compared with the general population (32%-44%), but their risk of progression to metastatic disease by the time of diagnosis was from 44% to 75% higher than that in the general population. CONCLUSIONS: Prostate cancer incidence patterns implicate higher incidence of preclinical disease and higher risk of metastatic progression among black men. The findings suggest screening black men earlier than white men and support further research into the benefit-harm tradeoffs of more aggressive screening policies for black men.

This research was motivated by a clinical trial with bladder cancer patients who went through a surgery and were followed up for cancer recurrence. One of the main objectives of the trial was to evaluate the time to cancer recurrence in patients in control and experimental groups. At the time of recurrence, the disease stage was also evaluated. Because the stage of cancer at recurrence significantly impacts future treatment and patient prognosis of survival, analyzing the time to cancer recurrence and the stage at recurrence jointly provides more clinically relevant information than analyzing the time to recurrence alone. In this paper, we propose a stochastic model for the joint distribution of time to recurrence and cancer stage that (1) accounts for the recurrence caused by cancer cells surviving a treatment or a surgery and for the recurrence caused by spontaneous carcinogenesis, and (2) incorporates parameters that have biological meaning. To estimate the parameters, we use the maximum-likelihood method combined with the EM algorithm. To demonstrate the performance of our modeling, we evaluate the data from a clinical trial in patients with bladder cancer. We also use simulations to assess the sensitivity of the method.

Study objective We evaluated a strategy to increase use of the test (Dix-Hallpike’s test [DHT]) and treatment (canalith repositioning maneuver [CRM]) for benign paroxysmal positional vertigo in emergency department (ED) dizziness visits. Methods We conducted a stepped-wedge randomized trial in 6 EDs. The population was visits with dizziness as a principal reason for the visit. The intervention included educational sessions and decision aid materials. Outcomes were DHT or CRM documentation (primary), head computed tomography (CT) use, length of stay, admission, and 90-day stroke events. The analysis was multilevel logistic regression with intervention, month, and hospital as fixed effects and provider as a random effect. We assessed fidelity with monitoring intervention use and semistructured interviews. Results We identified 7,635 dizziness visits during 18 months. The DHT or CRM was documented in 1.5% of control visits (45/3,077; 95% confidence interval 1% to 1.9%) and 3.5% of intervention visits (159/4,558; 95% confidence interval 3% to 4%; difference 2%, 95% confidence interval 1.3% to 2.7%). Head CT use was lower in intervention visits compared with control visits (44.0% [1,352/3,077] versus 36.9% [1,682/4,558]). No differences were observed in admission or 90-day subsequent stroke risk. In fidelity evaluations, providers who used the materials typically reported positive clinical experiences but provider engagement was low at facilities without an emergency medicine residency program. Conclusion These findings provide evidence that an implementation strategy of a benign paroxysmal positional vertigo–focused approach to ED dizziness visits can be successful and safe in promoting evidence-based care. Absolute rates of DHT and CRM use, however, were still low, which relates in part to our broad inclusion criteria for dizziness visits.

We are investigating the association of mammographic density with breast cancer occurrence. With IRB approval, we collected cases of women with screening-detected breast cancer and controls. A total of 2028 patients including 329 cases was collected from the screening cohort in our institution. An experienced MQSA radiologist retrospectively reviewed the earliest available digital mammograms (DMs) and assessed breast density in terms of BI-RADS categories and percent density (PD) estimated by interactive thresholding. Survival models were built based on BI-RADS categories and strata based on PD measures, respectively. Using the pairwise log-rank test, we observed a statistically significant difference at the 5% level between BI-RADS category A and C, category A and D, category B and C, & category B and D. Similarly, we found a significant difference between curves for women with

