Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells.

Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.

Observational study of pre-operative intravenous iron given to anaemic patients before elective cardiac surgery.

Cardiac surgical patients with anaemia experience increased morbidity and mortality. Iron deficiency is the most common cause of pre-operative anaemia in this group. We designed and implemented the Cardiff Pathway, a pre-assessment and treatment pathway to identify cardiac surgical patients with anaemia and iron deficiency. Patients identified with anaemia and/or iron deficiency (Hb < 130 g.l-1 and ferritin < 100 µg.l-1 ) were offered intravenous iron infusion 20 mg.kg-1 pre-operatively. Treatment success was defined as Hb ≥ 130g.l-1 on the day of surgery. We analysed data from 447 patients: 300 (67%) were not anaemic; 75 (17%) were anaemic and treated with intravenous iron; and 72 (16%) were anaemic and not treated. Haemoglobin concentration increased in successfully treated anaemic patients by a mean (95%CI) of 17 (13-21) g.l-1 and they received a median (IQR [range]) of 0 (0-2 [0-15]) units of blood peri-operatively. Transfusion was avoided in 54% of the successfully treated anaemic patients, which was significantly more than the unsuccessfully treated anaemic (22%, p = 0.005) and untreated anaemic (28%, p = 0.018) patients and similar to non-anaemic patients who received a median (IQR [range] of 0 (0-1 [0-16])) units of blood and, 63% avoided transfusion). Mean (95%CI) Hb fell between pre-assessment and surgery in the untreated anaemic (-2 (0 to -4) g.l-1 ) and non-anaemic groups (-2 (-1 to -3) g.l-1 ). Twenty-one (7%) of the non-anaemic group became newly anaemic waiting for surgery. The Cardiff Pathway reliably identified patients with anaemia and iron deficiency. Anaemic patients who had their Hb restored to normal after treatment required less blood peri-operatively and over half of them required no transfusion at all.

An in vitro investigation of the survival and/or growth of Campylobacter jejuni in broiler digestate from different feed types.

Campylobacter spp. is the leading cause of bacterial gastroenteritis worldwide and poultry are the primary reservoir. The aim of this study was to investigate the survival and/or growth of Campylobacter jejuni NCTC 11168 in broiler digestate prepared from commercial starter, grower and finisher feed formulations. Bolton broth and digestates were prepared, inoculated with C. jejuni NCTC 11168 (approximately 3 log10 CFU per ml) and incubated under microaerobic conditions at 42°C for 24 h. Samples were taken at t = 0 (immediately after inoculation) and every 3 h thereafter, serially diluted and plated onto mCCDA. Campylobacter jejuni grew as expected in Bolton broth (control) reaching the early stationary phase after approximately 15 h. In contrast, although bacterial concentrations were maintained for at least 9 h, none of the feed digestates supported the growth of C. jejuni, which were not detected after 15 h. It is suggested that the nutrients available in the feed digestates are not enough to support C. jejuni growth and that additional factors may be at play in the avian gastrointestinal tract.

First Precision Measurement of the Parity Violating Asymmetry in Cold Neutron Capture on

We report the first precision measurement of the parity-violating asymmetry in the direction of proton momentum with respect to the neutron spin, in the reaction ^{3}He(n,p)^{3}H, using the capture of polarized cold neutrons in an unpolarized active ^{3}He target. The asymmetry is a result of the weak interaction between nucleons, which remains one of the least well-understood aspects of electroweak theory. The measurement provides an important benchmark for modern effective field theory and potential model calculations. Measurements like this are necessary to determine the spin-isospin structure of the hadronic weak interaction. Our asymmetry result is A_{PV}=[1.55±0.97(stat)±0.24(sys)]×10^{-8}, which has the smallest uncertainty of any hadronic parity-violating asymmetry measurement so far.

Imaging Fluorescence of He_{2}

We show unequivocal evidence for formation of He_{2}^{*} excimers in liquid He II created by ionizing radiation produced through neutron capture. Laser beams induce fluorescence of the excimers. The fluorescence is recorded at a rate of 55.6 Hz by a camera. The location of the fluorescence is determined with an uncertainty of 5 µm. The technique provides an opportunity to record the flow of He_{2}^{*} excimers in a medium with very small viscosity and enables measurement of turbulence around macroscopic liter size objects or vortex matter in three dimensions.

Effects of a novel bites, steps and eating rate-focused weight loss randomised controlled trial intervention on body weight and eating behaviours.

