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The Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) have been leaders in protecting and promoting the U.S. public health by helping to ensure that safe and effective drugs and biological products are available in the United States for those who need them. The null hypothesis significance testing approach, along with other considerations, is typically used to demonstrate the effectiveness of a drug or biological product. The Bayesian framework presents an alternative approach to demonstrate the effectiveness of a treatment. This article discusses the Bayesian framework for drug and biological product development, highlights key settings in which Bayesian approaches may be appropriate, and provides recent examples of the use of Bayesian approaches within CDER and CBER.

PURPOSE On March 4, 2022, the US Food and Drug Administration (FDA) approved nivolumab plus platinum-doublet chemotherapy for the neoadjuvant treatment of patients with resectable non–small-cell lung cancer (NSCLC). We discuss the FDA's review of the key data and regulatory considerations supporting this approval. PATIENTS AND METHODS The approval was based on the results of CheckMate 816, an international, multiregional, active-controlled trial that randomly assigned 358 patients with resectable NSCLC, stage IB (≥4 cm) to IIIA (N2) per the American Joint Committee on Cancer seventh staging edition to receive either nivolumab plus platinum-doublet or platinum-doublet chemotherapy alone for three cycles before planned surgical resection. The major efficacy end point that supported this approval was event-free survival (EFS). RESULTS At the first planned interim analysis (IA), the hazard ratio (HR) for EFS was 0.63 (95% CI, 0.45 to 0.87; P = .0052; statistical significance boundary = .0262) favoring the nivolumab plus chemotherapy arm; the median EFS was 31.6 months (95% CI, 30.2 to not reached) in the nivolumab plus chemotherapy arm versus 20.8 months (95% CI, 14.0 to 26.7) in the chemotherapy-only arm. At the time of a prespecified IA for overall survival (OS), 26% of patients had died, and the HR for OS was 0.57 (95% CI, 0.38 to 0.87; P = .0079; statistical significance boundary = .0033). Eighty-three percent of patients in the nivolumab-containing arm versus 75% in the chemotherapy-only arm received definitive surgery. CONCLUSION This approval, the first for any regimen for the neoadjuvant treatment of NSCLC in the United States, was supported by a statistically significant and clinically meaningful improvement in EFS with no evidence of detriment in OS or negative impact on patients' receipt and timing of surgery or surgical outcomes.

IMPORTANCE: Immune checkpoint inhibitors (ICIs) and radiation therapy (RT) are widely used to treat various cancers, but little data are available to guide clinicians on ICI use sequentially with RT. OBJECTIVE: To assess whether there is an increased risk of serious adverse events (AEs) associated with RT given within 90 days prior to an ICI. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data were pooled from 68 prospective trials of ICIs submitted in initial or supplemental licensing applications in the US Food and Drug Administration (FDA) databases through December 2019. Two cohorts were generated: (1) patients who received RT within the 90 days prior to beginning ICI therapy and (2) those who did not receive RT within the 90 days prior to beginning ICI therapy, and AE frequencies were determined. A 1:1 propensity score–matched analysis was performed. INTERVENTIONS: All patients received an ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab); 1733 received RT within the 90 days prior to starting ICI therapy, and 13 956 did not. MAIN OUTCOMES AND MEASURES: The primary outcome was frequency and severity of AEs. Incidence of AEs was compared descriptively between participants who did vs did not receive RT in the propensity score–matched set. Because all analyses are exploratory (ie, not preplanned and no alpha allocated), assessment for statistical significance of the differences between groups was not considered appropriate. RESULTS: A total of 25 469 patients were identified; 8634 were excluded because they lacked comparators who had received RT (n = 976), did not receive an ICI (n = 4949), received RT outside of the target window (n = 2338), or had missing data in 1 or more variables used in the propensity analysis (n = 371), leaving 16 835 patients included in the analysis. The majority were younger than 65 years (9447 [56.1%]), male (10 459 [62.1%]), and White (13 422 [79.7%]). Patients receiving RT had generally similar rates of AEs overall to those patients who did not receive RT. The average absolute difference in rates across the AEs was 1.2%, and the difference ranged from 0% for neurologic AEs to 8% for fatigue. No difference in grade 3 to 4 AEs was observed between the 2 groups (absolute difference ranged from 0.01% to 2%). These findings persisted after propensity score matching. CONCLUSIONS AND RELEVANCE: In this pooled analysis, administration of an ICI within 90 days following RT did not appear to be associated with an increased risk of serious AEs. Thus, it would appear to be safe to administer an ICI within 90 days of receiving RT. These findings should be confirmed in future prospective trials.

