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An abstract of the article "Disclosure of Pharmacokinetic (PK) Drug Results Promotes Open Discourse on Non-adherence among Women in VOICE" by Ariane van der Straten, Petina Musara and colleagues is presented.

An abstract of the article "Reporting of Adherence in the VOICE Trial: Does Disclosure of Product Non-use Increase at the Termination Visit?" by Barbara S. Mensch, Elizabeth Brown and colleagues is presented.

Data are presented for intelligence in twelve regions in Turkey showing that intelligence is highest in the west and lowest in the east. The west–east intelligence gradient is significantly correlated with regional differences in educational attainment and per capita income and negatively correlated with fertility, infant mortality and the percentage of Kurds. [ABSTRACT FROM AUTHOR]

There is growing interest in the application of nature-based solutions to adapt to climate change and promote resilience, yet barriers exist to their implementation. These include a perceived lack of evidence of their functioning in comparison to conventional solutions and an inability for existing design, policy, and assessment processes to capture the multiple benefits of these solutions. Positing this as a challenge of operationalizing and measuring resilience, we argue that the concept of resilience needs to be given concrete meaning in applied management contexts. Starting with shoreline vulnerability as a policy problem and natural and naturebased shoreline features as a promising solution, we present a case study of a co-creative process to produce an interdisciplinary and locally relevant approach to understanding and capturing the benefits of natural and nature-based solutions. We develop the notion of resilience service to enable a concreteness to resilience that simultaneously takes into account ecological, technical, and social dimensions. Through the co-creative process, our researcher-practitioner network developed a monitoring framework for shoreline features in New York State to facilitate the comparison of natural and nature-based features with conventional shoreline approaches. We describe the process and assess the advantages and drawbacks of integrating scientific input and local knowledge. We present the monitoring framework, showing how the co-creative character of the process is consequential in the formulation of the final framework through the selection of parameters, indicators, and protocols. We argue that interdisciplinarity, co-creation, pragmatism, multi-scalar applicability, and policy relevance are critical principles to understand the functioning and facilitate the implementation of naturebased solutions, while recognizing that this work necessitates compromise and as such will lead to continued deliberation. We posit this is a strength of the process for it acknowledges the creation of resilience as a social process in which values are central and subject to change. [ABSTRACT FROM AUTHOR]

The Standard Progressive Matrices (SPM) was administered to a sample of 7226 school students aged 6 to 18 years in Sudan. There were no statistically significant sex differences between the total scores of the 6 to 13 year olds, but among 14 to 18 year olds males obtained higher average scores than females and among the 16, 17 and 18 years olds the average male advantage was 0.337 d , equivalent to 5 IQ points. An analysis of the data for the sex differences on the three factors of Gestalt Visualization, Verbal-analytic Reasoning and Visuospatial Ability identified by Lynn, Allik and Irwing (2004) showed similar age trends to those for the total scores. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is the third leading cause of cancer death in the United States, and while conventional chemotherapy remains the standard treatment, responses are poor. Safe and alternative therapeutic strategies are urgently needed 1 . A ketogenic diet has been shown to have anti-tumor effects across diverse cancer types but will unlikely have a significant effect alone. However, the diet shifts metabolism in tumors to create new vulnerabilities that can be targeted (1). Modulators of glutamine metabolism have shown promise in pre-clinical models but have failed to have a marked impact against cancer in the clinic. We show that a ketogenic diet increases TCA and glutamine-associated metabolites in murine pancreatic cancer models and under metabolic conditions that simulate a ketogenic diet in vitro. The metabolic shift leads to increased reliance on glutamine-mediated anaplerosis to compensate for low glucose abundance associated with a ketogenic diet. As a result, glutamine metabolism inhibitors, such as DON and CB839 in combination with a ketogenic diet had robust anti-cancer effects. These findings provide rationale to study the use of a ketogenic diet with glutamine targeted therapies in a clinical context.