BACKGROUND: Eating rate (ER), comprising the amount of food consumed per unit of time, is associated with obesity and energy intake (EI). METHODS: The present study tested whether adding a self-monitoring wearable device to a multifaceted 8-week weight loss intervention increased weight loss. In addition, the device's effect on secondary change outcomes in EI, ER and estimated energy expenditure was explored. Tertiary outcomes included examining eating behaviours measured by the Weight-Related Eating Questionnaire (WREQ). Seventy-two adults who were overweight or obese [mean (SD) age, 37.7 (15.3) years; body mass index, 31.3 (3.2) kg m-2 ] were randomised into two groups: intervention workbook plus device (WD) or intervention workbook only (WO). Three 24-h dietary recalls were obtained before weeks 0 and 8. Participants were weighed, consumed a test meal and completed 7-day Physical Activity Recall and WREQ at weeks 0 and 8. RESULTS: There was no significant difference between WD and WO groups with respect to weight change [-0.46 (1.11) vs. 0.26 (0.82) kg, respectively], ER, EI, energy expenditure or WREQ scores, although there were significant changes over time, and within-group changes on all of these variables. At week 8, participants were dichotomised into weight loss or weight stable/gainers groups. A significant time by group change was seen in susceptibility to external cues scores, with significant time effects for susceptibility and restraint. CONCLUSIONS: An intervention focused on reducing ER, energy density and increasing steps was effective for weight loss, although the wearable device provided no additional benefit. Participants with higher susceptibility to external eating may be more responsive to this intervention.

The Association between Physical Activity and Metabolic Syndrome in Older Adults with Obesity.

BACKGROUND: Physical activity reduces the likelihood of developing metabolic syndrome (MetS). However, the association between different physical activity levels and MetS remains unclear in older adults with obesity. METHODS: This cross-sectional study used four waves of data (2007-2008, 2009-2010, 2011-2012, 2013-2014) from two datasets: The National Health and Nutrition Examination Survey and United Sates Department of Agriculture's Food Patterns Equivalents Database. The sample included adults 60+ years of age (n= 613) with obesity who had physical activity and MetS data. Physical activity was assessed using the Global Physical Activity Questionnaire and categorized into three physical activity levels (low, medium, and high); and medium or high physical activity levels are aligned with or exceed current physical activity recommendations. Participants were classified as having MetS using a commonly agreed upon definition. Multiple logistic regression models examined the association between the three physical activity levels and MetS risk factors and MetS. All analyses adjusted for potential confounding variables and accounted for complex sampling. RESULTS: Of 613 respondents, 72.1% (n=431) were classified as having MetS, and 44.3% (n = 263) had not met physical activity recommendations. Participants with high levels of physical activity had a lower risk of MetS (OR = 0.31, 95%CI: 0.13, 0.72) and more healthful levels of high-density lipoprotein cholesterol (OR = 0.39, 95%CI: 0.18, 0.84), blood pressure (OR = 0.39, 95%CI: 0.20, 0.77), fasting glucose (OR = 0.34, 95%CI: 0.15, 0.78) than participants categorized as having low physical activity. CONCLUSIONS: Physical activity is associated with lower risk of MetS only for participants with the highest level of physical activity, which suggests that physical activity dosage is important to reduce MetS risk in older adults with obesity.

Relationship between Diet Quality, Physical Activity and Health-Related Quality of Life in Older Adults: Findings from 2007-2014 National Health and Nutrition Examination Survey.

BACKGROUND: A growing body of research shows that diet quality and physical activity (PA) are associated with health-related quality of life (HRQOL). However, no study to date has assessed this association using the Healthy Eating Index-2015 as a measure of diet quality. Furthermore, few studies have examined the association between PA dose and HRQOL among a nationally representative sample of older adults. OBJECTIVES: To investigate the relationship between diet quality, physical activity, and HRQOL. DESIGN: A cross-sectional analysis was conducted using data obtained from 5,311 adults aged 60+ years who took part in the National Health and Nutrition Examination Survey between 2007 and 2014. MEASUREMENTS: HRQOL was assessed by general health status, and number of physically unhealthy days, mentally unhealthy days, and inactive days in past 30 days. Diet quality was assessed by the Healthy Eating Index-2015 using data generated by two 24-hour dietary recalls. PA was measured by the Global Physical Activity Questionnaire. Multivariate logistic/or linear regression models were used to examine the association between diet quality, PA and HRQOL controlling for confounders and accounting for complex sampling. RESULTS: Approximately half of the participants (55.2%) were women, 45.1% met current PA recommendations, 65% had less healthful diets according to the Healthy Eating Index-2015. Diet quality was associated with HROQL. For every 1-point diet quality score increase, the likelihood of respondents rating their general health as being excellent/good increased by 3% (OR=1.03, 95%CI: 1.02, 1.04), and number of inactive days (ß =-0.03, 95%CI: -0.05, 0.00) and mental unhealthy days (ß =-0.03, 95%CI: -0.05, -0.01) declined by 0.03 days. PA was associated with all HROQL measures and respondents with high PA levels reported better general health (OR=3.53, 95%CI: 2.69, 4.63), fewer inactive days (ß =-1.53, 95%CI: -2.11, -0.95), fewer physical unhealthy days (ß =-1.88, 95%CI: -2.74, -1.02) than individuals with low PA levels but not fewer mentally unhealthy days. CONCLUSIONS: Among older adults in this study, eating a healthier diet and being physically active were associated with better general health and reporting fewer physical unhealthy days and inactive days. Study results provide valuable information that could inform policies, programs and interventions designed to improve HRQOL in older adults and reduce potentially preventable health disparities.

Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity.

Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.

First Observation of P-odd γ Asymmetry in Polarized Neutron Capture on Hydrogen.

We report the first observation of the parity-violating gamma-ray asymmetry A_{γ}^{np} in neutron-proton capture using polarized cold neutrons incident on a liquid parahydrogen target at the Spallation Neutron Source at Oak Ridge National Laboratory. A_{γ}^{np} isolates the ΔI=1, ^{3}S_{1}→^{3}P_{1} component of the weak nucleon-nucleon interaction, which is dominated by pion exchange and can be directly related to a single coupling constant in either the DDH meson exchange model or pionless effective field theory. We measured A_{γ}^{np}=[-3.0±1.4(stat)±0.2(syst)]×10^{-8}, which implies a DDH weak πNN coupling of h_{π}^{1}=[2.6±1.2(stat)±0.2(syst)]×10^{-7} and a pionless EFT constant of C^{^{3}S_{1}→^{3}P_{1}}/C_{0}=[-7.4±3.5(stat)±0.5(syst)]×10^{-11} MeV^{-1}. We describe the experiment, data analysis, systematic uncertainties, and implications of the result.

Path Analysis of Campus Walkability/Bikeability and College Students' Physical Activity Attitudes, Behaviors, and Body Mass Index.

PURPOSE: The purpose of this study was to assess the relationship between the walkability/bikeability of college campuses and students' body mass index (BMI) with student physical activity (PA) attitudes and behaviors as potential mediators. DESIGN: Cross-sectional. SETTING: Thirteen university campuses. PARTICIPANTS: A total of 1384 student participants. MEASURES: Walkability/bikeability environmental score (ES): 12-item audit assessed an average of 44 path segments per campus. Students were measured for height and weight and completed online surveys. Physical activity stage of change/behavior intentions were assessed using the transtheoretical model. The Cognitive Behavioral Physical Activity Questionnaire assessed outcome expectations, self-regulation, and personal barriers. International Physical Activity Questionnaire assessed walking-, moderate-, and vigorous-intensity PA. ANALYSIS: Descriptive statistics, zero-order correlations, and path analysis with maximum likelihood estimation. RESULTS: The overall model fit was good with χ2 of 171.388 ( df = 18), P < .001, comparative fit index value of .95, and a root mean square of approximation of .079. After controlling for gender, there was a direct negative association between walkability/bikeability ES and BMI (ß = -.085) and positive association between personal barriers and BMI (ß = .134). Walkability/bikeability ES was positively associated with walking-intensity PA (ß = .010). Self-regulation was positively associated with moderate-intensity PA (ß = .213), which, in turn, was negatively associated with BMI (ß = -.057). CONCLUSIONS: The ease of walking and biking on a campus was related to college students' walking behavior and their BMI. Students' PA behavioral intentions were associated with moderate PA and lower BMI. These results provide evidence to focus on policies and structural supports for walkable/bikeable environments to supplement and enhance interventions encouraging individual behavior change for PA and weight management.

Precision determination of absolute neutron flux.

A technique for establishing the total neutron rate of a highly-collimated monochromatic cold neutron beam was demonstrated using an alpha-gamma counter. The method involves only the counting of measured rates and is independent of neutron cross sections, decay chain branching ratios, and neutron beam energy. For the measurement, a target of 10B-enriched boron carbide totally absorbed the neutrons in a monochromatic beam, and the rate of absorbed neutrons was determined by counting 478 keV gamma rays from neutron capture on 10B with calibrated high-purity germanium detectors. A second measurement based on Bragg diffraction from a perfect silicon crystal was performed to determine the mean de Broglie wavelength of the beam to a precision of 0.024%. With these measurements, the detection efficiency of a neutron monitor based on neutron absorption on 6Li was determined to an overall uncertainty of 0.058%. We discuss the principle of the alpha-gamma method and present details of how the measurement was performed including the systematic effects. We also describe how this method may be used for applications in neutron dosimetry and metrology, fundamental neutron physics, and neutron cross section measurements.