Introduction: Seasonal influenza vaccination is recommended for pregnant women, but half of the pregnant women in the United States remain unvaccinated. Vaccine coverage in U.S.–Mexico border states has not been examined in depth even though risk factors for low vaccine coverage exist in these states, especially in the counties bordering Mexico. Method: Using 2012-2014 New Mexico (NM) Pregnancy Risk Assessment and Monitoring System data, this study examined the weighted annual seasonal influenza vaccination rates and the relationship of various factors to vaccination among NM residents with a live birth during those years. Results: Among respondents, 53.8% were Hispanic, 15.7% were Native American, and 30.5% were non-Hispanic White. The vaccination rate in NM increased from 49.0% in 2012 to 64.8% in 2014. The adjusted odds of vaccination were higher among women whose health care provider recommended/offered vaccination during the year prior to delivery compared to women whose provider did not (AOR = 11.92, 95% confidence interval [CI: 9.86, 14.42]) and among those living in the U.S.–Mexico nonborder counties compared to those living in the border counties (AOR = 1.23, 95% CI [1.18, 1.25]). Conclusion: Efforts to increase the vaccination rate among pregnant women in border states should concentrate on health care providers and the highest risk women, such as those resident in the border region.

PURPOSE Three cyclin-dependent kinase 4/6 inhibitors (CDKIs) are approved by the US Food and Drug Administration for the treatment of patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced or metastatic breast cancer in combination with hormonal therapy (HT). We hypothesized that on an individual basis, efficacy outcomes and adverse event (AE) development can be predicted using baseline patient and tumor characteristics. METHODS Individual-level data from seven randomized controlled trials submitted to the US Food and Drug Administration for new or supplemental marketing applications of CDKIs were pooled. Progression-free survival (PFS), overall survival (OS), and AE prediction models were developed for specific treatment regimens (HT v HT plus CDKI). An individual's characteristics were used in all models simultaneously to create a group of predicted outcomes that are comparable across treatment settings. RESULTS Accuracy of the PFS and OS prediction models for HT were 66% and 64%, respectively, with the strongest predictors being menopausal status and therapy line. The corresponding AE prediction models resulted in an average area under the curve of 0.613. Accuracy of the PFS and OS prediction models for HT plus CDKI were 62% and 63%, respectively, with the strongest predictors being histologic grade for both. The corresponding AE prediction models resulted in an average area under the curve of 0.639. CONCLUSION This exploratory analysis demonstrated that models of efficacy outcomes and AE development can be developed using baseline patient and tumor characteristics. Comparison of paired models can inform treatment selection for individuals on the basis of the patient's personalized goals and concerns. Although use of CDKIs is standard of care in the first- or second-line setting, this model provides prognostic information that may inform individual treatment decisions.

Background: End-of-life (EOL) care for Latinos with chronic illness is a critically important problem. Latinos with chronic illness suffer worse health outcomes and poorer quality of care due to various issues occurring in care delivery systems. Latinos are less likely than non-Hispanic whites to prepare an advance directive (AD) for health-care decision-making that impacts treatment decisions for when EOL is near. Advance care planning (ACP) interventions tailored specifically for Latinos have rarely been implemented. Objective: The primary aim examines whether a motivational interviewing (MI) intervention increased rates of AD documentation among older Latinos. The secondary aim was to examine whether MI improved communication with providers and family members. Methods: We pilot tested a randomized controlled trial with older Latinos >50 years with one or more chronic illnesses, including cancer. Participants were randomly assigned to usual care (UC) receiving ACP education alone versus treatment (TX), which received ACP education, plus MI counseling including interactive decisional support, emotional support, and barrier navigation. Results: Results of logistic regression indicate TX group participants were significantly more likely to document an AD than UC, however were less ready to talk with health-care providers or family members. Those reporting navigational barriers for talking about dying is difficult showed a significant negative relationship for AD completion even with significant intervention effects. Conclusion: When using MI to motivate individuals toward ACP EOL conversations other factors are important to consider. Further research is needed, especially among Latinos to understand best practices for ACP education and counseling for EOL care.

Background Few in-depth reports on cancer epidemiology in New Mexico or the United States-Mexico border region exist. We aim to quantify cancer incidence and survival in New Mexico and the United States-Mexico border region in New Mexico. Methods Incidence and survival were obtained using SEER*Stat 8.3. The data were divided into either New Mexico, or SEER 18 (comprised of the 17 remaining regions) and then further divided by county in New Mexico and by time period. Incidence rates were age-standardized to the 2000 US census. Five-year survival was calculated for each cancer type. Kaplan-Meier survival plots were produced, and significance was determined using log-rank analysis. Results Analysis demonstrated that cancers in New Mexico are diagnosed at a lower rate with the exception of thyroid, liver, and ovarian. Survival is generally lower in New Mexico with 10 of the 14 cancers having worse survival in New Mexico. Only uterine cancer had improved survival in New Mexico (77.9% vs 74.9%, P < .001). Additionally, breast (82.2%), prostate (83.3%), lung and bronchus (13.7%), colorectal (53.7%), melanoma (80.1%), kidney and renal pelvis (61.2%), uterine (78.5%), and ovarian (41.6%) all had lower survival in the border counties. Conclusion Comparing New Mexico to the other regions in the SEER 18 database, both cancer incidence and survival are consistently lower; these findings could be explained by lower access to healthcare, which can result in underreporting and delays in diagnosis.

A unified statistical methodology of sample size determination is developed for hierarchical designs that are frequently used in many areas, particularly in medical and health research studies. The solid foundation of the proposed methodology opens a new horizon for power analysis in presence of various conditions. Important features such as joint significance testing, unequal allocations of clusters across intervention groups, and differential attrition rates over follow up time points are integrated to address some useful questions that investigators often encounter while conducting such studies. Proposed methodology is shown to perform well in terms of maintaining type I error rates and achieving the target power under various conditions. Proposed method is also shown to be robust with respect to violation of distributional assumptions of random-effects.