Background Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder, and accounts for 8% of individuals with moderate or severe dizziness. BPPV patients experience substantial inconveniences and disabilities during symptomatic periods. BPPV therapeutic processes – the Dix-Hallpike Test (DHT) and the Canalith Repositioning Maneuver (CRM) – have an evidence base that is at the clinical practice guideline level. The most commonly used CRM is the modified Epley maneuver. The DHT is the gold standard test for BPPV and the CRM is supported by numerous randomized controlled trials and systematic reviews. Despite this, BPPV care processes are underutilized. Methods/design This is a stepped-wedge, randomized clinical trial of a multi-faceted educational and care-process-based intervention designed to improve the guideline-concordant care of patients with BPPV presenting to the emergency department (ED) with dizziness. The unit of randomization and target of intervention is the hospital. After an initial observation period, the six hospitals will undergo the intervention in five waves (two closely integrated hospitals will be paired). The order will be randomized. The primary endpoint is measured at the individual patient level, and is the presence of documentation of either the Dix-Hallpike Test or CRM. The secondary endpoints are referral to a health care provider qualified to treat dizziness for CRM and 90-day stroke rates following an ED dizziness visit. Formative evaluations are also performed to monitor and identify potential and actual influences on the progress and effectiveness of the implementation efforts. Discussion If this study safely increases documentation of the DHT/CRM, this will be an important step in implementing the use of these evidenced-based processes of care. Positive results will support conducting larger-scale follow-up studies that assess patient outcomes. The data collection also enables evaluation of potential and actual influences on the progress and effectiveness of the implementation efforts. Trial registration ClinicalTrials.gov, ID: NCT02809599. The record was first available to the public on 22 June 2016 prior to the enrollment of the first patients in October 2016. Electronic supplementary material The online version of this article (10.1186/s13063-018-3099-0) contains supplementary material, which is available to authorized users.

In cancer research, interest frequently centers on factors influencing a latent event that must precede a terminal event. In practice it is often impossible to observe the latent event precisely, making inference about this process difficult. To address this problem, we propose a joint model for the unobserved time to the latent and terminal events, with the two events linked by the baseline hazard. Covariates enter the model parametrically as linear combinations that multiply, respectively, the hazard for the latent event and the hazard for the terminal event conditional on the latent one. We derive the partial likelihood estimators for this problem assuming the latent event is observed, and propose a profile likelihood-based method for estimation when the latent event is unobserved. The baseline hazard in this case is estimated nonparametrically using the EM algorithm, which allows for closed-form Breslow-type estimators at each iteration, bringing improved computational efficiency and stability compared with maximizing the marginal likelihood directly. We present simulation studies to illustrate the finite-sample properties of the method; its use in practice is demonstrated in the analysis of a prostate cancer data set.

Falls are a major public health problem internationally. Many hospitals have implemented fall risk assessment tools, but few have implemented interventions to mitigate patient-specific fall risks. Little research has been done to examine the effect of implementing evidence-based fall prevention interventions to mitigate patient-specific fall risk factors in hospitalized adults.To evaluate the impact of implementing, in 3 U.S. hospitals, evidence-based fall prevention interventions targeted to patient-specific fall risk factors (Targeted Risk Factor Fall Prevention Bundle). Fall rates, fall injury rates, types of fall injuries and adoption of the Targeted Risk Factor Fall Prevention Bundle were compared prior to and following implementation.A prospective pre-post implementation cohort design.Thirteen adult medical-surgical units from three community hospitals in the Midwest region of the U.S.Nurses who were employed at least 20hours/week, provided direct patient care, and licensed as an RN (n=157 pre; 140 post); and medical records of patients 21years of age or older, who received care on the study unit for more than 24hours during the designated data collection period (n=390 pre and post).A multi-faceted Translating Research Into Practice Intervention was used to implement the Targeted Risk Factor Fall Prevention Bundle composed of evidence-based fall prevention interventions designed to mitigate patient-specific fall risks. Dependent variables (fall rates, fall injury rates, fall injury type, use of Targeted Risk Factor Fall Prevention Bundle) were collected at baseline, and following completion of the 15month implementation phase. Nurse questionnaires included the Stage of Adoption Scale, and the Use of Research Findings in Practice Scale to measure adoption of evidence-based fall prevention practices. A Medical Record Abstract Form was used to abstract data about use of targeted risk-specific fall prevention interventions. Number of falls, and number and types of fall injuries were collected for each study unit for 3months pre- and post-implementation. Data were analyzed using multivariate analysis.Fall rates declined 22% (p=0.09). Types of fall injuries changed from major and moderate to minor injuries. Fall injury rates did not decline. Use of fall prevention interventions improved significantly (p0.001) for mobility, toileting, cognition, and risk reduction for injury, but did not change for those targeting medications.Using the Translating Research Into Practice intervention promoted use of many evidence-based fall prevention interventions to mitigate patient-specific fall risk factors in hospitalized adults.

