Nonequilibrium Stationary States and Phase Transitions in Directed Ising Models

We study the nonequilibrium properties of directed Ising models with non conserved dynamics, in which each spin is influenced by only a subset of its nearest neighbours. We treat the following models: (i) the one-dimensional chain; (ii) the two-dimensional square lattice; (iii) the two-dimensional triangular lattice; (iv) the three-dimensional cubic lattice. We raise and answer the question: (a) Under what conditions is the stationary state described by the equilibrium Boltzmann-Gibbs distribution? We show that for models (i), (ii), and (iii), in which each spin "sees" only half of its neighbours, there is a unique set of transition rates, namely with exponential dependence in the local field, for which this is the case. For model (iv), we find that any rates satisfying the constraints required for the stationary measure to be Gibbsian should satisfy detailed balance, ruling out the possibility of directed dynamics. We finally show that directed models on lattices of coordination number $z\ge8$ with exponential rates cannot accommodate a Gibbsian stationary state. We conjecture that this property extends to any form of the rates. We are thus led to the conclusion that directed models with Gibbsian stationary states only exist in dimension one and two. We then raise the question: (b) Do directed Ising models, augmented by Glauber dynamics, exhibit a phase transition to a ferromagnetic state? For the models considered above, the answers are open problems, to the exception of the simple cases (i) and (ii). For Cayley trees, where each spin sees only the spins further from the root, we show that there is a phase transition provided the branching ratio, $q$, satisfies $q \ge 3$

Biomarker Validation of Recent Unprotected Sexual Intercourse in a Prospective Study of Young Women Engaged in Sex Work in Phnom Penh, Cambodia

Summary—A study of female sex workers in Phnom Penh, Cambodia found self-reported condom use to be of questionable validity, particularly among amphetamine-type stimulant (ATS) users and those with multiple partners. Background—Accurate measurement of unprotected sex is essential in HIV prevention research. Since 2001, the 100% Condom Use Program targeting female sex workers (FSW) has been a central element of the Cambodian National HIV/AIDS Strategy. We sought to assess the validity of self-reported condom use using the rapid prostate-specific antigen (PSA) test among Cambodian FSW. Methods—From 2009 to 2010 we enrolled 183 FSW in Phnom Penh in a prospective study of HIV risk behavior. PSA test results from the OneStep ABAcard® were compared to self-reported condom use in the past 48 hours at quarterly follow-up visits. Results—Among women positive for seminal fluid at the first follow-up visit, 42% reported only protected sex or no sex in the detection period. Discordant results were more likely among brothel and street-based FSW vs. entertainment (56% vs. 17%), recent (last 3 months) ATS users (53% vs. 20%), and those with \u3e5 partners in the past month (58% vs. 13%). In multivariable regression models, positive PSA results were associated with recent ATS use (Adjusted Risk Ratio (ARR) = 1.5; 95% confidence interval (CI):1.1 – 2.2), having a non-paying last sex partner (ARR=1.7; CI: 1.2 – 2.5), and sex work venue (ARR=3.0; CI:1.4 – 6.5). Correspondingly, women with a nonpaying last sex partner were more likely to report unprotected sex (ARR=1.5; CI:1.1 – 2.2), but no associations were found with sex work venue or ATS use. Conclusions—Results confirm the questionable validity of self-reported condom use among FSW. The PSA biomarker assay is an important monitoring tool in HIV/STI research including prevention trials

Risk estimation as a decision-making tool for genetic analysis of the breast cancer susceptibility genes. EC Demonstration Project on Familial Breast Cancer.

For genetic counselling of a woman on familial breast cancer, an accurate evaluation of the probability that she carries a germ-line mutation is needed to assist in making decisions about genetic-testing. We used data from eight collaborating centres comprising 618 families (346 breast cancer only, 239 breast or ovarian cancer) recruited as research families or counselled for familial breast cancer, representing a broad range of family structures. Screening was performed in affected women from 618 families for germ-line mutations in BRCA1 and in 176 families for BRCA2 mutations, using different methods including SSCP, CSGE, DGGE, FAMA and PTT analysis followed by direct sequencing. Germ-line BRCA1 mutations were detected in 132 families and BRCA2 mutations in 16 families. The probability of being a carrier of a dominant breast cancer gene was calculated for the screened individual under the established genetic model for breast cancer susceptibility, first, with parameters for age-specific penetrances for breast cancer only [7] and, second, with age-specific penetrances for ovarian cancer in addition [20]. Our results indicate that the estimated probability of carrying a dominant breast cancer gene gives a direct measure of the likelihood of detecting mutations in BRCA1 and BRCA2. For breast/ovarian cancer families, the genetic model according to Narod et al. [20] is preferable for calculating the proband's genetic risk, and gives detection rates that indicate a 50% sensitivity of the gene test. Due to the incomplete BRCA2 screening of the families, we cannot yet draw any conclusions with respect to the breast cancer only families

