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Abstract Background We aimed to determine how response to a parent-completed postal questionnaire measuring development, behaviour, impairment, and parental concerns and anxiety, varies in different European centres. Methods Prospective cohort study of 3 year old children, with and without congenital toxoplasmosis, who were identified by prenatal or neonatal screening for toxoplasmosis in 11 centres in 7 countries. Parents were mailed a questionnaire that comprised all or part of existing validated tools. We determined the effect of characteristics of the centre and child on response, age at questionnaire completion, and response to child drawing tasks. Results The questionnaire took 21 minutes to complete on average. 67% (714/1058) of parents responded. Few parents (60/1058) refused to participate. The strongest determinants of response were the score for organisational attributes of the study centre (such as direct involvement in follow up and access to an address register), and infection with congenital toxoplasmosis. Age at completion was associated with study centre, presence of neurological abnormalities in early infancy, and duration of prenatal treatment. Completion rates for individual questions exceeded 92% except for child completed drawings of a man (70%), which were completed more by girls, older children, and in certain centres. Conclusion Differences in response across European centres were predominantly related to the organisation of follow up and access to correct addresses. The questionnaire was acceptable in all six countries and offers a low cost tool for assessing development, behaviour, and parental concerns and anxiety, in multinational studies.

Methane Hydrates (MHs) are a promising energy source abundantly available in nature. Understanding the complex processes of MH formation and dissociation is critical for the development of safe and efficient technologies for energy recovery. Many laboratory and numerical studies have investigated these processes using synthesized MH-bearing sediments. A near-universal issue encountered in these studies is the spatial heterogeneous hydrate distribution in the testing apparatus. In the absence of direct observations (e.g. using X-ray computed tomography) coupled with real time production data, the common assumption made in almost all numerical studies is a homogeneous distribution of the various phases. In an earlier study (Yin et al., 2018) that involved the numerical description of a set of experiments on MH-formation in sandy medium using the excess water method, we showed that spatially heterogeneous phase distribution is inevitable and significant. In the present study, we use as a starting point the results and observations at the end of the MH formation and seek to numerically reproduce the laboratory experiments of depressurization-induced dissociation of the spatially-heterogeneous MH distribution. This numerical study faithfully reproduces the geometry of the laboratory apparatus, the initial and boundary conditions of the system, and the parameters of the dissociation stimulus, capturing accurately all stages of the experimental process. Using inverse modelling (history-matching) that minimized deviations between the experimental observations and numerical predictions, we determined the values of all the important flow, thermal, and kinetic parameters that control the system behaviour, which yielded simulation results that were in excellent agreement with the measurements of key monitored variables, i.e. pressure, temperature, cumulative production of gas and water over time. We determined that at the onset of depressurization (when the pressure drop – the driving force of dissociation – is at its maximum), the rate of MH dissociation approaches that of an equilibrium reaction and is limited by the heat transfer from the system surroundings. As the effect of depressurization declines over time, the dissociation reaction becomes kinetically limited despite significant heat inflows from the boundaries, which lead to localized temperature increases in the reactor.

We analyse numerically an earlier experimental study that involved the formation of methane hydrates by the excess water method in a small reactor filled with a sandy porous medium, and seek to address questions about the type of the hydration reaction and the phase heterogeneity in the resulting hydrate-bearing sand. Using a fine discretization describing the reactor assembly, the experimental process is faithfully replicated numerically. The multi-stage process of hydrate formation is subdivided in 7 steps. The experimental data from the continuously-monitored pressure and temperature during each step are used for comparison against the numerical predictions, the identification of the dominant processes and the determination of the associated parameters through a history-matching process that minimizes deviations between observations and simulation results. The results of this first-ever study on this subject demonstrate unequivocally that the hydration reaction is a kinetic (as opposed to an equilibrium) process, and that the spatial distributions of the various phases (aqueous, gas and hydrate) at the end of the formation process are strongly heterogeneous. This has serious implications in simulation studies of hydrate dissociation that assume uniform initial phase saturation distributions. The history-matching process indicates that (a) the system behaviour is sensitive to some flow parameters (porosity and irreducible water saturation) only during the first water injection, (b) it is insensitive to the sand intrinsic permeability during all steps of the study, and (c) thermal processes dominate after the first water injection, yielding estimates of the thermal properties of the sand and of time-variable key parameters of the kinetic reaction.