OBJECTIVES/SPECIFIC AIMS: The study aims to understand if pro inflammatory epicardial white adipose phenotype is positively associated with coronary atherosclerosis, while the brown adipose phenotype is negatively associated. Primary outcome is association between epicardial fat fraction and coronary atherosclerosis and cardiac function. Secondary outcome is transcriptomic and lipidomic profiling between epicardial, extra pericardial, and subcutaneous depots and how these profiles correlate with fat fraction. METHODS/STUDY POPULATION: Recruited patients undergoing open-heart surgery provided informed consent at their second visit and underwent laboratory testing and imaging (cardiac magnetic resonance including water-fat imaging and coronary calcium computed tomography) prior to their surgery. Cardiac function such as cardiac chamber volume, mass, function, and strain, and depo-specific fat fraction were calculated from cardiac MR and Agatston calcium score and epicardial adipose volume from CT images. At the time of surgery, a tissue specimens from the epicardial, extrapericardial, and subcutaneous depots were obtained for transcriptomic and lipidomic analysis. Linear and logistic regression analyses adjusted for other variables were performed to evaluate significance level between variables. RESULTS/ANTICIPATED RESULTS: 37 subjects were enrolled in the study, 13 (35%) of which were women. Cardiac function and fat fraction was quantified in all patients, whereas tissue analyses were performed in 22 patients. Epicardial and extrapericardial fat fraction were independently associated with coronary atherosclerosis (p-value 0.01 and 0.04 respectively) Only epicardial fat fraction was negatively associated with global circumferential shortening of the left ventricle (0.03), while neither the extrapericardial fat fraction nor epicardial adipose volume were not (p =0.33 and 0.97 respectively) All three adipose depots have unique gene signatures with differentially expressed genes and pathways. RNA sequencing of epicardial, extrapericardial, and subcutaneous depots demonstrated tight clustering of epicardial and subcutaneous signatures based on PCA analysis (Figure 2). 19 lipid classes and 59 lipids showed differential expression between at least 2 of the fat depots (Figure 3). Hierarchal clustering of the lipids showed that epicardial and extrapericardial depots were more closely related than subcutaneous adipose. Plasmenyl-phosphatidylcholines, with an ether-linked fatty acid at the sn-1 position of the lipid, were higher in subcutaneous fat while most other lipids were higher in epicardial fat per tissue weight, such as ceramides (p=0.002). DISCUSSION/SIGNIFICANCE OF IMPACT: Epicardial, extrapericardial, and subcutaneous adipose depots express different lipidome and transcriptome signatures and different pathways. GSEA analysis demonstrated enrichment of genes related to antigen presentation and B cell immunity in epicardial compared to subcutaneous adipose tissue. Epicardial fat fraction is associated with coronary atherosclerosis and decreased left ventricular global circumferential shortening as an early predictor of decreased left ventricular stroke volume. Epicardial fat fraction is also associated with cermides which may play role in the development of coronary atherosclerosis and decreased cardiac function.

Background: The current study was designed to test the hypothesis that the fibromyalgia survey criteria would be directly associated with increased opioid consumption after hysterectomy even when accounting for other factors previously described as being predictive for acute postoperative pain. Methods: Two hundred eight adult patients undergoing hysterectomy between October 2011 and December 2013 were phenotyped preoperatively with the use of validated self-reported questionnaires including the 2011 fibromyalgia survey criteria, measures of pain severity and descriptors, psychological measures, preoperative opioid use, and health information. The primary outcome was the total postoperative opioid consumption converted to oral morphine equivalents. Results: Higher fibromyalgia survey scores were significantly associated with worse preoperative pain characteristics, including higher pain severity, more neuropathic pain, greater psychological distress, and more preoperative opioid use. In a multivariate linear regression model, the fibromyalgia survey score was independently associated with increased postoperative opioid consumption, with an increase of 7-mg oral morphine equivalents for every 1-point increase on the 31-point measure (Estimate, 7.0; Standard Error, 1.7; P < 0.0001). In addition to the fibromyalgia survey score, multivariate analysis showed that more severe medical comorbidity, catastrophizing, laparotomy surgical approach, and preoperative opioid use were also predictive of increased postoperative opioid consumption. Conclusions: As was previously demonstrated in a total knee and hip arthroplasty cohort, this study demonstrated that increased fibromyalgia survey scores were predictive of postoperative opioid consumption in the posthysterectomy surgical population during their hospital stay. By demonstrating the generalizability in a second surgical cohort, these data suggest that patients with fibromyalgia-like characteristics may require a tailored perioperative analgesic regimen.