Ethical, social and economic issues in familial breast cancer: a compilation of views from the EC biomed II demonstration project

ABSTRACT: Demand for clinical services for familial breast cancer is continuing to rise across Europe. Service provision is far from uniform and, in most centres, its evolution has been determined by local conditions, specifically by local research interests, rather than by central planning. However, in a number of countries there is evidence of progress towards co-ordinated development and audit of clinics providing risk assessment, counselling, screening and, in some cases, prophylactic intervention. Much important information should emerge from continued observation and comparative assessment of these developments. In most countries for which relevant data are available, there is a distinct bias towards higher social class among those who avail themselves of clinic facilities (in line with findings from many other health-promotion initiatives). This should be addressed when considering future organisation of clinical services. Molecular genetic studies designed to identify the underlying mutations responsible for familial breast cancer are not generally regarded as part of the clinical service and are funded through research grants (if at all). Economic considerations suggest that there is a case for keeping this policy under review. Familial cancers throw into sharp relief certain ethical and legal issues that have received much recent attention from government advisory bodies, patients ’ representatives, professional commentators and the popular media. Two are of particular importance; first, the right to gain access to medical records of relatives, in order to provide accurate risk assessment for a given family member, versus the right to privacy in respect of personal medical information and, second, the obligation (or otherwise) to inform family members of their risk status if they have not actively sought that knowledge. The legal position seems to vary from country to country and, in many cases, is unclear. In view of pressures to establish uniform approaches to medical confidentiality across the EC, it is important to evaluate the experience of participants in this Demonstration Programme and to apply the principle of “ non-malfeasance ” in formulating regu- lations that should govern future practice in this field. Data on economic aspects of familial breast cancer are remarkably sparse and outdated. As evidence accrues on the influence of screening and intervention programmes on morbidity and mortality, there is a strong case for evaluating the cost-effectiveness of different models of service provisi

Utilisation of prophylactic mastectomy in 10 European centers

ABSTRACT: Increasingly women at high risk of breast cancer are opting for prophylactic surgery to reduce their risks. Data from 10 European centres that offer a risk counselling and screening service to women at risk show different approaches to the option of preventive surgery, although most centres adhere to a protocol including at least two risk counselling sessions and a psychological assessment. Thus far the combined centres have data on 174 women who have undergone prophylactic mastectomy with in excess of 400 women years of follow up. Operations were carried out on women with lifetime risks of 25–80%, with an average annual expected incidence rate of 1% per women. No breast cancers have occurred in this cohort. Long term follow up on an extended group of women will be necessary to truly address the risk of subsequent breast cancer and the psychological sequelae

The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease

Background: Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD. Methods: The EQUAL study is an ongoing observational cohort study of non-dialyzed patients with stage 4/5 CKD. EQUAL patients from Germany, Poland, Sweden and the UK were included in the present study (n = 795). Data and symptom self-report questionnaires were collected between April 2012 and September 2020. Baseline uric acid and parathyroid hormone and 10 uremic toxins were quantified. We tested the association between uremic toxins and symptoms and adjusted P-values for multiple testing. Results: Symptoms were more frequent in women than in men with stage 4/5 CKD, while levels of various uremic toxins were higher in men. Only trimethylamine N-oxide (TMAO; positive association with fatigue), p-cresyl sulfate (PCS) with constipation and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (negative association with shortness of breath) demonstrated moderately strong associations with symptoms in adjusted analyses. The association of phenylacetylglutamine with shortness of breath was consistent in both sexes, although it only reached statistical significance in the full population. In contrast, TMAO (fatigue) and PCS and phenylacetylglutamine (constipation) were only associated with symptoms in men, who presented higher serum levels than women. Conclusion: Only a limited number of toxins were associated with symptoms in persons with stage 4/5 CKD. Other uremic toxins, uremia-related factors or psychosocial factors not yet explored might contribute to symptom burden.</p