Based on a sample of 8271 mothers, this study explored a set of psychological and sociodemographic factors associated with their vocabulary, drawing on data from a large, nationally representative sample of children born in 2000. The dependent variable was maternal vocabulary assessed when cohort members were at fourteen years of age, and the mothers were in their mid-forties. Data were also collected when cohort members were at birth, 9 months old, and at ages 3, 7, 11 and 14 years. Correlational analysis showed that family income at birth, parent-child relationship quality at age 3, maternal educational qualifications at age 11, and maternal personality trait Openness at age 14 were significantly and positively associated with maternal vocabulary. It also showed maternal malaise at 9 months and children's behavioral adjustment at age 7, and maternal traits Neuroticism and Agreeableness at age 14 were significantly and negatively associated with maternal vocabulary. Maternal age was also significantly and positively associated with vocabulary. Regression analysis showed that maternal age, malaise, parent-child relationship quality, children's behavioral adjustment, maternal educational qualifications, and traits Openness and Agreeableness were significant predictors of maternal vocabulary, accounting for 33% of total variance. The implications and limitations are discussed., Competing Interests: The authors declare no conflict of interest

This study set out to examine to what extent a set of psychological, health and socio-demographic factors are associated with self-efficacy (SE) in a large sample of over 12,000 participants over a two-year period. We were interested in the correlates of self-efficacy (criterion variable) with gender, age, education and occupation, the Big-Five personality factors and cognitive ability, as well as mental and physical health (predictor variables). Regression analyses showed that four of the Big-Five personality factors (extraversion, neuroticism, conscientiousness, and openness), cognitive ability, mental and physical health, gender, education and occupation were all significant and independent predictors of self-efficacy, accounting for 23% of the variance of the outcome variable. Personality variables, particularly Neuroticism and Conscientiousness, were the most powerful predictors of SE two years later. The implications for encouraging SE in individuals are discussed., (© 2023 The Authors. Scandinavian Journal of Psychology published by Scandinavian Psychological Associations and John Wiley & Sons Ltd.)

This study explored correlates of the trait Conscientiousness drawing on longitudinal data from the Millennium Cohort Study (MCS), with a sample of 7,436 mothers. Data were collected when participants' children were born and again at ages nine months, 3, 11, and 14 years. Structural equation modeling showed that the family poverty indicator, self-esteem, parent-child relationship, children's behavioral problems, and education all had significant and direct effects on maternal trait Conscientiousness. The strongest predictor was self-esteem (measured over 13 years previously), followed by children's behavioral problems and parent-child relationship quality. The implications for helping mothers and their children are considered and limitations are discussed.

This study explored a set of psychological and socio-demographic factors in childhood and adulthood associated with migraines assessed at age 42 years. Data were drawn from a large, nationally representative, prospective longitudinal study: the 1970 British Cohort Study (BCS70). In total, 5628 cohort members with data on parental social class at birth, cognitive ability (intelligence), self-esteem and locus of control at age 10 years, psychological distress and educational qualifications at age 34, and current occupation at age 42 years were examined. We assessed whether or not they regularly experienced migraines at age 42 years. Logistic regression analysis showed that childhood migraine, gender and adult psychological distress, as well as childhood locus of control (for females only), were significant and independent predictors of the prevalence of migraine in adulthood. Childhood migraine seemed to have a long-lasting effect on adult migraine, and psychological distress also appeared to detrimentally affect adult migraine over time.

The present study investigated biomedical, social, and psychological factors associated with self-reported heart conditions in adulthood in a British cohort. In total, 5697 (50.7% males) participants with data on parental socioeconomic status, childhood cognitive ability, childhood heart problems, educational qualifications, current occupational levels, adulthood personality traits, and the prevalence of self-reported heart conditions in adulthood were included in the study. The prevalence of self-reported heart conditions measured at age 54 years was the outcome variable. Hierarchical logistic regression analysis showed that childhood heart problems identified by physicians (OR = 3.47:1.74-6.92, p  < 0.001) and trait emotional stability (OR = 0.83:0.75-0.93, p  < 0.001) were the significant and independent predictors of self-reported heart conditions in adulthood. There were also significant sex effects on the prevalence of the outcome variable (OR = 0.53:0.42-0.63, p  < 0.001). Both a biomedical and a psychological factor were significantly associated with self-reported heart conditions in adulthood.