In this study we incorporate depression screening questionnaires/tools and a screening protocol into primary care practice. The effectiveness of the intervention was evaluated in establishing depression screening practice in the clinic. Implementation of the depression screening questionnaires in patients' electronic health records along with the depression screening protocol resulted in increased screening. Using this approach led to increased detection of depression risk in adult patients with chronic medical conditions, such as type 2 diabetes, in the primary care setting. Our study findings show that integration of the intake screening questionnaires into the electronic health record makes the screening process easier and more efficient in the primary care setting.

Hispanic women living along the US-Mexico border have higher cesarean delivery rates than non-Hispanic white women, African American women, and other Hispanic women in the USA. Their rates also exceed those of other Hispanic women in states that border Mexico and non-Hispanic white women along the border. Our objective was to determine the causes of the disparities in border Hispanic cesarean rates. Using the 2015 birth certificate file and other sources, we performed a twofold Oaxaca-Blinder decomposition analysis of the disparities in low-risk primary and repeat cesarean rates between Hispanic and non-Hispanic white women in the US-Mexico border counties and Hispanic women residing in nonborder counties of border states. Rates of low-risk primary cesarean among border Hispanic, nonborder Hispanic, and border non-Hispanic white women were 21.1%, 15.0%, and 16.5%, respectively. Higher Hispanic concentration in county of residence, a larger proportion of for-profit hospital beds, and greater poverty accounted for 24.7%, 22.1%, and 11.1% of the border-nonborder Hispanic difference, respectively. No other variable explained more than 5% of the difference. Higher Hispanic concentration, more for-profit beds, less attendance by an MD, higher BMI, and greater poverty explained 60.6%, 42.4%, 42.4%, 27.4%, and 21.3%, respectively, of the Hispanic-non-Hispanic white difference. Hispanic concentration and for-profit beds were also important explanatory variables for low-risk repeat cesareans. Efforts to address potentially unnecessary cesareans among Hispanic women on the border should recognize that community demographic and health delivery system characteristics are more influential than maternal medical risk factors.

Hispanic women living on the US-Mexico border have had higher cesarean delivery rates than other Hispanic women in the US. Using birth certificate and other data, we compared cesarean rates among Hispanic women living in US border counties with rates among other Hispanic women in border states during 2015. Using linear regression, we also determined which medical, hospital, and sociodemographic characteristics accounted for intercounty variations in rates. In border counties the rates were 38.3 percent for all births, 31.3 percent for low-risk nulliparous mothers, 21.0 percent for primary cesareans, and 94.7 percent for repeat cesareans. In nonborder counties the rates were 30.9 percent, 24.4 percent, 15.1 percent, and 90.5 percent, respectively. Maternal medical characteristics explained over 50 percent of the variation for all cesarean outcomes. Other characteristics that were major contributors to higher cesarean rates included for-profit hospital status, delivery by a physician as opposed to a midwife, and residence in a county with a larger Hispanic fraction of the population. Addressing potentially unnecessary cesareans among Hispanic women on the border will likely require a multicomponent strategy.

Background: Advance care planning for end-of-life care emerged in the mid-1970’s to address the need for tools, such as the advance directive (AD) legal document, to guide medical decision-making among seriously ill patients, their families, and healthcare providers. Objective: Study aims examine providers’ perspectives on AD education that involve examining (1) a range of attitudes about educating patients, (2) whether prior knowledge was associated with practice behaviors in educating patients, and (3) specific factors among healthcare providers such as characteristics of work setting, knowledge, attitudes, and behaviors that may influence AD education and documentation. Design: To examine providers’ views, we conducted a cross-sectional, online survey questionnaire of healthcare providers using social media outreach methods for recruitment. Methods: This study used a cross-sectional survey design to examine the proposed aims. Healthcare providers, recruited through a broad approach using snowball methods, were invited to participate in an online survey. Logistic regression analyses were used to examine providers’ views toward AD education. Results: Of 520 participants, findings indicate that most healthcare providers said that they were knowledgeable about AD education. They also viewed providing education as beneficial to their practice. These findings suggest that having a positive attitude toward AD education and experiencing less organizational barriers indicate a higher likelihood that providers will educate patients regarding ADs. Conclusion: Various disciplines are represented in this study, which indicates that attitudes and knowledge influence AD discussions. The importance of AD discussions initiated by healthcare providers is critical to providing optimal patient-centered care.

Aim To examine how factors such as a sense of belonging to a nursing work group, work environmental characteristics, and workplace violence effects the duration of employment in professional settings in a southwest region of the United States. Design The descriptive correlational survey study conducted in 2014. Methods A random sample of 700 licensed registered nurses (RN) from a Board of Nursing's list of currently licensed RNs' (approximate n = 2300). Participants completed and returned four survey tools to the principal investigator. The return rate was 36.8% (258/700). Results/findings Analysis indicated that a sense of belonging, as well as supportive workplace characteristics, played a role in why nurses stay. The three survey tools provided strong correlations in the survey data and further authenticated the tools' reliability. A healthy work environment supports nurse retention. Conclusion The three survey tools used in this study showed substantial and significant correlations. Although not all sub-scales correlated, those that did had strong Cronbach alpha scores. The weakest correlations were with the belongingness scale. Rapid turnover rates of nursing staff continue to plague healthcare organizations. A variety of reasons including difficult practice settings and stressful work environments contribute to the outflow of nurses. Impact Health care administration and management leaders can improve retention via their efforts to continue to create and sustain healthy work environments that address affiliation, belongingness, and the characteristics that attract and retain nurses.

