Magneto-hydrodynamics of multi-phase flows in heterogeneous systems with large property gradients.

The complex interplay between thermal, hydrodynamic, and electromagnetic, forces governs the evolution of multi-phase systems in high technology applications, such as advanced manufacturing and fusion power plant operation. In this work, a new formulation of the time dependent magnetic induction equation is fully coupled to a set of conservation laws for multi-phase fluid flow, energy transport and chemical species transport that describes melting and solidification state transitions. A finite-volume discretisation of the resulting system of equations is performed, where a novel projection method is formulated to ensure that the magnetic field remains divergence free. The proposed framework is validated by accurately replicating a Hartmann flow profile. Further validation is performed through correctly predicting the experimentally observed trajectory of Argon bubbles rising in a liquid metal under varying applied magnetic fields. Finally, the applicability of the framework to technologically relevant processes is illustrated through the simulation of an electrical arc welding process between dissimilar metals. The proposed framework addresses an urgent need for numerical methods to understand the evolution of multi-phase systems with large electromagnetic property contrast.

Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study.

BACKGROUND: Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth. METHODS AND FINDINGS: In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08-0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24-0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11-0.90, p = 0.031 and 0.53, 0.28-0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics. CONCLUSIONS: Preconceptional folate supplementation is associated with a 50%-70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.

Phase-Field Simulation of Grain Boundary Evolution In Microstructures Containing Second-Phase Particles with Heterogeneous Thermal Properties.

Understanding the interaction between complex thermal fields and metallic structures at the meso-scale is crucial for the prediction of microstructural evolution during thermomechanical processing. The competitive growth of crystal grains, driven by thermodynamic forces at the grain boundaries, is one of the most fundamental phenomena in metallurgy and solid state physics. The presence of second phase particles, which act as pinning sites for boundaries, drastically alters the coarsening behaviour of the system; particularly when considering that these particles have different thermal properties to the primary phase. In this work a multi-phase field model, incorporating thermal gradient and curvature driving forces, is used to predict grain growth in a Ti6Al4V alloy system with second phase particle inclusions representative of oxide and carbide precipitates. The multi-phase field framework is fully coupled to the heat equation. The incorporation of the thermal gradient driving force enables the detailed behaviour of the grain boundaries around the particles to be predicted. It is shown that the inclusion of particles with a lower thermal conductivity has a significant influence on the coarsening behaviour of various systems of grains, due to the combined effects of thermal shielding and the generation of thermal gradient driving forces between the boundaries and pinning particles.

Straight-to-test for the two-week-wait colorectal cancer pathway under the updated NICE guidelines reduces time to cancer diagnosis and treatment.

INTRODUCTION: The 2015 National Institute for Health and Care Excellence guidelines widened the referral criteria for the two-week-wait pathway for suspected lower gastrointestinal cancer. We implemented a straight-to-test protocol to accommodate the anticipated increase in referrals. We evaluated the impact of these changes for relevant pathway metrics and clinical outcomes using a retrospective cohort study with historic controls. MATERIALS AND METHODS: We analysed data from all patients referred to a teaching hospital via the two-week-wait pathway for suspected lower gastrointestinal cancer under the previous guidelines between 1 March and 31 August 2015 compared with the same period in 2016, when the updated guidelines and straight-to-test protocol had been implemented. RESULTS: In the 2015 cohort, there were 64 cancer diagnoses from 664 referrals (9.6% pick-up) compared with 58 cancer diagnoses from 954 referrals in the 2016 cohort (6.1% pick-up). Our straight-to-test protocol reduced the median time to cancer diagnosis by 12.5 days (P < 0.001) and reduced the median time to cancer treatment by 7.5 days (P < 0.05) An increased proportion of non-colorectal cancers were diagnosed in 2016 compared with 2015, (37.9% vs 17.2%, P < 0.05) and more adenomas were removed in 2016 compared with 2015 (377 vs 193). DISCUSSION AND CONCLUSION: Our straight-to-test protocol has resulted in a reduction in times to cancer diagnosis and cancer treatment, despite an increase in the number of referrals. The new referral criteria have considerable resource implications, but their implementation did not result in an increase in the total number of cancers diagnosed.

Linkage study between manic-depressive illness and chromosome 21.

Chromosome 21, of interest as potentially containing a disease gene for manic-depressive illness as possible evidence for a gene pre-disposing to affective disorder, has recently been reported in a single large family as well as samples of families. The present study investigates for linkage between manic-depressive illness and markers covering the long arm of chromosome 21 in two manic-depressive families, using ten microsatellite polymorphisms as markers. No conclusive evidence for a disease gene on the long arm of chromosome 21 was found. Assuming either a dominant or recessive mode of inheritance, close linkage to the marker PFKL, which has been reported as possibly linked to affective disorder, seems unlikely in the families studied here. PFKL and more telomeric markers yielded small positive lod scores at higher recombination fractions in the largest family, and small positive lod scores at lower recombination fractions in the affected-only analyses in the smallest family.