The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease

Background: Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD. Methods: The EQUAL study is an ongoing observational cohort study of non-dialyzed patients with stage 4/5 CKD. EQUAL patients from Germany, Poland, Sweden and the UK were included in the present study (n = 795). Data and symptom self-report questionnaires were collected between April 2012 and September 2020. Baseline uric acid and parathyroid hormone and 10 uremic toxins were quantified. We tested the association between uremic toxins and symptoms and adjusted P-values for multiple testing. Results: Symptoms were more frequent in women than in men with stage 4/5 CKD, while levels of various uremic toxins were higher in men. Only trimethylamine N-oxide (TMAO; positive association with fatigue), p-cresyl sulfate (PCS) with constipation and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (negative association with shortness of breath) demonstrated moderately strong associations with symptoms in adjusted analyses. The association of phenylacetylglutamine with shortness of breath was consistent in both sexes, although it only reached statistical significance in the full population. In contrast, TMAO (fatigue) and PCS and phenylacetylglutamine (constipation) were only associated with symptoms in men, who presented higher serum levels than women. Conclusion: Only a limited number of toxins were associated with symptoms in persons with stage 4/5 CKD. Other uremic toxins, uremia-related factors or psychosocial factors not yet explored might contribute to symptom burden.</p

Dynamics of the directed Ising chain

The study by Glauber of the time-dependent statistics of the Ising chain is extended to the case where each spin is influenced unequally by its nearest neighbours. The asymmetry of the dynamics implies the failure of the detailed balance condition. The functional form of the rate at which an individual spin changes its state is constrained by the global balance condition with respect to the equilibrium measure of the Ising chain. The local magnetization, the equal-time and two-time correlation functions and the linear response to an external magnetic field obey linear equations which are solved explicitly. The behaviour of these quantities and the relation between the correlation and response functions are analyzed both in the stationary state and in the zero-temperature scaling regime. In the stationary state, a transition between two behaviours of the correlation function occurs when the amplitude of the asymmetry crosses a critical value, with the consequence that the limit fluctuation-dissipation ratio decays continuously from the value 1, for the equilibrium state in the absence of asymmetry, to 0 for this critical value. At zero temperature, under asymmetric dynamics, the system loses its critical character, yet keeping many of the characteristic features of a coarsening system

Guidelines for follow-up of women at high risk for inherited breast cancer: Consensus statement from the Biomed 2 Demonstration Programme on Inherited Breast Cancer

Protocols for activity aiming at early diagnosis and treatment of inherited breast or breast-ovarian cancer have been reported. Available reports on outcome of such programmes are considered here. It is concluded that the ongoing activities should continue with minor modifications. Direct evidence of a survival benefit from breast and ovarian screening is not yet available. On the basis of expert opinion and preliminary results from intervention programmes indicating good detection rates for early breast cancers and 5-year survival concordant with early diagnosis, we propose that women at high risk for inherited breast cancer be offered genetic counselling, education in ‘breast awareness’ and annual mammography and clinical expert examination from around 30 years of age. Mammography every second year may be sufficient from 60 years on. BRCA1 mutation carriers may benefit from more frequent examinations and cancer risk may be reduced by oophorectomy before 40–50 years of age. We strongly advocate that all activities should be organized as multicentre studies subjected to continuous evaluation to measure the effects of the interventions on long-term mortality, to match management options more precisely to individual risks and to prepare the ground for studies on chemoprevention

The "Ram Effect": A "Non-Classical" Mechanism for Inducing LH Surges in Sheep

During spring sheep do not normally ovulate but exposure to a ram can induce ovulation. In some ewes an LH surge is induced immediately after exposure to a ram thus raising questions about the control of this precocious LH surge. Our first aim was to determine the plasma concentrations of oestradiol (E2) E2 in anoestrous ewes before and after the "ram effect" in ewes that had a "precocious" LH surge (starting within 6 hours), a "normal" surge (between 6 and 28h) and "late» surge (not detected by 56h). In another experiment we tested if a small increase in circulating E2 could induce an LH surge in anoestrus ewes. The concentration of E2 significantly was not different at the time of ram introduction among ewes with the three types of LH surge. "Precocious" LH surges were not preceded by a large increase in E2 unlike "normal" surges and small elevations of circulating E2 alone were unable to induce LH surges. These results show that the "precocious" LH surge was not the result of E2 positive feedback. Our second aim was to test if noradrenaline (NA) is involved in the LH response to the "ram effect". Using double labelling for Fos and tyrosine hydroxylase (TH) we showed that exposure of anoestrous ewes to a ram induced a higher density of cells positive for both in the A1 nucleus and the Locus Coeruleus complex compared to unstimulated controls. Finally, the administration by retrodialysis into the preoptic area, of NA increased the proportion of ewes with an LH response to ram odor whereas treatment with the α1 antagonist Prazosin decreased the LH pulse frequency and amplitude induced by a sexually active ram. Collectively these results suggest that in anoestrous ewes NA is involved in ram-induced LH secretion as observed in other induced ovulators