This paper investigates estimating and testing treatment effects in randomized control trials where imperfect diagnostic device is used to assign subjects to treatment and control group(s). The paper focuses on pre-post design and proposes two new methods for estimating and testing treatment effects. Furthermore, methods for computing sample sizes for such design accounting for misclassification of the subjects are devised. The methods are compared with each other and with a traditional method that ignores the imperfection of the diagnostic device. In particular, the likelihood-based approach shows a significant advantage in terms of power, coverage probability and, consequently, in reduction of the required sample size. The application of the results are illustrated with data from an aging trial for dementia and data from electroencephalogram (EEG) recordings of alcoholic and non-alcoholic subjects. Copyright © 2016 John Wiley & Sons, Ltd.

Data sets originating from wide range of research studies are composed of multiple variables that are correlated and of dissimilar types, primarily of count, binary/ordinal and continuous attributes. The present paper builds on the previous works on multivariate data generation and develops a framework for generating multivariate mixed data with a pre-specified correlation matrix. The generated data consist of components that are marginally count, binary, ordinal and continuous, where the count and continuous variables follow the generalized Poisson and normal distributions, respectively. The use of the generalized Poisson distribution provides a flexible mechanism which allows under- and over-dispersed count variables generally encountered in practice. A step-by-step algorithm is provided and its performance is evaluated using simulated and real-data scenarios.

12038 Background: The FDA has approved three androgen receptor (AR) inhibitors for nonmetastatic castration-resistant prostate cancer (nmCRPC) based on improvements in metastasis-free survival (MFS). MFS is an earlier endpoint, defined as the time from randomization to either imaging-detectable distant disease or death. This pooled analysis examines MFS, time to initiation of cytotoxic chemotherapy (TTCyto), and safety outcomes in men over 80 treated with AR inhibitors. Methods: Data was pooled from three randomized controlled studies (n=4117) of AR inhibitors for nmCRPC. The treatment effect of AR inhibitors on MFS and TTCyto across age groups was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. Hazard Ratios for MFS and TTCyto were adjusted for baseline ECOG, total Gleason score, PSA doubling time, and prior bone-targeting therapy. Results: For patients age 80 years or older (n=675) who were treated with AR inhibitors, the hazard ratio was 0.38 (95% CI 0.29, 0.49) with an estimated median MFS of 40 months (95% CI 36, 41) versus 22 months (95% CI 18, 29) for those treated with placebo (n=348). For patients

3018 Background: Immune checkpoint inhibitors (ICIs) are widely used in the treatment of multiple advanced malignancies. Radiotherapy (RT) has been used in combination with ICIs to activate tumor-specific T cell responses, and RT also promotes non-specific acute and chronic inflammatory responses both locally and systemically. More than 50% of patients receive RT at some point during their course of cancer therapy, and relatively little information is available pertaining to the impact of RT, if any, on the risk of adverse events (AEs) in patients receiving ICIs. Methods: Pooled data from prospective trials of ICIs submitted to the FDA in initial or supplemental BLAs or NDAs through 12/2019 were included (N=66). Trials from applications that were withdrawn or not approved were not included. Patients were subdivided by whether or not radiotherapy was administered at any time during the course of their cancer treatment. AEs common to both ICI treatment and RT were identified to focus on the following reactions: neutropenia, thrombocytopenia, colitis, hepatitis, pneumonitis, and myocarditis. Descriptive statistics were used to examine AEs associated with the use of radiation and ICIs. Results: A total of 25,836 patients were identified, of which 9087 (35%) received RT and 16,749 (65%) did not. Radiation was associated with similar rates of AEs overall with numerically higher hematologic toxicities and pneumonitis and numerically lower colitis, hepatitis and myocarditis (Table). Patients receiving RT were more likely to experience Grade 3-5 hematologic toxicities compared to those not receiving RT. Conclusions: To our knowledge, this is the largest report of AE risk associated with the use of radiation and ICIs. Our results show that the incidence of hematologic toxicity and pneumonitis in patients receiving RT may be slightly higher. Analysis to determine comparability of baseline demographic characteristics, comprehensive AE profile, and timing of RT is underway. [Table: see text]

The medial olivocochlear efferent fibers control outer hair cell responses and inhibit the cochlear-amplifier gain. Measuring efferent function is both theoretically and clinically relevant. In humans, medial efferent inhibition can be assayed via otoacoustic emissions (OAEs). OAEs arise by two fundamentally different mechanisms-nonlinear distortion and coherent reflection. Distortion and reflection emissions are typically applied in isolation for studying the efferent inhibition. Such an approach inadvertently assumes that efferent-induced shifts in distortion and reflection emissions provide redundant information. In this study, efferent-induced shifts in distortion and reflection emissions (click-evoked and stimulus frequency OAEs) were measured in the same subjects-5- to 10-yr-old children. Consistent with the OAE generation theory, efferent-induced shifts in distortion and reflection emissions did not correlate, whereas the two reflection emission shifts correlated. This suggests that using either OAE types provides fragmented information on efferent inhibition and highlights the need to use both distortion and reflection emissions for describing efferent effects.

