18F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials.

Purpose: Evaluate 18F-fluoroestradiol (FES) PET/CT as a biomarker of estrogen receptor (ER) occupancy and/or downregulation during phase I dose escalation of the novel ER targeting therapeutic GDC-0810 and help select drug dosage for subsequent clinical trials.Experimental Design: In a phase I clinical trial of GDC-0810, patients with ER-positive metastatic breast cancer underwent FES PET/CT before beginning therapy and at cycle 2, day 3 of GDC-0810 therapy. Up to five target lesions were selected per patient, and FES standardized uptake value (SUV) corrected for background was recorded for each lesion pretherapy and on-therapy. Complete ER downregulation was defined as ≥90% decrease in FES SUV. The effect of prior tamoxifen and fulvestrant therapy on FES SUV was assessed.Results: Of 30 patients who underwent paired FES-PET scans, 24 (80%) achieved ≥90% decrease in FES avidity, including 1 of 3 patients receiving 200 mg/day, 2 of 4 patients receiving 400 mg/day, 14 of 16 patients receiving 600 mg/day, and 7 of 7 patients receiving 800 mg/day. Withdrawal of tamoxifen 2 months prior to FES PET/CT and withdrawal of fulvestrant 6 months prior to FES PET/CT both appeared sufficient to prevent effects on FES SUV. A dosage of 600 mg GDC-0810 per day was selected for phase II in part due to decreases in FES SUV achieved in phase I.Conclusions: FES PET/CT was a useful biomarker of ER occupancy and/or downregulation in a phase I dose escalation trial of GDC-0810 and helped select the dosage of the ER antagonist/degrader for phase II trials. Clin Cancer Res; 23(12); 3053-60. ©2016 AACR.

An experimental test of control theory-based interventions for physical activity.

OBJECTIVES: To provide an experimental test of control theory to promote physical activity. DESIGN: Parallel groups, simple randomized design with an equal chance of allocation to any group. METHODS: Participants not meeting recommended levels of physical activity but physically safe to do so (N = 124) were recruited on a UK university campus and randomized to goal-setting + self-monitoring + feedback (GS + SM + F, n = 40), goal-setting + self-monitoring (GS + SM, n = 40), or goal-setting only (GS, n = 44) conditions that differentially tapped the key features of control theory. Accelerometers assessed physical activity (primary outcome) as well as self-report over a 7-day period directly before/after the start of the intervention. RESULTS: The participants in the GS + SM + F condition significantly outperformed those in the GS condition, d = 0.62, 95% CI d = 0.15-1.08, and marginally outperformed those in the GS + SM condition in terms of total physical activity at follow-up on the accelerometer measure, d = 0.33, 95% CI d = -0.13 to 0.78. The feedback manipulation (GS + SM + F vs. GS + SM and GS) was most effective when baseline intentions were weak. These patterns did not emerge on the self-report measure but, on the basis of this measure, the feedback manipulation increased the risk that participants coasted in relation to their goal in the first few days of the intervention period. CONCLUSIONS: Using behaviour change techniques consistent with control theory can lead to significant short-term improvements on objectively assessed physical activity. Further research is needed to examine the underlying theoretical principles of the model. Statement of contribution What is already known on this subject? Interventions incorporating more techniques that are consistent with control theory are associated with larger positive changes in health behaviours and related outcomes (see reviews by Dombrowski et al., ; Michie et al., ). However, none of the studies included in these reviews were explicitly based on control theory (see Prestwich et al., ). What does this study add? This study is the first experimental test of the cumulative effects of behaviour change techniques as proposed by control theory. Intervening on all aspects of the feedback loop noted by control theory leads to more change; however, the risk that some participants coast in relation to their set goal is significant. This approach increased physical activity more in those with weaker intentions pre-intervention.

Dose Optimization of the Administered Activity in Pediatric Bone Scintigraphy: Validation of the North American Consensus Guidelines.

UNLABELLED: The 2010 North American Consensus Guidelines (NACG) for pediatric administered doses and the European Association of Nuclear Medicine (EANM) Dosage Card guidelines recommend lower activities than those administered at our institution. We compared the quality of the lower-activity images with the higher-activity images to determine whether the reduction in counts affects overall image quality. METHODS: Twenty patients presenting to our pediatric radiology department for bone scintigraphy were evaluated. Their mean weight was 20 kg. The patients were referred for oncologic (n = 10), infectious/inflammatory (n = 5), and pain (n = 5) evaluation. Dynamic anterior and posterior images were acquired for 5 min for each patient. Data were subsampled to represent different administered activities corresponding to the activities recommended by the NACG and the EANM Dosage Card. Images were evaluated twice, first for diagnostic quality and then for acceptability for daily clinical use. RESULTS: There was no statistically significant difference in the diagnostic quality of the images from any of the 3 protocols. Pathologic uptake was correctly identified independent of the administered activity, although there was a single false-positive result for an EANM image. When images were subjectively evaluated as acceptable for daily clinical use, there was a slight preference for the higher-activity images over the NACG (P = 0.04). CONCLUSION: The recommended administered activities of the NACG produce images of diagnostic quality while reducing patient radiation exposure.