Objective: To identify personality, biomedical and behavioural factors associated with adult obesity in a large longitudinal sample., Method: In total, 5360 participants with data on personality, neurological functioning, maternal smoking during pregnancy, education and occupation, physical exercise, adult self-reported BMI and obesity were included in the study. Obesity at 55 years was the outcome variable., Results: The rates of obesity increased from 9.5 to 22.8% from age 33 to 55 years. Logistic regression analyses (adjusted estimates) showed that childhood neurological functioning (OR = 1.32: 1.07-1.63, P < 0.01), maternal smoking during pregnancy (OR = 1.42: 1.22-1.65, P < 0.001), educational qualifications (OR = 0.54: 0.37-0.79, P < 0.01), trait conscientiousness (OR = 0.80:0.74-0.86, P < 0.001) and physical exercise (OR = 0.87: 0.82-0.92, P < 0.001) were significant predictors of obesity at age 55 years for both men and women. Trait extraversion for men (OR = 1.16: 1.07-1.26, P < 0.001) and trait emotional stability for women (OR = 0.90: 0.82-0.99, P < 0.05) were also significant predictors of the outcome variable., Conclusion: Biomedical, psychological, environmental and behavioural factors were all associated with adult obesity., (© The Author(s) 2019. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To investigate to what extent locus of control, self-esteem, psychological distress, physical exercise, as well as socio-demographic factors are associated with obesity in 42-year-old adults in a longitudinal birth cohort study., Method: The sample consisted of 5645 participants born in Great Britain in 1970 and followed up at 10, 34 and 42 years with data on body mass index measured at 34 and 42 years., Results: There was an increase of adult obesity from 15.5% at age 34 to 21.2% at 42 years. Locus of control and self-esteem measured at age 10 years, psychological distress and educational qualifications assessed at age 34, and current occupational levels and physical exercise were all significantly associated with adult obesity at age 42. The associations remained significant after controlling for birth weight and gestation, maternal and paternal BMI, childhood BMI, and intelligence., Conclusion: Childhood locus of control and self-esteem, educational qualifications, psychological distress and physical exercise were all significantly and independently associated with adult obesity., (© The Author(s) 2018. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study investigated the change in the General Health Questionnaire (GHQ-12) scores from teenage years to young adulthood using a large, nationally representative sample in the UK. It took account of socio-demographic variables, childhood intelligence, behavioural problems and self-esteem at teenage and educational qualifications in early adulthood. In total, 3942 cohort members had the complete data on GHQ at ages 16 and 30 years. T-tests showed that there was statistically significant increase of GHQ mean scores over the 14 years (p < .001), however at the item level there were changes in both directions. The analysis showed that over 14 years the test-retest correlation was r = 0.24, indicating a modest level of stability. The GHQ was significantly and negatively associated with self-esteem, and positively associated with childhood behavioural problems. Regression analysis showed that gender, self-esteem, and behavioural problems measured in the teenage years were all significant predictors of GHQ at both time points, indicating the long-term effects of psychological and behavioural factors on teenagers and young adults' mental health outcome. The implications for early interventions in school and family settings are discussed., (Copyright © 2019. Published by Elsevier Ltd.)

Our objective was to investigate various psychological and socio-demographic factors in childhood and adulthood that relate to alcohol intake and binge drinking at age 42 years. Data were drawn from the 1970 British Cohort Study (BCS70), a prospective longitudinal study monitoring the development of babies born in 1970, with nine follow-ups. The analytic sample comprised 5190 cohort members with complete data on parental social class at birth, cognitive ability at age 10 years, locus of control at age 16 years, psychological distress at age 30 years, educational qualifications obtained at age 34 years, and current occupation and alcohol consumption at age 42 years. Results showed that sex (male), lower parental social class, adolescent external locus of control, psychological distress, lower scores on childhood intelligence, lower educational qualifications, and less-professional occupations were all significantly and positively associated with binge drinking in adulthood. Hierarchical logistic regression analyses showed that sex (OR = 0.52, CI: 0.44-0.60, p < .001), parental social class (OR = 0.67, CI: 0.50-0.92 to OR = 0.49, CI: 0.31-0.57, p < .05 to p < .01), locus of control beliefs (OR = 0.90, CI: 0.84-0.96, p < .01), adult psychological distress (OR = 1.28, CI: 1.04-1.58, p < .05), educational qualifications (OR = 0.70, CI: 0.53-0.92 to OR = 0.39, CI: 0.25-0.61, p < .05 to p < .001), and occupational prestige (OR = 0.59, CI: 0.38-0.95 to OR = 0.36, CI: 0.20-0.65, p < .05 to p < .01) were all significant and independent predictors of adult binge drinking. Both psychological and socio-demographic factors associated with adult excessive alcohol consumption. Adolescent locus of control beliefs had a significant effect on adult binge drinking 26 years later., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Biota Project communicates science to populations historically ignored by the scientific community. The Biota Project is comprised of a team of young professionals from a myriad of backgrounds and locations with interests in promoting science accessibility and equity. We do this by highlighting research conducted by scientists from underrepresented groups in relatable yet underrated locations with the intention of increasing the participation of underrepresented populations in science. The Biota Project centers on the scientific definition of symbiosis as a tool for both educating and learning from its followers. We deliver stories on the environments of our own backyards by merging art and science and distributing these publicly available stories widely online through short films, media clips, drawings, paintings, blogs, and e-newsletters. This project demonstrates a fresh, transferable perspective on strengthening science communication in a way that conjoins scientific discovery with social justice through the promotion of critical thinking by its target audience. Likewise, contributors learn how to better support local communities with each new story and environment. The Biota Project thus sets a symbiotic tone for re-calibrating the balance between academics, researchers, and local communities. When science is made relevant through understanding, its quality and significance are enhanced, and public recognition of its value is increased.