Supplemental Material, APPENDIX.Survey_Questionnaire_Final for Healthcare Providers’ Attitudes, Knowledge, and Practice Behaviors for Educating Patients About Advance Directives: A National Survey by Frances R. Nedjat-Haiem, Tamara J. Cadet, Anup Amatya, and Shiraz I. Mishra in American Journal of Hospice and Palliative Medicine®

OBJECTIVES: To systematically examine prevalence of first trimester prenatal care (FTPNC) in the 44 US counties and 80 Mexican municipios of the binational border region; and to describe disparities between border and nonborder areas within states border states and countries. METHODS: We combined 2009 records of singleton live births from the 10 US-Mexico border states (N=1370206) into a single file. We included FTPNC; county/municipio state and country of maternal residence; and demographic variables common to all records. We computed prevalence of FTPNC for border and nonborder residents by state and country. Using multivariable regression we computed adjusted prevalence ratios (aPR) for FTPNC in border relative to nonborder residents states relative to one another and the US relative to Mexico. RESULTS: In 2009 68.8% of US-Mexico border mothers and 72.9% of nonborder mothers received FTPNC. After adjustment nonborder residents had higher prevalence of FTPNC than border residents in Sonora New Mexico Arizona Coahuila and Chihuahua (aPR=1.09-124). In US states prevalence was 13%-36% higher in New Mexico Arizona and California than Texas. In Mexico when compared with Coahuila adjusted prevalence was 12%-20% higher in neighboring states. Between countries FTPNC prevalence in border counties/municipios was higher in Mexico among women with low parity/low education and in the United States among women with high parity/high education. CONCLUSIONS: In the US and Mexico women in border counties/municipios receive less timely prenatal care than their nonborder counterparts but the magnitude of the disparity varies by state. Lack of a consistent binational approach to birth data collection requires cautious interpretation of findings.

In this article, the operational details of the R package PoisNor that is designed for simulating multivariate data with count and continuous variables with a prespecified correlation matrix are described, and examples of some important functions are given. The data-generation mechanism is a combination of the “NORmal To Anything” principle and a recently established connection between Poisson and normal correlations. The package provides a unique and useful tool that has been lacking for generating multivariate mixed data with Poisson and normal components.

In this article, operational details of an R package MultiOrd that is designed for the generation of correlated ordinal data are described, and examples of some important functions are given. The package provides a valuable and needed tool that has been lacking for generating multivariate ordinal data.

The present paper develops a procedure for simulating multivariate data with count and continuous variables with a pre-specified correlation matrix. The count and continuous variables are assumed to have Poisson and normal marginals, respectively. The data generation mechanism is a combination of the normal to anything principle and a newly established connection between Poisson and normal correlations in the mixture. A step-by-step algorithm is provided and its performance is evaluated using two simulated and one real-data scenarios.

Although growing research focuses on breast cancer screenings, little is known about breast cancer prevention with risk reduction awareness for ethnic differences among college-age women. This study examined breast cancer prevention knowledge, beliefs, and information sources between non-Hispanic and Hispanic college women. Using a cross-sectional study, women at a university in the Southwest completed a 51-item survey about breast cancer risk factors, beliefs, and media and interpersonal information sources. The study was guided by McGuire's Input Output Persuasion Model. Of the 546 participants, non-Hispanic college women (n = 277) and Hispanic college women (n = 269) reported similar basic knowledge levels of modifiable breast cancer risk factors for alcohol consumption (52 %), obesity (72 %), childbearing after age 35 (63 %), and menopausal hormone therapy (68 %) using bivariate analyses. Most common information sources were Internet (75 %), magazines (69 %), provider (76 %) and friends (61 %). Least common sources were radio (44 %), newspapers (34 %), and mothers (36 %). Non-Hispanic college women with breast cancer family history were more likely to receive information from providers, friends, and mothers. Hispanic college women with a breast cancer family history were more likely to receive information from their mothers. Breast cancer prevention education for college women is needed to include risk reduction for modifiable health behavior changes as a new focus. Health professionals may target college women with more information sources including the Internet or apps.

The Turkestan cockroach, Blatta lateralis (Walker), has become the most important peridomestic species in urban areas of the Southwestern United States. The aim of this study was to evaluate the use of botanical compounds to control this urban pest. We tested the acute toxicity and repellency of six botanical constituents and three essential oils on Turkestan cockroach nymphs. Chemical composition of the essential oils was also determined. Topical and fumigant assays with nymphs showed that thymol was the most toxic essential oil constituent, with a LD50 of 0.34 mg/nymph and a LC50 of 27.6 mg/liter air, respectively. Contact toxicity was also observed in assays with trans-Cinnamaldehyde, eugenol, geraniol, methyl eugenol, and p-Cymene. Methyl eugenol and geraniol had limited fumigant toxicity. The essential oils from red thyme, clove bud, and Java citronella exhibited toxicity against nymphs. Cockroaches avoided fresh dry residues of thymol and essential oils. Chemical analysis of the essential oils confirmed high contents of effective essential oil constituents. Our results demonstrated that essential oils and some of their constituents have potential as eco-friendly insecticides for the management of Turkestan cockroaches.