Partner- and planning-based interventions to reduce fat consumption: randomized controlled trial.

OBJECTIVE: The research tested the efficacy of partner- and planning-based interventions to reduce dietary fat intake over a 6-month period. DESIGN: Randomized controlled, blinded, parallel trial. METHODS: A computer randomization feature was used to allocate council employees (N = 427, of which 393 completed baseline measures) to one of four conditions (partner + implementation intentions, partner-only, implementation intentions, and control group) before they completed measures at baseline and follow-ups at 1, 3, and 6 months post-baseline. Outcome measures were comprised of validated self-report measures of dietary fat intake (saturated fat intake, fat intake, ratio of 'good' fats to 'bad' fats); psychosocial mediators (enjoyment, intention, self-efficacy, social influence, partner support); weight and waist size (baseline and 6 months only). RESULTS: Data from 393 participants were analysed in accordance with intention-to-treat analyses. All intervention groups reported greater reductions in fat intake than the control group at 3 months. The partner-based groups increased the ratio of 'good' fats to 'bad' fats at 3 and 6 months and lost more inches on their waist, versus the non-partner groups. The impacts of the partner-based manipulations on outcomes were partially mediated by greater perceived social influences, partner support, and enjoyment of avoiding high-fat foods. The partner-based interventions also increased intention and self-efficacy. However, the effects in this study were typically small and generally marginally significant. CONCLUSIONS: Partner-based interventions had some positive benefits on dietary-related outcomes at 3 and 6 months. Support for implementation intentions was more limited.

Exploring the question-behaviour effect: randomized controlled trial of motivational and question-behaviour interventions.

PURPOSE: Measuring intentions and other cognitions to perform a behaviour can promote performance of that behaviour (the question-behaviour effect, QBE). It has been suggested that this effect may be amplified for individuals motivated to perform the behaviour. The present research tested the efficacy of combining a motivational intervention (providing personal risk information) with measuring intentions and other cognitions in a fully crossed 2 × 2 design with an objective measure of behaviour in an at-risk population using a randomized controlled trial (RCT). METHODS: Participants with elevated serum cholesterol levels were randomized to one of four conditions: a combined group receiving both a motivational intervention (personalized cardiovascular disease risk information) and a QBE manipulation (completing a questionnaire about diet), one group receiving a motivational intervention, one group receiving a QBE intervention, or one group receiving neither. All participants subsequently had the opportunity to obtain a personalized health plan linked to reducing personal risk for coronary heart disease. RESULTS: Neither the motivational nor the QBE manipulations alone significantly increased rates of obtaining the health plan. However, the interaction between conditions was significant. Decomposition of the interaction indicated that the combined condition (motivational plus QBE manipulation) produced significantly higher rates of obtaining the health plan (96.2%) compared to the other three groups combined (80.3%). CONCLUSIONS: The findings provide insights into the mechanism underlying the QBE and suggest the importance of motivation to perform the behaviour in observing the effect. STATEMENT OF CONTRIBUTION: What is already known on this subject? Research has indicated that merely asking questions about a behaviour may be sufficient to produce changes in that or related behaviours (referred to as the question-behaviour effect; QBE). Previous studies have suggested that the QBE may be moderated by the individual's motivation to change the behaviour, i.e., the QBE will only produce increases in the behaviour among those with strong motivation to perform the behaviour. However, no study has directly tested this prediction by manipulating motivation and examining impacts on the QBE. What does this study add? The present study tested the individual and combined effects of a motivational and a QBE intervention in a fully crossed design using a randomized controlled trial (RCT) and showed that: a combined intervention significantly increased behaviour. effect partially mediated by cognitions.

Randomized controlled trial of collaborative implementation intentions targeting working adults' physical activity.