Understanding doctors' attitudes towards self-disclosure of mental ill health.

BACKGROUND: Understanding of doctors' attitudes towards disclosing their own mental illness has improved but assumptions are still made. AIMS: To investigate doctors' attitudes to disclosing mental illness and the obstacles and enablers to seeking support. METHODS: An anonymous, UK-wide online survey of doctors with and without a history of mental illness. The main outcome measure was likelihood of workplace disclosure of mental illness. RESULTS: In total, 1954 doctors responded and 60% had experienced mental illness. There was a discrepancy between how doctors think they might behave and how they actually behaved when experiencing mental illness. Younger doctors were least likely to disclose, as were trainees. There were multiple obstacles which varied across age and training grade. CONCLUSIONS: For all doctors, regardless of role, this study found that what they think they would do is different to what they actually do when they become unwell. Trainees, staff and associate speciality doctors and locums appeared most vulnerable, being reluctant to disclose mental ill health. Doctors continued to have concerns about disclosure and a lack of care pathways was evident. Concerns about being labelled, confidentiality and not understanding the support structures available were identified as key obstacles to disclosure. Addressing obstacles and enablers is imperative to shape future interventions.

Standards for 'Health for Health Professionals' services in the UK.

BACKGROUND: Doctors are more likely to suffer from work-related mental ill-health than other professions in the UK and internationally. Services to support doctors with health problems are emerging in the UK and have diverse models of delivery and funding. Services should be able to demonstrate agreed standards of practice for those who wish to commission, develop or access them. AIMS: To develop consensus about standards for 'Health for Health Professionals' (HHP) services in the UK through a modified Delphi study. METHODS: We conducted a two-stage Delphi study over 6 months. The questionnaire development took place during the UK Association of Physician Health (UKAPH) meeting in London in 2012, an invited meeting for clinicians with a specific interest in the area of physician health. The final questionnaire was disseminated via the UKAPH database. RESULTS: Forty-four people took part in round 1 and 40 in round 2. Participants were mainly GPs, occupational physicians and psychiatrists. Consensus was reached on major criteria for HHP services, with greatest consensus (45% agreement or greater) for four statements concerning the clarity and transparency of the services offered and one statement that anyone working within the service should have received suitable training in physician health. Consensus about some statements varied among the three specialities. CONCLUSIONS: This study will assist discussion about providing and improving consistent services across the UK, while recognizing the flexibility required in view of geographical differences.

Improved determination of the neutron lifetime.

The most precise determination of the neutron lifetime using the beam method was completed in 2005 and reported a result of τ(n)=(886.3±1.2[stat]±3.2[syst]) s. The dominant uncertainties were attributed to the absolute determination of the fluence of the neutron beam (2.7 s). The fluence was measured with a neutron monitor that counted the neutron-induced charged particles from absorption in a thin, well-characterized 6Li deposit. The detection efficiency of the monitor was calculated from the areal density of the deposit, the detector solid angle, and the evaluated nuclear data file, ENDF/B-VI 6Li(n,t)4He thermal neutron cross section. In the current work, we measure the detection efficiency of the same monitor used in the neutron lifetime measurement with a second, totally absorbing neutron detector. This direct approach does not rely on the 6Li(n,t)4He cross section or any other nuclear data. The detection efficiency is consistent with the value used in 2005 but is measured with a precision of 0.057%, which represents a fivefold improvement in the uncertainty. We verify the temporal stability of the neutron monitor through ancillary measurements, allowing us to apply the measured neutron monitor efficiency to the lifetime result from the 2005 experiment. The updated lifetime is τ(n)=(887.7±1.2[stat]±1.9[syst]) s.

Endoscopic vein harvest of the lesser saphenous vein in the supine position: a unique approach to an old problem.