This article describes the package BinNor, which is designed for generating multiple binary and normal variables simultaneously given marginal characteristics and association structure via combining well-established results from the random number generation literature, based on the methodology proposed by Demirtas and Doganay.

BACKGROUND The effect of HLA match on renal graft survival has become controversial as has the policy of mandatory sharing of kidneys. METHOD We performed a retrospective analysis of HLA matched (M) and mismatched (MM) kidney transplants in our center. Tacrolimus, mycophenolic acid, and steroids were used as maintenance therapy and basiliximab induction was added for high-risk patients. RESULT A total of 229 kidney transplants were included with median follow-up of 5.1 years. The 5-year death-censored graft survival by Kaplan-Meier method was significantly higher in the M group than in the MM group for deceased-donor kidney transplants (log-rank, p = .018). This graft survival advantage was detected in patients with a peak panel reactive antibody (PRA) greater than 20% (p = .023), but not in those with a PRA level of less than 20% (p = .32). The graft survival was not statistically different for live donor kidney transplants (p = .077). A mismatched kidney was an independent risk for graft loss (hazard ratio: 2.27, 95% confidence interval: 1.009–5.09, p = .047) and acute rejection was a significant cause of graft loss in mismatched deceased-donor transplants (p = .035). CONCLUSION Acute rejection remains a significant cause of graft loss in HLA-6-antigen mismatched deceased-donor kidney transplants. Our data support mandatory sharing of HLA-matched kidneys in sensitized patients with a PRA level greater than 20%.

Meta-analysis has been used extensively for evaluation of efficacy and safety of medical interventions. Its advantages and utilities are well known. However, recent studies have raised questions about the accuracy of the commonly used moment-based meta-analytic methods in general and for rare binary outcomes in particular. The issue is further complicated for studies with heterogeneous effect sizes. Likelihood-based mixed-effects modeling provides an alternative to moment-based methods such as inverse-variance weighted fixed- and random-effects estimators. In this article, we compare and contrast different mixed-effect modeling strategies in the context of meta-analysis. Their performance in estimation and testing of overall effect and heterogeneity are evaluated when combining results from studies with a binary outcome. Models that allow heterogeneity in both baseline rate and treatment effect across studies have low type I and type II error rates, and their estimates are the least biased among the models considered.

The purpose of this study was to examine among college women acquired breast cancer prevention information-seeking, desired apps and texts, and information given to mothers. Using a cross-sectional study, a survey was administered to college women at a southwestern university. College women (n = 546) used the Internet (44 %) for active breast cancer prevention information-seeking and used the Internet (74 %), magazines (69 %), and television (59 %) for passive information receipt. Over half of the participants desired breast cancer prevention apps (54 %) and texts (51 %). Logistic regression analyses revealed predictors for interest to receive apps were ethnicity (Hispanic), lower self-efficacy, actively seeking online information, and older age and predictors for interest to receive texts were lower self-efficacy and higher university level. Eighteen percent of college women (n = 99) reported giving information to mothers and reported in an open-ended item the types of information given to mothers. Predictors for giving information to mothers were actively and passively seeking online information, breast self-exam practice, and higher university level. Screenings were the most frequent types of information given to mothers. Breast cancer prevention information using apps, texts, or Internet and daughter-initiated information for mothers should be considered in health promotion targeting college students or young women in communities. Future research is needed to examine the quality of apps, texts, and online information and cultural differences for breast cancer prevention sources.

Background Our objective was to develop and validate a multi-feature nuclear score based on image analysis of direct DNA staining, and to test its association with field effects and subsequent detection of prostate cancer (PCa) in benign biopsies. Methods Tissue sections from 39 prostatectomies were Feulgen-stained and digitally scanned (400×), providing maps of DNA content per pixel. PCa and benign epithelial nuclei were randomly selected for measurement of 52 basic morphometric features. Logistic regression models discriminating benign from PCa nuclei, and benign from malignant nuclear populations, were built and cross-validated by AUC analysis. Nuclear populations were randomly collected 5 mm from cancer foci, and from cancer-free prostates, HGPIN, and PCa Gleason grade 3–5. Nuclei also were collected from negative biopsy subjects who had a subsequent diagnosis of PCa and age-matched cancer-free controls (20 pairs). Results A multi-feature nuclear score discriminated cancer from benign cell populations with AUCs of 0.91 and 0.79, respectively, in training and validation sets of patients. In prostatectomy samples, both nuclear- and population-level models revealed cancer-like features in benign nuclei adjacent to PCa, compared to nuclei that were more distant or from PCa-free glands. In negative biopsies, a validated model with 5 variance features yielded significantly higher scores in cases than controls (P = 0.026). Conclusions A multifeature nuclear morphometric score, obtained by automated digital analysis, was validated for discrimination of benign from cancer nuclei. This score demonstrated field effects in benign epithelial nuclei at varying distance from PCa lesions, and was associated with subsequent PCa detection in negative biopsies. Impact This nuclear score shows promise as a risk predictor among men with negative biopsies and as an intermediate biomarker in Phase II chemoprevention trials. The results also suggest that subvisual disturbances in nuclear structure precede the development of pre-neoplastic lesions.

