Residual Stress Engineering for Wire Drawing of Austenitic Stainless Steel X5CrNi18-10 by Variation in Die Geometries-Effect of Drawing Speed and Process Temperature.

As a result of conventional wire-forming processes, the residual stress distribution in wires is frequently unfavorable for subsequent forming processes such as bending operations. High tensile residual stresses typically occur in the near-surface region of the wires and can limit further application and processability of the semi-finished products. This paper presents an approach for tailoring the residual stress distribution by modifying the forming process, especially with regard to the die geometry and the influence of the drawing velocity as well as the wire temperature. The aim is to mitigate the near-surface tensile residual stresses induced by the drawing process. Preliminary studies have shown that modifications in the forming zone of the dies have a significant impact on the plastic strain and deformation direction, and the approach can be applied to effectively reduce the process-induced near-surface residual stress distributions without affecting the diameter of the product geometry. In this first approach, the process variant using three different drawing die geometries was established for the metastable austenitic stainless steel X5CrNi18-10 (1.4301) using slow (20 mm/s) and fast (2000 mm/s) drawing velocities. The residual stress depth distributions were determined by means of incremental hole drilling. Complementary X-ray stress analysis was carried out to analyze the phase-specific residual stresses since strain-induced martensitic transformations occurred close to the surface as a consequence of the shear deformation and the frictional loading. This paper describes the setup of the drawing tools as well as the results of the experimental tests.

Understanding the role of mask-wearing during COVID-19 on the island of Ireland.

Non-pharmaceutical interventions have played a key role in managing the COVID-19 pandemic, but it is challenging to estimate their impacts on disease spread and outcomes. On the island of Ireland, population mobility restrictions were imposed during the first wave, but mask-wearing was not mandated until about six months into the pandemic. We use data on mask-wearing, mobility, and season, over the first year of the pandemic to predict independently the weekly infectious contact estimated by an epidemiological model. Using our models, we make counterfactual predictions of infectious contact, and ensuing hospitalizations, under a hypothetical intervention where 90% of the population wore masks from the beginning of community spread until the dates of the mask mandates. Over periods including the first wave of the pandemic, there were 1601 hospitalizations with COVID-19 in Northern Ireland and 1521 in the Republic of Ireland. Under the counterfactual mask-wearing scenario, we estimate 512 (95% CI 400, 730) and 344 (95% CI 266, 526) hospitalizations in the respective jurisdictions during the same periods. This could be partly due to other factors that were also changing over time.

Estimating time-dependent contact: a multi-strain epidemiological model of SARS-CoV-2 on the island of Ireland.

Mathematical modelling plays a key role in understanding and predicting the epidemiological dynamics of infectious diseases. We construct a flexible discrete-time model that incorporates multiple viral strains with different transmissibilities to estimate the changing patterns of human contact that generates new infections. Using a Bayesian approach, we fit the model to longitudinal data on hospitalisation with COVID-19 from the Republic of Ireland and Northern Ireland during the first year of the pandemic. We describe the estimated change in human contact in the context of government-mandated non-pharmaceutical interventions in the two jurisdictions on the island of Ireland. We take advantage of the fitted model to conduct counterfactual analyses exploring the impact of lockdown timing and introducing a novel, more transmissible variant. We found substantial differences in human contact between the two jurisdictions during periods of varied restriction easing and December holidays. Our counterfactual analyses reveal that implementing lockdowns earlier would have decreased subsequent hospitalisation substantially in most, but not all cases, and that an introduction of a more transmissible variant - without necessarily being more severe - can cause a large impact on the health care burden.

Reductions in serum lipids with a 4-year decline in serum perfluorooctanoic acid and perfluorooctanesulfonic acid.

BACKGROUND: Several epidemiological cross-sectional studies have found positive associations between serum concentrations of lipids and perfluorooctanoic acid (PFOA, or C8). A longitudinal study should be less susceptible to biases from uncontrolled confounding or reverse causality. METHODS: We investigated the association between within-individual changes in serum PFOA and perfluorooctanesulfonic acid (PFOS) and changes in serum lipid levels (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglycerides) over a 4.4-year period. The study population consisted of 560 adults living in parts of Ohio and West Virginia where public drinking water had been contaminated with PFOA. They had participated in a cross-sectional study in 2005-2006, and were followed up in 2010, by which time exposure to PFOA had been substantially reduced. RESULTS: Overall serum concentrations of PFOA and PFOS fell by half from initial geometric means of 74.8 and 18.5 ng/mL, respectively, with little corresponding change in LDL cholesterol (mean increase 1.8%, standard deviation 26.6%). However, there was a tendency for people with greater declines in serum PFOA or PFOS to have greater LDL decrease. For a person whose serum PFOA fell by half, the predicted fall in LDL cholesterol was 3.6% (95% confidence interval = 1.5-5.7%). The association with a decline in PFOS was even stronger, with a 5% decrease in LDL (2.5-7.4%). CONCLUSIONS: Our findings from this longitudinal study support previous evidence from cross-sectional studies of positive associations between PFOA and PFOS in serum and LDL cholesterol.