Linkage analysis between manic-depressive illness and markers on the long arm of chromosome 11.

The long arm of chromosome 11 is one of the most interesting regions in the search for major genes involved in the etiology of manic-depressive illness. Several candidate genes have been identified, including the gene encoding the dopamine D2 receptor, the M1 muscarinic receptor, and porfobillinogen deaminase. Furthermore, different families with co-segregation of psychiatric illness and structural chromosome abnormalities involving regions 11q21, 11q22.3, and 11q25 have been reported. Using narrow as well as broad phenotypic models, conservative genetic parameters, models with dominant or recessive modes of inheritance, and various methods to reduce misclassification, the present study did not find evidence for a major gene causing manic-depressive illness on the long arm of chromosome 11. In the broader phenotypic models multi-point analyses excluded at least 11q14 to 11q23.3, approximately 60 cM, even in one large family. Assuming homogeneity close linkage to DRD2 was excluded for all dominant models, and also in the affecteds-only analyses in the large family alone.

Characterization of deletions in the dystrophin gene giving mild phenotypes.

We have characterized deletions of the dystrophin gene in patients suffering from relatively mild muscular dystrophy. Our data show that most of the Becker muscular dystrophy (BMD) patients have intragenic deletions which leave the protein reading frame in phase. Remarkably, large deletions of the region corresponding to the central triple helical repeats in the protein can result in an exceptionally mild phenotype. Three brothers suffering from BMD, glycerol kinase deficiency, and adrenal hypoplasia possess a deletion at the 3' end of the gene. They also display developmental delay. Thus the 3' processing of the gene must be necessary for the correct function of the dystrophin molecule.

Search for common haplotypes on chromosome 22q in patients with schizophrenia or bipolar disorder from the Faroe Islands.

Chromosome 22q may harbor risk genes for schizophrenia and bipolar affective disorder. This is evidenced through genetic mapping studies, investigations of cytogenetic abnormalities, and direct examination of candidate genes. Patients with schizophrenia and bipolar affective disorder from the Faroe Islands were typed for 35 evenly distributed polymorphic markers on 22q in a search for shared risk genes in the two disorders. No single marker was strongly associated with either disease, but five two-marker segments that cluster within two regions on the chromosome have haplotypes occurring with different frequencies in patients compared to controls. Two segments were of most interest when the results of the association tests were combined with the probabilities of identity by descent of single haplotypes. For bipolar patients, the strongest evidence for a candidate region harboring a risk gene was found at a segment of at least 1.1 cM including markers D22S1161 and D22S922 (P=0.0081 in the test for association). Our results also support the a priori evidence of a susceptibility gene to schizophrenia at a segment of at least 0.45 cM including markers D22S279 and D22S276 (P=0.0075). Patients were tested for the presence of a missense mutation in the WKL1 gene encoding a putative cation channel close to segment D22S1161--D22S922, which has been associated with schizophrenia. We did not find this mutation in schizophrenic or bipolar patients or the controls from the Faroe Islands.

Exclusion of linkage between manic depressive illness and tyrosine hydroxylase and dopamine D2 receptor genes.

Mutations at the tyrosine hydroxylase or dopamine D2 receptor loci causing manic depressive illness are unlikely in two families reported here. Linkage was excluded for both loci assuming a dominant mode of transmission and for the tyrosine hydroxylase locus also assuming a recessive mode of transmission. The exclusion was significant using models based on severity of psychopathology and a model requiring severe illness also in first-degree relatives. Conservative genetic parameters were used to minimize misclassification.

Linkage analysis between manic depressive illness and the region on chromosome 12q involved in Darier's disease.

Co-segregation between Darier's disease and manic depressive illness has been reported. A gene causing Darier's disease has recently been mapped to chromosome 12q23-q24.1, and this region may thus be considered a candidate region potentially containing a gene involved in the aetiology of manic depressive illness. At least one possible candidate gene for manic depressive illness, pro-melanin-concentrating hormone, is located on chromosome 12q23-q24. The present study investigated linkage between manic depressive illness and this region on chromosome 12q, using three microsatellite polymorphisms as genetic markers which flank the gene causing Darier's disease. For all dominant models close linkage was excluded. For broader phenotypic models linkage was excluded in the interval between markers, even in one large family alone.

Linkage analysis between manic depressive illness and the dopamine beta-hydroxylase gene.

The dopamine beta-hydroxylase (DBH) gene is a candidate gene in manic depressive illness. DBH is required for conversion of dopamine to norepinephrine, the third step in catecholamine biosynthesis. A few earlier linkage studies have found low to moderately positive lod scores in manic depressive families for ABO which is closely linked to DBH. Based on several studies an association between manic depressive illness and ABO blood type has been suggested. Mutations at the DBH locus might thus be involved in the etiology of manic depressive illness in some families. The DBH gene is reported here as unlikely to be a major gene causing manic depressive illness in a large family. Linkage was excluded assuming a dominant mode of transmission. Several methods were used to minimize misclassification.