OBJECTIVE: The research tested the efficacy of planning and partner-based interventions to promote physical activity over six months. METHOD: Local government (council) employees (N = 257) were randomly allocated to one of four conditions (collaborative implementation intentions; partner-only; implementation intentions; control group) before completing measures at baseline and follow-ups at 1, 3 and 6 months. Outcome measures comprised validated self-report measures of physical activity: the international physical activity questionnaire (IPAQ; Craig et al., 2003) and self-report walking and exercise tables (SWET; Prestwich et al., 2012); psychosocial mediators (enjoyment, intention, self-efficacy, social influence); weight and waist size (baseline and 6 months only). RESULTS: As well as losing the most weight, there was evidence that participants in the collaborative implementation-intention group were more physically active than each of the other three groups at 1-, 3- and 6-month follow-ups. Those in the implementation-intention and partner-only conditions did not outperform the control group on most measures. CONCLUSION: Collaborative implementation intentions represent a potentially useful intervention to change important health behaviors that help reduce weight.

Do implicit measures of attitudes incrementally predict snacking behaviour over explicit affect-related measures?

Various studies have demonstrated an association between implicit measures of attitudes and dietary-related behaviours. However, no study has tested whether implicit measures of attitudes predict dietary behaviour after controlling for explicit measures of palatability. In a prospective design, two studies assessed the validity of measures of implicit attitude (Implicit Association Test, IAT) and explicit measures of palatability and health-related attitudes on self-reported (Studies 1 and 2) and objective food (fruit vs. chocolate) choice (Study 2). Following regression analyses, in both studies, implicit measures of attitudes were correlated with food choice but failed to significantly predict food choice when controlling specifically for explicit measures of palatability. These consistent relationships emerged despite using different category labels within the IAT in the two studies. The current research suggests implicit measures of attitudes may not predict dietary behaviours after taking into account the palatability of food. This is important in order to establish determinants that explain unique variance in dietary behaviours and to inform dietary change interventions.

Humoral immunity following chickenpox is influenced by geography and ethnicity.

OBJECTIVES: To investigate the contribution of ethnicity and geographical location to varicella-zoster virus (VZV) serostatus and antibody concentrations. METHODS: The presence and concentrations of antibodies to VZV were measured in 639 Bangladeshi women born in Bangladesh (BBB), 94 Bangladeshi women born in the UK (BUK) and 262 White women born in the UK (WUK). The results were analysed in relation to demographic and social data. RESULTS: BBB women were significantly less likely to be VZV seropositive at all ages than both BUK and WUK women. However, the odds of a Bangladeshi-born woman being seropositive increased by 1.04 for each year under the age of 15 spent in the UK. In contrast, antibody concentrations were significantly lower in ethnic Bangladeshi women, irrespective of country of birth. White, but not Bangladeshi women, showed evidence of antibody boosting over time despite the latter having more exposure to children. CONCLUSION: Geographical location during childhood is the major influence on age of primary infection with VZV while the level of antibody is related to ethnicity. Since the risk of re-infection with VZV following both natural infection and vaccination is increased as antibody concentrations fall, these results have implications for VZV vaccination programmes particularly in non-White populations.

Crossing two types of implementation intentions with a protection motivation intervention for the reduction of saturated fat intake: a randomized trial.

Implementation intentions, namely specific plans regarding when, where and how an individual will act, increase the likelihood of action. There is evidence that implementation intentions should be particularly efficacious when combined with motivational interventions. However, this is yet to be tested in relation to the reduction of unhealthy behaviour. Thus the aim of this study was to examine the efficacy of combined motivation and implementation intention interventions for the reduction of saturated fat intake. It also tested a new form of implementation intention (reasoning implementation intentions). Participants from the UK (n = 210) were randomized to condition and asked either to form standard implementation intentions, reasoning implementation intentions, or received no implementation intention manipulation; and were exposed to protection motivation-based information, or not. Results showed that standard and reasoning implementation intentions were successful in reducing the proportion of food energy derived from saturated fat but the effects of the standard implementation intention were dependent on whether participants read the motivational message or not.

Relations between implicit and explicit measures of attitudes and measures of behavior: evidence of moderation by individual difference variables.

The moderating role of individual difference variables (Self-Reported Habit Index [SRHI], Need for Cognition [NFC]) on relationships between implicit (Implicit Association Test [IAT], Extrinsic Affective Simon Test [EAST]) or explicit measures of attitude and behavior is assessed in two studies. A dissociation pattern is found on self-report diary measures of behavior. In Study 1, the EAST-behavior relationship is moderated by SRHI; explicit measures of the attitude-behavior relationship are moderated by NFC. In Study 2, the IAT-behavior relationship is moderated by SRHI; explicit measures of the attitude-behavior relationship are moderated by NFC. Higher levels of SRHI and NFC are associated with stronger relationships between the implicit or explicit measures of attitude and the measure of behavior. In Study 2, the SRHI x IAT interaction is replicated for an objective behavior measure. Implications for understanding the relationship between implicit and explicit measures of attitudes and measures of behavior are discussed.