Objective While psychosocial factors have been associated with poorer outcomes after knee and hip arthroplasty, we hypothesized that augmented pain perception, as occurs in conditions such as fibromyalgia, may account for decreased responsiveness to primary knee and hip arthroplasty. Methods A prospective, observational cohort study was conducted. Preoperative phenotyping was conducted using validated questionnaires to assess pain, function, depression, anxiety, and catastrophizing. Participants also completed the 2011 fibromyalgia survey questionnaire, which addresses the widespread body pain and comorbid symptoms associated with characteristics of fibromyalgia. Results Of the 665 participants, 464 were retained 6 months after surgery. Since individuals who met criteria for being classified as having fibromyalgia were expected to respond less favorably, all primary analyses excluded these individuals (6% of the cohort). In the multivariate linear regression model predicting change in knee/hip pain (primary outcome), a higher fibromyalgia survey score was independently predictive of less improvement in pain (estimate −0.25, SE 0.044; P

BACKGROUND Molecular stratification of prostate cancer (PCa) based on genetic aberrations including ETS or RAF gene-rearrangements, PTEN deletion, and SPINK1 over-expression show clear prognostic and diagnostic utility. Gene rearrangements involving ETS transcription factors are frequent pathogenetic somatic events observed in PCa. Incidence of ETS rearrangements in Caucasian PCa patients has been reported, however, occurrence in Indian population is largely unknown. The aim of this study was to determine the prevalence of the ETS and RAF kinase gene rearrangements, SPINK1 over-expression, and PTEN deletion in this cohort. METHODS In this multi-center study, formalin-fixed paraffin embedded (FFPE) PCa specimens (n = 121) were procured from four major medical institutions in India. The tissues were sectioned and molecular profiling was done using immunohistochemistry (IHC), RNA in situ hybridization (RNA-ISH) and/or fluorescence in situ hybridization (FISH). RESULTS ERG over-expression was detected in 48.9% (46/94) PCa specimens by IHC, which was confirmed in a subset of cases by FISH. Among other ETS family members, while ETV1 transcript was detected in one case by RNA-ISH, no alteration in ETV4 was observed. SPINK1 over-expression was observed in 12.5% (12/96) and PTEN deletion in 21.52% (17/79) of the total PCa cases. Interestingly, PTEN deletion was found in 30% of the ERG-positive cases (P = 0.017) but in only one case with SPINK1 over-expression (P = 0.67). BRAF and RAF1 gene rearrangements were detected in ∼1% and ∼4.5% of the PCa cases, respectively. CONCLUSIONS This is the first report on comprehensive molecular profiling of the major spectrum of the causal aberrations in Indian men with PCa. Our findings suggest that ETS gene rearrangement and SPINK1 over-expression patterns in North Indian population largely resembled those observed in Caucasian population but differed from Japanese and Chinese PCa patients. The molecular profiling data presented in this study could help in clinical decision-making for the pursuit of surgery, diagnosis, and in selection of therapeutic intervention. Prostate 75:1051–1062, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

Background and Objectives Facet interventions for spine pain have high failure rates, and preprocedural prediction of response is nearly impossible. A potential explanation may be aberrant central pain processing as that existing in conditions like fibromyalgia. To test this hypothesis, we conducted a retrospective study investigating the impact of having characteristics of fibromyalgia on the acute analgesic response to a first diagnostic medial branch block (MBB). Methods We evaluated the analgesic responses of 187 patients that underwent MBB. Patients were categorized as “fibromyalgia-positive” or “fibromyalgia-negative” using the 2011 fibromyalgia survey criteria. Preprocedural and postprocedural pain scores and patient-completed pain diaries up to 24 hours postprocedure were collected. A linear mixed model was used to study longitudinal effects of MBB on pain responses. Results Fibromyalgia-positive patients had a worse preprocedural pain phenotype (ie, greater pain severity, higher levels of depressive and anxiety symptoms, reduced function). Binary categorization of fibromyalgia status was not associated with a difference in immediate postprocedural pain relief; however, the longitudinal analgesic response across time varied significantly between groups (P = 0.0005). Fibromyalgia-negative subjects showed the expected steep decline in pain scores, followed by gradual return to baseline, whereas a more aberrant pattern was noted in the fibromyalgia-positive group. Pain scores for fibromyalgia-negative patients were also lower by −1.07 (SE = 0.37) on average after the MBB (P = 0.005). Conclusions Characteristics of fibromyalgia may indicate pain that is more centralized in nature, a factor that may explain the aberrant analgesic response to this peripheral intervention. This may have implications for future prediction of treatment response, although prospective studies are needed.