OBJECTIVES: To obtain a suitable conduit from the lesser (short) saphenous system for use in coronary artery bypass surgery. We wanted to perform this while the patient was in the supine position as to not disrupt the standard operation, and at the same time, utilizing the endoscopic vein harvest technique with its obvious abilities to decrease vein harvest morbidity. We also theorized that through endoscopic techniques instead of the open technique we could harvest greater lengths of conduit, thus providing quality vein segments for additional grafts if needed. METHODS: We were able to perform endoscopic vein harvest while in the supine position with one unique centrally located incision that has not been previously described. RESULTS: The lesser saphenous vein harvested in the described technique provided excellent conduit for our patients that were conduit poor. The endoscopic technique allowed increased length of harvested segments, by giving us the ability to travel under the gastrocnemius muscle with minimal morbidity as opposed to the open technique, where the traditional endpoint is the aforementioned muscle. Conduits were harvested successfully from 14 of 16 candidates. No wound infections or healing problems were experienced. Neurovascular integrity was maintained in all patients. CONCLUSIONS: Endoscopic vein harvest of the lesser saphenous vein with the patient in the supine position is safe, effective and affords conduits for a unique subset of patients undergoing coronary artery bypass grafting.

Mode of data elicitation, acquisition and response to surveys: a systematic review.

BACKGROUND: Many studies in health sciences research rely on collecting participant-reported outcomes and attention is increasingly being paid to the mode of data collection. Consideration needs to be given to the validity of response via different modes and the impact that choice of mode might have on study conclusions. OBJECTIVES: (1) To provide an overview of the theoretical models of survey response and how they relate to health research; (2) to review all studies comparing two modes of administration for subjective outcomes and assess the impact of mode of administration on response quality; (3) to explore the impact of findings for key identified health-related measures; and (4) to inform the analysis of multimode studies. DATA SOURCES: A broad range of databases (for example EMBASE, PsychINFO, MEDLINE, EconLit, SPORTDiscus, etc.) were chosen to allow as comprehensive a selection as possible, and they were searched up until the end of 2004. REVIEW METHODS: The abstracts were reviewed against inclusion/exclusion criteria. Full papers were retrieved for all selected abstracts and then screened again using more detailed inclusion criteria related to the measures used. Papers that were still included were reviewed in full and detailed data extracted. At each stage, abstracts or papers were reviewed by a single reviewer. RESULTS: The search strategy identified 39,253 unique references, of which 2156 were considered as full papers, with 381 finally included in the review. Two features of mode were clearly associated with bias in response; however, none of the features of mode was associated with changes in precision. How the measure was administered, by an interviewer or by the person themselves, was highly significantly associated with bias (p < 0.001). A difference in sensory stimuli was also significant (p = 0.03). When both of these were present the average overall bias was < 1 point on a percentage scale. In terms of mediating factors, there was some suggestion that there was an interaction between both telephone and computer for data collection and date of publication, supporting the theory that differences disappear as new technologies become commonplace. Single-item measures were also related to greater degrees of bias than multi-item scales (p = 0.01). Individual analysis of the Short Form questionnaire-36 items and Minnesota Multiphasic Personality Inventory (MMPI) showed a varied pattern across the different subscales, with conflicting results between the two types of study. None of the MMPI measures used to detect deviant responding showed a relationship with the mode features tested. The limits of agreement analysis showed how variable measures were between modes at an individual rather than a group mean level. LIMITATIONS: The search strategy covered the period up to 2004, so any new and emerging technologies were not included. Not all potential mode features were tested and there was limited information on potential mediating factors. CONCLUSIONS: Researchers need to be aware of the different mode features that could have an impact on their results when selecting a mode of data collection for subjective outcomes. Further mode comparison studies, which manipulate mode features and directly assess impact over time, would be beneficial.

RAC3 is a pro-migratory co-activator of ERα.

Estrogen receptor alpha (ERα) is a ligand-dependent nuclear receptor that is important in breast cancer genesis, behavior and response to hormone-based therapies. A T7 phage display screen against full-length human ERα, coupled with genome-wide exon arrays, was used to identify RAC3 as a putative ERα co-regulator. RAC3 is a Rho family small GTPase that is associated with cytoskeletal rearrangement. We demonstrate a novel role for nuclear RAC3 as an ERα transcriptional activator, with prognostic implications for metastatic disease. Through in vitro and cell-based studies, RAC3 was shown to exist in a GTP-bound state and act as a ligand specific ERα co-activator of E2-induced transcription. Overexpression of RAC3 induced pro-growth and pro-migratory genes that resulted in increased migration of ERα-positive breast cancer cells. Chemical inhibition and genetic knockdown of RAC3 antagonized E2-induced cell proliferation, cell migration and ERα mediated gene expression, indicating that RAC3 is necessary for full ERα transcriptional activity. In agreement with the molecular and cellular data, RAC3 overexpression in ERα-positive breast cancers correlated with a significant decrease in recurrence free survival and a significant increase in the odds ratio of metastasis. In conclusion, RAC3 is a novel ERα co-activator that promotes cell migration and has prognostic value for ERα-positive breast cancer metastasis. RAC3 may also be a useful therapeutic target for ERα-positive breast cancers.