No evidence of linkage between manic depressive illness and the dopa decarboxylase gene or nearby region on chromosome 7p.

Dopa decarboxylase (DDC) is involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. The present study investigated two Danish families for linkage between manic depressive illness, a marker at the DDC locus which has been mapped to 7p11-p13 and 10 microsatellite markers covering chromosome 7q11-p15. No evidence of linkage was found assuming a dominant or a recessive mode of inheritance. We have earlier reported evidence against linkage between manic depressive illness and tyrosine hydroxylase and dopamine beta-hydroxylase. Mutations of major importance in the genes encoding the three enzymes involved in the synthesis of dopamine and noradrenaline seem less likely in the families we have studied. Further investigations of genetic and other pathophysiological mechanisms in relation to the monoamine hypotheses for manic depressive illness are still of relevance. There is a need for further linkage and association studies as well as a search for possible mutations in the relevant genes involved in the monoaminergic pathways to clarify their possible role in the aetiology of manic depressive illness.

A possible locus for manic depressive illness on chromosome 16p13.

We have previously reported possible evidence for linkage between manic depressive illness and the locus at 16p13.3 encoding the enzyme phosphoglycolate phosphatase (PGP), in the larger of two Danish families. As PGP was not fully informative, 12 additional DNA markers were tested in these families to clarify if a gene involved in the etiology of manic depressive illness might be located on chromosome 16p13. Though not reaching a lod score level of 3.0, the possible presence of a disease gene for manic depressive illness on chromosome 16p13 was still suggested. The evidence for a dominant locus near PGP was weakened. However, when assuming a recessive mode of inheritance and including both families a two-point lod score of 2.52 was found for marker D16S510, and a three-point lod score of 2.65 in both families combined and 2.29 in the large family alone was obtained in the same area. Simulations indicated that lod scores as obtained for several markers in the large family alone, would occur only rarely with an unlinked marker.

A functional variant of the serotonin transporter gene in families with bipolar affective disorder.

BACKGROUND: The serotonin transporter protein (SERT) reuptakes serotonin from synapses and has been implied as the site of therapeutic action of many antidepressant drugs. SERT is one of the most relevant candidate genes for bipolar affective disorder. Recently a functionally important 44 basepair deletion in the regulatory region of the SERT gene was described. Association between this variant and affective disorder has been suggested. METHODS: The present study analysed this variation and another variation in the SERT gene and nearby DNA markers in order to test for linkage between SERT and bipolar affective disorder in two Danish families. RESULTS AND CONCLUSION: There was no evidence that variants in the SERT gene were a stronger dominant disease gene for the development of affective disorder in the families. The possibility of a recessive disease gene at or near SERT could not be excluded. LIMITATIONS: The present study cannot exclude if variations at or near the SERT gene were weak susceptibility genes or determine if they are important for other characteristics than presence or absence of disease. CLINICAL RELEVANCE: Further studies of the SERT gene in affective and other disorders, as well as in relation to treatment response to antidepressants are needed.

The application of eight reported temperature-based algorithms to calculate the postmortem interval.

There exist numerous temperature-based techniques to calculate the early postmortem interval of human corpses. This paper presents eight commonly used time of death algorithms and describes how they were applied to eight corpses.

The use of either the nose or outer ear as a means of determining the postmortem period of a human corpse.

Presented in this paper are the initial results involving the use of the nose or outer ear as temperature measurement sites to determine the postmortem period of the human corpse. Simple mathematical models for both sites are developed based on cooling curves of five corpses. Analysis of errors between actual and calculated postmortem intervals suggest that in its present form, the described methods would not be suitable for use in accurately determining the time since death of human corpses.

Investigations into the analysis of the rate of decay of the compound action potentials recorded from the rat sciatic nerve after death: significance for the prediction of the post-mortem period.

There have been a number of papers that have reported the investigations of electrical stimulation of muscle groups in order to determine the post-mortem period. To the authors knowledge, no techniques have been described that analyse the compound action potentials (CAP) of various nerve fibre groups after death. This paper reports the monitoring of both the amplitude and latency changes of the CAP recorded from a stimulated rat sciatic nerve after death. Initial results suggest that the method my be useful in determining the early post-mortem period within 1 or 2 h after death. It may also be of use in measuring nerve conduction delay in various pathological conditions that can affect the neural network; for example diabetes.

Multifocal bullous emphysema with concurrent bronchial hypoplasia in two aged Afghan hounds.

Multiple scattered foci of bullous emphysema were detected in the lungs of two aged Afghan Hounds. The affected parenchyma contained bronchi with rudimentary cartilage and small smooth muscle bundles. The bronchi were generally lined by cuboidal epithelium. The animals were generally asymptomatic throughout their entire lives. One, the female, developed dyspnoea and tachypnoea terminally, following the rupture of two bullae.