Accurate estimates of study product use are critical to understanding and addressing adherence challenges in HIV prevention trials. The VOICE trial exposed a significant gap between self-reported adherence and drug detection. The VOICE-D qualitative study was designed to better understand non-adherence during VOICE, and was conducted in 2 stages: before (stage 1) and after (stage 2) drug detection results were provided to participants. Transcripts from 44 women who participated in both stages were analysed to understand the effect of presenting drug detection data on narratives of product use. Thirty-six women reported high adherence in stage 1, yet admitted non-use in stage 2, three reported high adherence in both stages (contrary to their drug detection results) and five had consistent responses across both stages and drug results. Presenting objective measures of use may facilitate more accurate product use reporting and should be evaluated in future prevention trials.

Engaging highly marginalized HIV positive people in sustained medical care is vital for optimized health and prevention efforts. Prior studies have found that strengths-based case management helps link people who use drugs to HIV care. We conducted a pilot to assess whether a strengths-based case management intervention may help people who use injection drugs (PWID) or smoke crack cocaine (PWSC) achieve undetectable HIV viral load. PWID and PWSC were recruited in Oakland, California using targeted sampling methods and referral from jails and were tested for HIV. HIV positive participants not receiving HIV care (n = 19) were enrolled in a pilot strengths-based case management intervention and HIV positive participants already in HIV care (n = 29) were followed as comparison participants. The intervention was conducted by a social worker and an HIV physician. Special attention was given to coordinating care as participants cycled through jail and community settings. Surveys and HIV viral load tests were conducted quarterly for up to 11 visits. HIV viral load became undetectable for significantly more participants in the intervention than in the comparison group by their last follow-up (intervention participants: 32% at baseline and 74% at last follow-up; comparison participants: 45% at baseline and 34% at last follow-up; p = 0.008). In repeated measures analysis, PBO intervention participants had higher odds of achieving undetectable viral load over time than comparison participants (p = 0.033). Strengths-based case management may help this highly vulnerable group achieve undetectable HIV viral load over time.

This study explores factors in childhood and adulthood that affect adult trait Neuroticism in a large, nationally representative sample. 5785 participants provided information on family social background measured at birth; Intelligence assessed at 11 years; Behavioural problems measured at 11 years; Malaise assessed at 23 years; Educational qualifications obtained at 33 years; Occupational levels at 42 years, and personality trait Neuroticism measured at 50 years. Structural equation modelling showed that sex, childhood Behavioural Problems, childhood Intelligence, Malaise in early adulthood, and Occupation were all significant and independent predictors of adult trait Neuroticism. Parental social status was significantly and negatively associated with Malaise at age 23, but was not a significant predictor of trait Neuroticism at age 50 years. Education predicted Neuroticism mainly through occupation. The strongest predictor of trait Neuroticism at 50 years was Malaise measured at 23 years, with a corrected correlation of r = .42 over the 27 year period. The results suggest some underlying biological/genetic mechanism., (Copyright © 2017 Elsevier B.V. All rights reserved.)

There were 5834 participants with complete data on parental social class at birth, childhood cognitive ability tests scores at 11 years, educational qualifications at 33 years, the Big Five-Factor personality traits, occupational levels and eczema (measured at age 50 years). Results showed that eczema in childhood, educational achievement and occupational levels were significantly associated with the occurrence of reported eczema in adulthood. Emotionally Stable people (non-neurotic) were less likely to have eczema, but those with high Agreeableness and Openness more likely to have eczema. Childhood cognitive ability was significantly and positively associated with eczema in adulthood.