The expected performance of single nucleotide polymorphism loci in paternity testing.

We discuss the utility of single nucleotide polymorphism loci for full trio and mother-unavailable paternity testing cases, in the presence of population substructure and relatedness of putative and actual fathers. We focus primarily on the expected number of loci required to gain specified probabilities of mismatches, and report the expected proportion of paternity indices greater than three threshold values for these loci.

Calculating the exclusion probability and paternity index for X-chromosomal loci in the presence of substructure.

There has been recent interest in the use of X-chromosomal loci for forensic and relatedness testing casework, with many authors developing new X-linked short tandem repeat (STR) loci suitable for forensic use. Here we present formulae for two key quantities in paternity testing, the average probability of exclusion and the paternity index, which are suitable for X-chromosomal loci in the presence of population substructure.

Gene conversion and evolution of Xq28 duplicons involved in recurring inversions causing severe hemophilia A.

Inversions breaking the 1041 bp int1h-1 or the 9.5-kb int22h-1 sequence of the F8 gene cause hemophilia A in 1/30,000 males. These inversions are due to homologous recombination between the above sequences and their inverted copies on the same DNA molecule, respectively, int1h-2 and int22h-2 or int22h-3. We find that (1) int1h and int22h duplicated more than 25 million years ago; (2) the identity of the copies (>99%) of these sequences in humans and other primates is due to gene conversion; (3) gene conversion is most frequent in the internal regions of int22h; (4) breakpoints of int22h-related inversions also tend to involve the internal regions of int22h; (5) sequence variations in a sample of human X chromosomes defined eight haplotypes of int22h-1 and 27 of int22h-2 plus int22h-3; (6) the latter two sequences, which lie, respectively, 500 and 600 kb telomeric to int22h-1 are five-fold more identical when in cis than when in trans, thus suggesting that gene conversion may be predominantly intrachromosomal; (7) int1h, int22h, and flanking sequences evolved at a rate of about 0.1% substitutions per million years during the divergence between humans and other primates, except for int1h during the human-chimpanzee divergence, when its rate of evolution was significantly lower. This is reminiscent of the slower evolution of palindrome arms in the male specific regions of the Y chromosome and we propose, as an explanation, that intrachromosomal gene conversion and cosegregation of the duplicated regions favors retention of the ancestral sequence and thus reduces the evolution rate.

Detecting non-multiplicative genotype relative risks from transmissions of parental alleles to affected children.

The differential transmission of alleles from parents to affected children indicates that the locus under investigation is either directly involved in the occurrence of the disease or that there are allelic associations with other loci that are directly involved. Conditional logistic regression applied to a diallelic locus leads to a test with two degrees of freedom. The power of a single degree of freedom test to detect non-multiplicative allelic effects is discussed here.

Linkage disequilibrium assessment via log-linear modeling of SNP haplotype frequencies.

Analyses of high-density single-nucleotide polymorphism (SNP) data, such as genetic mapping and linkage disequilibrium (LD) studies, require phase-known haplotypes to allow for the correlation between tightly linked loci. However, current SNP genotyping technology cannot determine phase, which must be inferred statistically. In this paper, we present a new Bayesian Markov chain Monte Carlo (MCMC) algorithm for population haplotype frequency estimation, particularly in the context of LD assessment. The novel feature of the method is the incorporation of a log-linear prior model for population haplotype frequencies. We present simulations to suggest that 1) the log-linear prior model is more appropriate than the standard coalescent process in the presence of recombination (>0.02 cM between adjacent loci), and 2) there is substantial inflation in measures of LD obtained by a "two-stage" approach to the analysis by treating the "best" haplotype configuration as correct, without regard to uncertainty in the recombination process.

Implications for DNA identification arising from an analysis of Australian forensic databases.

Previous analyses of Australian samples have suggested that populations of the same broad racial group (Caucasian, Asian, Aboriginal) tend to be genetically similar across states. This suggests that a single national Australian database for each such group may be feasible, which would greatly facilitate casework. We have investigated samples drawn from each of these groups in different Australian states, and have quantified the genetic homogeneity across states within each racial group in terms of the "coancestry coefficient" F(ST). In accord with earlier results, we find that F(ST) values, as estimated from these data, are very small for Caucasians and Asians, usually <0.5%. We find that "declared" Aborigines (which includes many with partly Aboriginal genetic heritage) are also genetically similar across states, although they display some differentiation from a "pure" Aboriginal population (almost entirely of Aboriginal genetic heritage).