Although breast cancer prevention targets mostly women ages 40 and older, little is known about breast cancer prevention for young women and mother’s advice. The purpose of this study was to examine breast cancer prevention knowledge, attitudes, and behaviors among college women and mother–daughter communication. Hispanic and non-Hispanic students at a southwestern university completed a breast cancer prevention survey with items for mother’s advice, breast self-awareness and risk reduction knowledge, self-efficacy, susceptibility, family history, provider breast self-exam (BSE) recommendation, peer norms, BSE practice, and demographics. An openended item was also used to elicit types of mother’s advice. Logistic regression was used to assess predictors for receiving mother’s advice for breast cancer prevention and BSE practice. Self-reported data using a survey were obtained from 546 college women with a mean age of 23.3 (SD = 7.75). Nearly 36 % received mothers’ advice and 55 % conducted BSE. Predictors for receiving mother’s advice were age, self-efficacy, and family history of breast cancer. Predictors for BSE practice were mother’s advice, age, self-efficacy, and provider BSE recommendation. Family history of breast cancer and knowledge were not significant predictors for BSE practice. Findings support the need for clinicians, community health educators, and mothers to provide breast cancer prevention education targeting college women.

Globesity (the global epidemic of obesity), like undernutrition at the opposite end of the malnutrition spectrum, affects virtually all age and socioeconomic groups in developed and developing countries. Genetics, comorbid diseases and lifestyle factors have been associated with obesity and weight gain for college students. Little is known about obesity and lifestyle factors of campus students and employees located in rural areas. The purpose of this study was to examine the prevalence of overweight/obesity and socioecological elements of the obesogenic environment at a rural-serving US-Mexico border university.Data were collected using a cross-sectional, convenience sample by anasynchronous electronic survey submitted to approximately 23 000 students, faculty and staff on the main campus of New Mexico State University. Self-reported anthropometric indicators were used as proxy measures of nutritional status. Factors analyzed include the prevalence overweight/obesity from calculated body mass index (BMI) and self-identified body image in the contexts of sex, age, ethnicity, role at the university (student or employee) and residence. Body mass index categories were analyzed for associations with reported prevalence of stress indicators such as clinically diagnosed anxiety or depression, and major diseases such as diabetes, hypertension, heart disease, cancer and stroke.A total of 3962 completed surveys were analyzed. Self-reported respondent rates (n = 3962) of overweight and obese individuals (47.2%) were less than those reported for the state (60.7%) in a 2010 national survey. When BMI was analyzed by sex, there was a significant difference (p = 0.003) between males and females. More males were overweight and obese than females. When BMI and BMI categories were assessed by age, ethnicity, role at the university and residence, each variable was found to have statistically significant differences.No one demographic or socioecological factor appears to have a predominant role in predicting obesity in the participants studied at this rural-serving university. The authors conclude that levels of overweight and obesity are multifactorial and should be addressed with more holistic actions. These findings suggest that future studies should look more closely at stressors in the environment as well as culturally acceptable versus ideal notions of weight and corpulence. Study findings also suggest that early intervention will be critical to reducing levels of overweight/obesity and associated complications as the population ages. Finally, this study provides evidence for health educators and policy makers to go beyond exercise and calories in/out to develop educational materials that can cross many barriers of culture, age, ethnicity, educational level, residence and body image.

We consider the problem of sample size determination for count data. Such data arise naturally in the context of multicenter (or cluster) randomized clinical trials, where patients are nested within research centers. We consider cluster-specific and population-averaged estimators (maximum likelihood based on generalized mixed-effect regression and generalized estimating equations, respectively) for subject-level and cluster-level randomized designs, respectively. We provide simple expressions for calculating the number of clusters when comparing event rates of two groups in cross-sectional studies. The expressions we derive have closed-form solutions and are based on either between-cluster variation or intercluster correlation for cross-sectional studies. We provide both theoretical and numerical comparisons of our methods with other existing methods. We specifically show that the performance of the proposed method is better for subject-level randomized designs, whereas the comparative performance depends on the rate ratio for the cluster-level randomized designs. We also provide a versatile method for longitudinal studies. Three real data examples illustrate the results.