We evaluated the adherence and acceptability of a vaginal ring containing dapivirine, maraviroc, or both drugs for 28 days during a Phase I placebo-controlled trial in 48 HIV-negative sexually abstinent U.S. women aged 18-40. Adherence was assessed weekly by clinical interview and computer-assisted self-interviewing; acceptability assessment occurred at the last product-use visit. Study retention was 98 % (47/48); 94 % (45/48) reported being fully adherent with ring use during the 28-day period. Two participants experienced the ring partially coming out. Analysis was blinded and behavioral data were combined across study groups. Most women reported being very comfortable having the ring in their vagina; 44 % preferred continuous use, whereas 51 % had no preference compared to episodic use. Although a range of minor ring concerns were expressed, few were actually experienced. High adherence to and acceptability of this vaginal ring in this Phase I trial contributes to its promise as a sustained mechanism for multidrug vaginal microbicide delivery.

This study investigated the effects of socio-demographic and psychological factors in childhood and adulthood on the prevalence of migraine in adulthood using data from The National Child Development Studies (NCDS), a birth cohort in the UK. The analytical sample comprises 5799 participants with complete data. Logistic regression analysis showed that higher professional parental social class (OR=2.0: 1.05, 3.86, p<0.05), female sex (OR=2.24: 1.68-2.99, p<0.001), migraine in childhood diagnosed by physicians (OR=1.76: 1.23-2.50, p<0.01), and higher trait neuroticism (OR=1.17:1.26-1.06, p<0.01):<0 were all significantly associated with the prevalence of migraine in adulthood. Both socio-demographic and personality factors were significantly associated with the prevalence of migraine in adulthood., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The VOICE Adherence Strengthening Program (VASP) was implemented in May 2011 to improve adherence counseling in VOICE (MTN-003), a multisite placebo-controlled trial of daily oral or vaginal tenofovir-based Pre-Exposure Prophylaxis (PrEP). Anonymous baseline (N = 82) and final follow-up (N = 75) surveys were administered to counselors and pharmacists at 15 VOICE sites, and baseline (N = 18) and final (N = 26) qualitative in-depth interviews were conducted with purposively selected counseling staff at 13 VOICE sites. Qualitative interviews with VOICE participants (N = 38) were also analyzed for segments related to counseling. Behavioral and biological measures of product use collected in the 6 months prior to VASP implementation were compared to those collected during the 6 months following implementation. Results show that the majority of staff preferred VASP and thought that participants preferred VASP over the previous education and counseling strategy, although there was no evidence to suggest that participants noticed modifications in the counseling approach. No meaningful changes were observed in pre/post levels of reported use or drug detection. Interpretation of results is complicated by mid-trial implementation of VASP and its proximity to early closure of oral and vaginal tenofovir study arms because of futility.

Background: Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age., Methods: Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors., Results: Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3-6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes., Conclusions: Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging., (Copyright © 2015 by the American Academy of Pediatrics.)

We assessed the feasibility of a breath test to detect women's single or concurrent use of vaginal products by adding ester taggants to vaginal gel and condom lubricant. Healthy non-pregnant women were enrolled into a two-day cohort (N = 13) and a single-day cohort (N = 12) in San Francisco. Within each cohort, women were randomized (5:1) to tagged or untagged products, and inserted in a clinical setting: 4 mL of tenofovir placebo gel (ten tagged with 15 mg 2-pentyl acetate; three untagged), and an artificial phallus with a lubricated condom (11 tagged with 15 mg 2-butyl acetate; two untagged), on two separate days (two-day cohort) or concurrently (single-day cohort). Using a portable mini-gas chromatograph, the presence/absence of taggants was determined in breath specimens collected prior to, and at timed intervals following product exposure. Demographic, clinical and product use experience data were collected by structured interview. All participants completed all visits and inserted their assigned products. At 5 min post-insertion, the breath test was 100% accurate in identifying insertion of the tagged (or untagged) gel and/or condom. The half-life in breath of the two esters tested was <1 h with large variability between individuals, taggants and cohorts. Overall, among those receiving tagged product, six mild and two moderate product-related AEs were reported. All were transient and resolved spontaneously. Additional sensations included taste in mouth (N = 4) and scent (N = 5). The tagged products were well tolerated. This breath test has the potential to accurately and objectively monitor adherence to vaginal gel and condom used separately or concurrently.