Numerical simulation is essential for the prediction and evaluation of hydrocarbon reservoir performance. Numerical simulators developed for the description of the behavior of hydrates under production and the corresponding flow of fluids and heat accounting for all known processes are powerful, but they need validation through comparison to field or experimental data in order to instill confidence in their predictions. In this study, we analyze by means of numerical simulation the results of an experiment of methane hydrate dissociation by thermal stimulation in unconsolidated porous media heated through the vessel walls. The physics captured by the model include multicomponent heat and mass transfer, multiphase flow through porous media, and the phase behavior of the CH4 + H2O system involved in methane hydrate formation and dissociation. The set of governing equations consists of the mass and energy conservation equations coupled with constitutive relationships, i.e., the dissolution of gas in H2O, relative permeability and capillary pressure models, composite thermal conductivity models, and methane hydrate phase equilibria. The model geometry describes accurately the hydrate reactor used in a recent experimental study investigating methane hydrate dissociation behavior [Chong et. al. Appl. Energy 2016, 177, 409-421]. The cumulative gas production is estimated and validated against three tests of experimental data involving different boundary temperatures, showing a good agreement between observations and numerical predictions. The predicted evolution of the spatial distributions of different phases over time shows that hydrate dissociation progresses inward from the reactor boundary to the center, methane gas accumulates to the top of the reactor because of buoyancy, and water migrates down to the bottom of the reactor because of gravity. A sharp hydrate dissociation front is predicted, and the estimated location of hydrate dissociation front suggests a linear relationship with the square root of time. A sensitivity analysis on the thermal conductivity of sand under fully saturated conditions is conducted to elucidate its effect on the gas production behavior. In addition, the energy efficiency ratio computed from the simulation of this boundary-wall heating technique varies from 14.0 to 16.2. Deviations between observations and predictions of the evolution of the temperature profile are attributed to initial heterogeneous distribution of the hydrate phase in the hydrate reactor.

AIMS: To determine the incidence and severity of symptomatic toxoplasma infection presenting during childhood due to congenital or postnatally acquired infection. METHODS: Between 2002 and 2004, newly diagnosed children (<16 years) with signs or symptoms of congenital or ocular toxoplasmosis were reported by clinicians to the British Paediatric and Ophthalmic Surveillance Units or by toxoplasma referral laboratories. Confirmed cases were estimated to have a greater than 50% probability of congenital and/or ocular toxoplasmosis, based on clinical and serological findings. RESULTS: Thirty eight children had confirmed toxoplasma infection. Twenty two (58%) were classified with congenital infection (cumulative incidence for England and Wales 3.4/100,000 live births; 95% CI 2.4 to 4.8), of whom 2 (9%) were stillborn, 7 (32%) live births had intracranial abnormalities and/or developmental delay (5 of whom had retinochoroiditis), and 10 (45%) had retinochoroiditis with no other abnormalities reported. A further 16 (42%) children were classified as infected after birth; all had retinochoroiditis. CONCLUSIONS: The low burden of symptomatic congenital toxoplasmosis combined with the lack of evidence of an effective treatment support current policy not to offer prenatal or neonatal screening for toxoplasma infection. Primary prevention strategies need to address acquisition of infection in childhood which accounts for half the ocular disease due to toxoplasma infection in children in the UK and Ireland. [ABSTRACT FROM AUTHOR]

DNA methylation and mRNA expression correlations are often presented with inconsistent evidence supporting causal regulation. We hypothesized that causal regulatory methylation elements would exhibit heightened demethylation sensitivity. To investigate, we analyzed 20 whole-genomic bisulfite sequenced samples before and after demethylation and identified narrow-width (45-294 bp) elements within a short plateau, termed Methylation Mesa (MM). The Mesa signature was conserved across species and was independent of CpG islands. Mesa also demonstrate high concordance with primed and active histone marks. To assess causality, we developed CRISPR-DiR, a highly precise targeted demethylation technology. Targeted demethylation of a Mesa triggers locus and distal chromatin rewiring events that initiate mRNA expression significantly greater than promoter-CpG island targeting. Thus, Mesa are self-sustaining epigenetic regulatory elements that maintain long-term gene activation through focused demethylation only within the Mesa core, resulting in subsequent histone modifications and chromatin rewiring events that interact with distal elements also marked as Mesas., Competing Interests: Competing interests The authors declare no competing interests for this project.