Intrathoracic fat volume, more specifically, epicardial fat volume, is an emerging imaging biomarker of adverse cardiovascular events. The purpose of this work is to show the feasibility and reproducibility of intrathoracic fat volume measurement applied to contrast-enhanced multidetector computed tomography images. A retrospective cohort study of 62 subjects free of cardiovascular disease (55% females, age = 49 ± 11 years) conducted from 2008 to 2011 formed the study group. Intrathoracic fat volume was defined as all fat voxels measuring −50 to −250 Hounsfield Unit within the intrathoracic cavity from the level of the pulmonary artery bifurcation to the heart apex. The intrathoracic fat was separated into epicardial and extrapericardial fat by tracing the pericardium. The measurements were obtained by 2 readers and compared for interrater reproducibility. The fat volume measurements for the study group were 141 ± 72 cm3 for intrathoracic fat, 58 ± 27 cm3 for epicardial fat, and 84 ± 50 cm3 for extrapericardial fat. There was no statistically significant difference in intrathoracic fat volume measurements between the 2 readers, with correlation coefficients of 0.88 (P = .55) for intrathoracic fat volume and −0.12 (P = .33) for epicardial fat volume. Voxel-based measurement of intrathoracic fat, including the separation into epicardial and extrapericardial fat, is feasible and highly reproducible from multidetector computed tomography scans.

Objective Fibromyalgia is a chronic pain condition with few effective treatments. Many fibromyalgia patients seek acupuncture for analgesia; however, its efficacy is limited and not fully understood. This may be due to heterogeneous pathologies among participants in acupuncture clinical trials. We hypothesized that pressure pain tenderness would differentially classify treatment response to verum and sham acupuncture in fibromyalgia patients. Design Baseline pressure pain sensitivity at the thumbnail at baseline was used in linear mixed models as a modifier of differential treatment response to sham versus verum acupuncture. Similarly, needle-induced sensation was also analyzed to determine its differential effect of treatment on clinical pain. Methods and Patients A cohort of 114 fibromyalgia patients received baseline pressure pain testing and were randomized to either verum (N = 59) or sham (N = 55) acupuncture. Participants received treatments from once a week to three times a week, increasing in three-week blocks for a total of 18 treatments. Clinical pain was measured on a 101-point visual analog scale, and needle sensation was measured by questionnaire throughout the trial. Results Participants who had higher pain pressure thresholds had greater reduction in clinical pain following verum acupuncture while participants who had lower pain pressure thresholds showed better analgesic response to sham acupuncture. Moreover, patients with lower pressure pain thresholds had exacerbated clinical pain following verum acupuncture. Similar relationships were observed for sensitivity to acupuncture needling. Conclusions These findings suggest that acupuncture efficacy in fibromyalgia may be underestimated and a more personalized treatment for fibromyalgia may also be possible.

Continuous outcome data with a proportion of observations equal to zero (often referred to as semicontinuous data) arise frequently in biomedical studies. Typical approaches involve two-part models, with one part a logistic model for the probability of observing a zero and some parametric continuous distribution for modeling the positive part of the data. We propose a semiparametric model based on a biological system with competing damage manifestation and resistance processes. This allows us to derive a closed-form profile likelihood based on the retro-hazard function, leading to a flexible procedure for modeling continuous data with a point mass at zero. A simulation study is presented to examine the properties of the method in finite samples. We apply the method to a data set consisting of pulmonary capillary hemorrhage area in lab rats subjected to diagnostic ultrasound. Copyright © 2017 John Wiley & Sons, Ltd.

The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction.To evaluate whether effects of screening on prostate cancer mortality relative to no screening differed between the ERSPC and PLCO.Cox regression of prostate cancer death in each trial group, adjusted for age and trial. Extended analyses accounted for increased incidence due to screening and diagnostic work-up in each group via mean lead times (MLTs), which were estimated empirically and using analytic or microsimulation models.Randomized controlled trials in Europe and the United States.Men aged 55 to 69 (ERSPC) or 55 to 74 (PLCO) years at randomization.Prostate cancer screening.Prostate cancer incidence and survival from randomization; prostate cancer incidence in the United States before screening began.Estimated MLTs were similar in the ERSPC and PLCO intervention groups but were longer in the PLCO control group than the ERSPC control group. Extended analyses found no evidence that effects of screening differed between trials (P = 0.37 to 0.47 [range across MLT estimation approaches]) but strong evidence that benefit increased with MLT (P = 0.0027 to 0.0032). Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening.The MLT is a simple metric of screening and diagnostic work-up.After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality.National Cancer Institute.