The Wisebag™, a lunchbag-style container with an electronic events-monitoring system, was designed as a real-time indirect objective measure of microbicide gel use. Due to cost, alternative functionalities (i.e. use of offline and dummy versions) were explored. We conducted a three-arm, double-blinded pilot study among 50 HIV-negative women in Durban, South Africa to assess participant adherence and Wisebag acceptability and performance. Participants were randomized 2:2:1 to Wisebag with online (events transmitted via cellular signal in real-time), offline (events stored in device memory) or inactive "dummy" devices. Participants were instructed to open the Wisebag daily for 2 weeks, retrieve a study sticker and affix it on a diary card. All participants completed the study. At exit, 94 % did not know which device they had received, nor could they differentiate the Wisebag types when presented with the three options. Five offline devices failed (no data recorded). Per Wisebag events, 26 % of women were perfectly adherent compared to 48 % by self-report and 46 % per diary card. Of reported non-adherence, 92 % did not open the Wisebag (travelling or forgot) and 22 % opened Wisebag >1×/day (curiosity). Participants liked and were comfortable carrying Wisebag. Successful blinding will allow inclusion of offline and/or dummy Wisebags in future study designs. Perfect adherence by opening events was significantly lower than by self-report, highlighting the importance of objective measures of adherence in clinical trials. Additional studies to validate Wisebag data with actual products, with and without SMS and online functionality, in different populations and settings, and in comparison to biomarkers are warranted.

Background: We examine changes in sexual risk behaviors before and after HIV seroconversion in southern African women enrolled in the Methods for Improving Reproductive Health in Africa trial., Methods: HIV testing and counseling, and assessment of sexual behaviors by audio computer-assisted self-interviewing were performed approximately every 3 months. We compared the following sexual behaviors: being sexually active, coital frequency, consistent male condom use, use of any female condoms, anal sex, and >1 sex partner, at study visits before and after HIV seroconversion., Results: During the trial, 327 women seroconverted to HIV, contributing 718 pre-HIV and 1110 post-HIV study visits. Women were significantly more likely to report consistent condom use at visits after HIV seroconversion compared with visits before HIV infection [adjusted odds ratio, (AOR): 1.36 (95% confidence interval (CI): 1.11 to 1.67)] and were less likely to have >1 male sex partner after serconversion [AOR: 0.66 (95% CI: 0.48 to 0.91)]. Women reported less frequently being sexually active [AOR: 0.63 (95% CI: 0.39 to 1.02)], fewer episodes of sex [>4 sex acts over the past week AOR: 0.74 (95% CI: 0.60 to 0.91)], and a reduction in anal sex [AOR: 0.58 (95% CI: 0.36 to 0.95)] at visits after HIV seroconversion. The observed reductions in sexual risk behaviors persisted over time., Conclusions: Women significantly decreased their sexual risk behaviors after HIV seroconversion, but these changes were relatively modest, suggesting the need for further secondary prevention. Timely notification of HIV status coupled with prevention messages can contribute to reductions in sexual risk behaviors.

The androgen receptor (AR) plays a pivotal role in the progression of prostate cancer from the androgen-dependent to the castration-resistant state, making it a potential target for therapy. In this chapter, we describe the preparation and use of sublines of LNCaP and C4-2 human prostate cancer cells which have been engineered to stably express a doxycycline (DOX)-inducible AR shRNA in order to study the in vitro and in vivo effects of AR knockdown.