Pathogenic variants in RAD51C confer an elevated risk of breast and ovarian cancer, while individuals homozygous for specific RAD51C alleles may develop Fanconi anemia. Using saturation genome editing (SGE), we functionally assess 9,188 unique variants, including >99.5% of all possible coding sequence single-nucleotide alterations. By computing changes in variant abundance and Gaussian mixture modeling (GMM), we functionally classify 3,094 variants to be disruptive and use clinical truth sets to reveal an accuracy/concordance of variant classification >99.9%. Cell fitness was the primary assay readout allowing us to observe a phenomenon where specific missense variants exhibit distinct depletion kinetics potentially suggesting that they represent hypomorphic alleles. We further explored our exhaustive functional map, revealing critical residues on the RAD51C structure and resolving variants found in cancer-segregating kindred. Furthermore, through interrogation of UK Biobank and a large multi-center ovarian cancer cohort, we find significant associations between SGE-depleted variants and cancer diagnoses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: There is increasing evidence demonstrating the safety and benefits of physical activity (PA) in uncomplicated pregnancies. Literature has shown that pregnant women around the world do not engage in adequate exercise. This study aims to assess the current practices of exercise among pregnant women in Singapore, determine the proportion of women meeting different PA targets and evaluate the factors influencing the practice of exercise., Methods: In this cross-sectional study, pregnant women in different trimesters of pregnancy from KK Women's and Children's Hospital and Singapore General Hospital were surveyed. Information regarding patient demographics, attitudes and perceptions of exercise, and practice of exercise was collected. The International Physical Activity Questionnaire (IPAQ) was used to determine the amount of PA., Results: A total of 201 pregnant women aged 20-44 years were surveyed. Almost all (99.0%) participants thought that exercise was beneficial in pregnancy. Only 31.6% of them engaged in any moderate or vigorous leisure-time PA (LTPA) and they were active for a median of 120 min/week. Only 12.6% of the pregnant women met the national recommendations of at least 150 min of moderate exercise per week. The amount of total PA performed was lower among women in later trimesters of pregnancy and higher among working mothers., Conclusion: Although most Singaporean pregnant women perceived exercise as beneficial, the majority did not engage in PA. Most of the participants did not meet the international PA targets and recently published national guidelines. More can be done to promote the uptake of exercise in pregnancy and optimise metabolic management of pregnant women in Singapore., (Copyright © 2024 Copyright: © 2024 Singapore Medical Journal.)

Spintronics-based artificial neural networks (ANNs) exhibiting nonvolatile, fast, and energy-efficient computing capabilities are promising neuromorphic hardware for performing complex cognitive tasks of artificial intelligence and machine learning. Early experimental efforts focused on multistate device concepts to enhance synaptic weight precisions, albeit compromising on cognitive accuracy due to their low magnetoresistance. Here, we propose a hybrid approach based on the tuning of tunnel magnetoresistance (TMR) and the number of states in the compound magnetic tunnel junctions (MTJs) to improve the cognitive performance of an all-spin ANN. A TMR variation of 33-78% is controlled by the free layer (FL) thickness wedge (1.6-2.6 nm) across the wafer. Meanwhile, the number of resistance states in the compound MTJ is manipulated by varying the number of constituent MTJ cells ( n = 1-3), generating n + 1 states with a TMR difference between consecutive states of at least 21%. Using MNIST handwritten digit and fashion object databases, the test accuracy of the compound MTJ ANN is observed to increase with the number of intermediate states for a fixed FL thickness or TMR. Meanwhile, the test accuracy for a 1-cell MTJ increases linearly by 8.3% and 7.4% for handwritten digits and fashion objects, respectively, with increasing TMR. Interestingly, a multifarious TMR dependence of test accuracy is observed with the increasing synaptic complexity in the 2- and 3-cell MTJs. By leveraging on the bimodal tuning of multilevel and TMR, we establish viable paths for enhancing the cognitive performance of spintronic ANN for in-memory and neuromorphic computing.

Objective: During COVID-19, governments imposed restrictions that reduced pandemic-related health risks but likely increased personal and societal mental health risk, partly through reductions in household income. This study aimed to quantify the public's willingness to accept trade-offs between pandemic health risks, household income reduction, and increased risk of mental illness that may result from future pandemic-related policies., Methods: A total of 547 adults from an online panel participated in a discrete choice experiment where they were asked to choose between hypothetical future pandemic scenarios. Each scenario was characterized by personal and societal risks of dying from the pandemic, experiencing long-term complications, developing anxiety/depression, and reductions in household income. A latent class regression was used to estimate trade-offs., Results: Respondents state a willingness to make trade-offs across these attributes if the benefits are large enough. They are willing to accept 0.8% lower household income (0.7-1.0), 2.7% higher personal risk of anxiety/depression (1.8-3.6), or 3.2% higher societal rate of anxiety/depression (1.7-4.7) in exchange for 300 fewer deaths from the pandemic., Conclusion: Results reveal that individuals are willing to accept lower household income and higher rates of mental illness, both personal and societal, if the physical health benefits are large enough. Respondents placed greater emphasis on maintaining personal, as opposed to societal, mental health risk and were most interested in preventing pandemic-related deaths. Governments should consider less restrictive policies when pandemics have high morbidity but low mortality to avoid the prospect of improving physical health while simultaneously reducing net social welfare., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)