Summary Previous investigations have linked decreased nuclear expression of the cell cycle inhibitor p27 with poor outcome in prostate cancer. However, these reports are inconsistent regarding the magnitude of that association and its independence from other predictors. Moreover, cytoplasmic translocation of p27 has been proposed as a negative prognostic sign. Given the cost and accuracy limitations of manual scoring, particularly of tissue microarrays, we determined if laser-based fluorescence microscopy could provide automated analysis of p27 in both nuclear and cytoplasmic locations and, thus, clarify its significance as a prognostic biomarker. We constructed tissue microarrays covering 202 recurrent cases (rising prostate-specific antigen) and 202 matched controls without recurrence. Quadruplicate tumor samples encompassed 5 slides and 1616 cancer histospots. Cases and controls matched on age, Gleason grade, stage, and hospital. We immunolabeled epithelial cytoplasm with Alexafluor 647, p27 with Alexafluor 488, and nuclei with 4c6-diamidino-2-phenylindole·2HCl. Slides were scanned on an iCys laser scanning cytometer (CompuCyte Corp, Cambridge, MA). Nuclear crowding required a stereological approach—random arrays of circles (phantoms) were layered on images and the content of each phantom was analyzed in scatter plots. Both nuclear and cytoplasmic p27 were significantly lower in cases versus controls ( P = .014 and P = .004, respectively). Regression models controlling for matching variables plus prostate-specific antigen showed strong linear trends for increased risk of recurrence with lower p27 in both nucleus and cytoplasm (highest versus lowest quartile; odds ratio, 0.35; P = .006). Manual scoring identified an inverse association between p27 expression and tumor grade but no independent association with recurrence. In conclusion, we developed an automated method for subcellular scoring of p27 without the need to segment individual cells. Our method identified a strong relationship, independent of tumor grade, stage, and prostate-specific antigen, between p27 expression—regardless of subcellular location—and prostate cancer recurrence. This relationship was not observed with manual scoring.

Human immunodeficiency virus (HIV) and drugs of abuse affect common neural systems underlying procedural memory, including the striatum. The authors compared performance of 48 HIV seropositive (HIV+) and 48 HIV seronegative (HIV-) participants with history of cocaine and/or heroin dependence across multiple Trial Blocks of three procedural learning (PL) tasks: Rotary Pursuit (RP), Mirror Star Tracing (MST), and Weather Prediction (WP). Groups were well matched on demographic, psychiatric, and substance use parameters, and all participants were verified abstinent from drugs. Mixed model analyses of variance revealed that the individuals in the HIV+ group performed more poorly across all tasks, with a significant main effect of HIV serostatus observed on the Mirror Star Tracing and a trend toward significance obtained for the Rotary Pursuit task. No significant differences were observed on the Weather Prediction task. Both groups demonstrated significant improvements in performance across all three procedural learning tasks. It is important to note that no significant Serostatus x Trial Block interactions were observed on any task. Thus, the individuals in the HIV+ group tended to perform worse than those in the HIV- group across all trial blocks of procedural learning tasks with motor demands, but showed no differences in their rate of improvement across all tasks. These findings are consistent with HIV--associated deficits in complex motor skills, but not in procedural learning.

Purpose: Subtle changes in nuclear shape, size and texture precede the histological recognition of prostate cancer (PCa) and thus might provide a useful biomarker for high-risk benign tissue. The objective of this study was to develop and validate a multifeature nuclear score based on direct DNA staining and test its association with field effects and the subsequent detection of PCa in benign biopsies. Methods: Whole tissue sections from 39 radical prostatectomy subjects were Feulgen-stained and scanned (400x) on a digital microscope, allowing maps of DNA content per nuclear pixel to be generated in Matlab@. Samples of PCa and benign epithelial nuclei were randomly selected for measurement of 51 morphometric features. Logistic regression models for discriminating benign from PCa nuclei were built and cross-validated by AUC analysis. Subject-level models, for discriminating benign from malignant nuclear populations taken from individual subjects, were also built and similarly validated. Both backwards elimination and all-subsets approaches were used to select covariates. Nuclear populations were randomly collected < 1mm or > 5mm from cancer foci, and from cancer-free prostates, HGPIN, and PCa Gleason grade 3-5. In addition, nuclear images were collected from negative biopsy cases and controls matched on age and date of biopsy (20 pairs); cases had PCa detected at least 2 years later, controls remained cancer-free and had at least 2 additional negative biopsies. For the case-control study, nuclei were selected using an automatic process that correlated well with results from manual selection. Frequency distributions for multifeature nuclear score from various tissue compartments were compared using the Kolmogorov D statistic. Scores for cases vs. controls were compared using a t test for paired data. Results: In prostatectomy samples, both nuclear- and populationlevel models revealed cancer-like features in benign nuclei adjacent to PCa, compared to nuclei that were more distant or were obtained from PCa-free glands. The score distribution for distant nuclei was also significantly shifted compared to nuclei from cancer-free glands. Interestingly, the best model by leave-one-out cross-validation (AUC = 0.91, 95% CI: 0.81-1.00) included only 5 variance features, reflecting the importance of nuclear pleomorphism. In negative biopsies, a validated model with 5 variance features (including features related to DNA content, size and texture) yielded significantly higher scores in cases than controls (P=0.026). This model had an AUC = 0.71 (95% CI: 0.54-0.87) for discriminating cases from controls. Conclusions: A multifeature nuclear morphometric score, obtained by automated digital analysis, was validated for discrimination of benign from cancer nuclei. This score demonstrated field effects in benign epithelial nuclei at varying distance from PCa lesions, and was associated with subsequent PCa detection in negative biopsies. This biomarker shows definite promise as an intermediate endpoint in chemoprevention trials; however, its utility as an independent predictor of PCa in the clinical setting requires much further study. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B38.