Background: Adherence problems with coitally dependent, female-initiated HIV prevention methods have contributed to several trials' failure to establish efficacy. Continuous use of a cervical barrier with once-daily cleaning and immediate reinsertion may simplify use for women and improve adherence. We assessed the acceptability and safety of precoital and continuous use of the Duet, a cervical barrier and gel delivery system, in Zimbabwean women., Methods: Using a two-arm crossover design with a parallel observation group, we randomized 103 women in a 2:2:1 ratio: (1) to use the Duet continuously for 14 days, followed by a minimum of seven days of washout and then 14 days of precoital use; (2) to use the same Duet regimens in reverse order; or (3) for observation only. Women were aged 18 to 40 years; half were recruited from a pool of previous diaphragm study participants and the other half from the general community. Acceptability and adherence were assessed through an interviewer-administered questionnaire at each of two follow-up visits. Safety was monitored through pelvic speculum exams and report of adverse events., Results: The proportion of women who reported consistent Duet use during sex was virtually identical during continuous and precoital regimens (88.6% vs. 88.9%). Partner refusal was the most common reason cited for non-use during sex in both use regimens. Not having the device handy was the most common reason cited for non-daily use (in the continuous regimen). Most women were "very comfortable" using it continuously (86.3%) and inserting it precoitally (92.8%). The most favoured Duet attribute was that it did not interfere with "natural" sex (55%). The least favoured Duet attribute was the concern that it might come out during sex (71.3%). No serious adverse events were reported during the study; 57 participants reported 90 adverse events classified as mild or moderate. There were no statistically significant differences in: (1) the proportion of women reporting adverse events; (2) the severity of events among those using the Duet and observational controls; or (3) event severity reported during each regimen use period., Conclusions: In this study, the Duet was found to be acceptable and safe when inserted precoitally or used continuously for 14 days. Assignment to use of the Duet continuously did not increase adherence to the Duet during sex. Future HIV prevention trials should evaluate use of the Duet (precoitally and continuously) with promising microbicide candidates.

The acceptability and use of the diaphragm and lubricant gel were assessed as part of a large randomized controlled trial to determine the effectiveness of the methods in women's HIV acquisition. 2,452 intervention-arm women were enrolled at five Southern African clinics and followed quarterly for 12-24 months. Acceptability and use data were collected by face-to-face interviews at Month 3 and Exit. Participants were "very comfortable" with the physical mechanics of diaphragm use throughout the trial, and approval of the gel consistency, quantity and the applicator was high. At Exit, consistent disclosure of use (AOR 1.97, 95% CI: 1.10-3.55); an overall high diaphragm rating (AOR 1.84, 95% CI: 1.45-2.34) and perception of partner approval (AOR 1.75, 95% CI: 1.35-2.26) were the most significant acceptability factors independently associated with consistent use. Despite being female-initiated, disclosure of use to male partners and his perceived approval of the products were factors significantly associated with their consistent use.

Purpose: Progression to the castration-resistant state is the incurable and lethal end stage of prostate cancer, and there is strong evidence that androgen receptor (AR) still plays a central role in this process. We hypothesize that knocking down AR will have a major effect on inhibiting growth of castration-resistant tumors., Experimental Design: Castration-resistant C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) were generated to directly test the effects of AR knockdown in C4-2 human prostate cancer cells and tumors., Results: In vitro expression of AR shRNA resulted in decreased levels of AR mRNA and protein, decreased expression of prostate-specific antigen (PSA), reduced activation of the PSA-luciferase reporter, and growth inhibition of C4-2 cells. Gene microarray analyses revealed that AR knockdown under hormone-deprived conditions resulted in activation of genes involved in apoptosis, cell cycle regulation, protein synthesis, and tumorigenesis. To ensure that tumors were truly castration-resistant in vivo, inducible AR shRNA expressing C4-2 tumors were grown in castrated mice to an average volume of 450 mm(3). In all of the animals, serum PSA decreased, and in 50% of them, there was complete tumor regression and disappearance of serum PSA., Conclusions: Whereas castration is ineffective in castration-resistant prostate tumors, knockdown of AR can decrease serum PSA, inhibit tumor growth, and frequently cause tumor regression. This study is the first direct evidence that knockdown of AR is a viable therapeutic strategy for treatment of prostate tumors that have already progressed to the castration-resistant state.

Defining the precise promoter DNA sequence motifs where nuclear receptors and other transcription factors bind is an essential prerequisite for understanding how these proteins modulate the expression of their specific target genes. The purpose of this chapter is to provide the reader with a detailed guide with respect to the materials and the key methods required to perform this type of DNA-binding analysis. Irrespective of whether starting with purified DNA-binding proteins or somewhat crude cellular extracts, the tried-and-true procedures described here will enable one to accurately access the capacity of specific proteins to bind to DNA as well as to determine the exact sequences and DNA contact nucleotides involved. For illustrative purposes, we primarily have used the interaction of the androgen receptor with the rat probasin proximal promoter as our model system.

Secreted mucins protect the underlying epithelium by serving as the major determinant of the rheological property of mucus secretion and the receptors for pathogens. These functions can be affected by the three branch structures, including core 2, core 4, and blood group I, which are synthesized by the mucus-type core 2 beta1,6 N-acetylglucosaminyltransferase (C2GnT-M). Decreased activity of this enzyme and expression of this gene have been found in colorectal cancer, which supports the important role of this enzyme in the protective functions of secreted mucins. We cloned full-length mouse (m) C2GnT-M cDNAs and showed that the deduced amino acid sequence was homologous to those of other C2GnT-Ms. The recombinant protein generated by mC2GnT-M cDNA exhibited core 2, core 4, and blood group I enzyme activities with a ratio of 1.00:0.46:1.05. We identified two different size transcripts by rapid amplification of cDNA ends and RT-PCR. Derived from the 6.6 kb mC2GnT-M gene composed of three exons and two introns, these two transcripts were intronless and differed by the length of the 3' untranslated region. In addition, exon 2 was found to be heterogeneous in size. This gene was highly expressed in the gastrointestinal tract, including colon, stomach, and small intestine. Antibodies generated against mC2GnT-M identified this enzyme in the goblet cells and other mucus cells/glands. This report provides the basis for further characterization of the regulation of mC2GnT-M gene expression and the biological functions of this gene.

Bovine core 2 beta1,6-N-acetylglucosaminyltransferase-M (bC2GnT-M) catalyzes the formation of all mucin beta1,6-N-acetylglucosaminides, including core 2, core 4, and blood group I structures. These structures expand the complexity of mucin carbohydrate structure and thus the functional potential of mucins. The four known mucin beta1,6-N-acetylglucosaminyltransferases contain nine conserved cysteines. We determined the disulfide bond assignments of these cysteines in [(35)S]cysteine-labeled bC2GnT-M isolated from the serum-free conditioned medium of Chinese hamster ovary cells stably transfected with a pSecTag plasmid. This plasmid contains bC2GnT-M cDNA devoid of the 5'-sequence coding the cytoplasmic tail and transmembrane domain. The C18 reversed phase high performance liquid chromatographic profile of the tryptic peptides of reduced-alkylated (35)S-labeled C2GnT-M was established using microsequencing. Each cystine pair was identified by rechromatography of the C8 high performance liquid chromatographic radiolabeled tryptic peptides of alkylated bC2GnT-M on C18 column. Among the conserved cysteines in bC2GnT-M, the second (Cys(113)) was a free thiol, whereas the other eight cysteines formed four disulfide bridges, which included the first (Cys(73)) and sixth (Cys(230)), third (Cys(164)) and seventh (Cys(384)), fourth (Cys(185)) and fifth (Cys(212)), and eighth (Cys(393)) and ninth (Cys(425)) cysteine residues. This pattern of disulfide bond formation differs from that of mouse C2GnT-L, which may contribute to the difference in substrate specificity between these two enzymes. Molecular modeling using disulfide bond assignments and the fold recognition/threading method to search the Protein Data Bank found a match with aspartate aminotransferase structure. This structure is different from the two major protein folds proposed for glycosyltransferases.

We provide evidence that the androgen receptor (AR) can promote nuclear translocation of beta-catenin in LNCaP and PC3 prostate cancer cells. Using AR-expressing cells (LNCaP) and non-AR-expressing cells (PC3) we showed by time course cell fractionation that the AR can shuttle beta-catenin into the nucleus when exposed to exogenous androgen. Cells exposed to the synthetic androgen, R1881, show distinct, punctate, nuclear co-localization of the AR and beta-catenin. We further showed that the AR does not interact with adenomatous polyposis coli or glycogen synthase kinase-3beta and, therefore, conclude that androgen-mediated transport of beta-catenin occurs through a distinct pathway. The minimal necessary components of the AR and beta-catenin required for binding nuclear accumulation of beta-catenin nuclear import appears to be the DNA/ligand binding regions and the Armadillo repeats of beta-catenin. We also employed a novel DNA binding assay to illustrate that beta-catenin has the capacity to bind to the probasin promoter in an AR-dependent manner. The physiological relevance of AR-mediated transport of beta-catenin and binding to an AR promoter appeared to be a substantial increase in AR transcriptional reporter activity. AR-mediated import represents a novel mode of nuclear accumulation of beta-catenin.