Comparison between free serum thyroxine levels, measured by analog and dialysis methods, in the presence of perfluorooctane sulfonate and perfluorooctanoate.

Results from animal studies have shown that negative associations between serum levels of free thyroxine (FT4) and perfluorooctane sulfonate (PFOS) at concentrations much higher than those reported for any exposed population may be due to bias in analog methods used for measuring FT4. We aimed to assess if there is evidence of differences between human FT4 measurements in serum by an analog and a dialysis method due to the presence of PFOS or perfluorooctanoate (PFOA) in a population of 50 adults with typical US serum PFOS concentrations but higher PFOA concentrations. Mean analog-dialysis difference was -0.02 (95% CI=-0.06, 0.02). Regressing the difference between FT4 measurements on either PFOA or PFOS serum concentrations yielded slopes close to zero. The present findings do not indicate any observable bias from the use of the analog with respect to the dialysis method, across the range of PFOS and PFOA concentrations in this population.

Heartwatch: the effect of a primary care-delivered secondary prevention programme for cardiovascular disease on medication use and risk factor profiles.

BACKGROUND: Heartwatch is a secondary prevention programme of coronary heart disease (CHD) in primary care in Ireland. The aim was to further examine the effect of the Heartwatch programme on cardiovascular risk factors and treatments of patients with a follow-up of 3.5 years. DESIGN: Prospective cohort study of 12,358 patients with established CHD (myocardial infarction, percutaneous cardiac intervention, coronary artery bypass graft) recruited by participating general practitioners; patients invited to attend on a quarterly basis, with continuing care implemented according to defined clinical protocols. METHODS: Changes in risk factors and treatments at 1, 2, 3 and 3.5-year follow-up from baseline were made using paired t-test for continuous and McNemar's test for categorical data. RESULTS: Important changes in systolic and diastolic blood pressure, total and low-density lipoprotein cholesterol and smoking status were observed at 1, 2, 3 and 3.5 years (P < 0.0001) with significant increase in proportions of patients within the target. However, changes in body mass index were small, with no significant improvement in waist circumference. There was a significant increase in prescription of secondary preventive medications and good patient compliance. Males were more likely to be within the target for systolic blood pressure, total cholesterol, waist circumference and exercise level at 3.5 years, but less likely for body mass index. CONCLUSION: Studies of cardiac rehabilitation without any follow-up programmes show that over time patients revert in part to previous lifestyle habits; this primary care-delivered programme has shown sustained improvements in major risk factors, particularly smoking, blood pressure and cholesterol, and treatments for CHD. Weight management presents a greater challenge.

Stroke associated with atrial fibrillation--incidence and early outcomes in the north Dublin population stroke study.

BACKGROUND: Prospective population-based studies are important to accurately determine the incidence and characteristics of stroke associated with atrial fibrillation (AF), while avoiding selection bias which may complicate hospital-based studies. METHODS: We investigated AF-associated stroke within the North Dublin Population Stroke Study, a prospective cohort study of stroke/transient ischaemic attack in 294,592 individuals, according to recommended criteria for rigorous stroke epidemiological studies. RESULTS: Of 568 stroke patients ascertained in the first year, 31.2% (177/568) were associated with AF (90.4%, i.e. 160/177 ischaemic infarcts). The crude incidence rate of all AF-associated stroke was 60/100,000 person-years (95% CI = 52-70). Prior stroke was almost twice as common in AF compared to non-AF groups (21.9 vs. 12.8%, p = 0.01). The frequency of AF progressively increased across ischaemic stroke patients stratified by increasing stroke severity (NIHSS 0-4, 29.7%; 5-9, 38.1%; 10-14, 43.8%; >or=15, 53.3%, p < 0.0001). The 90-day trajectory of recovery of AF-associated stroke was identical to that of non-AF stroke, but Rankin scores in AF stroke remained higher at 7, 28 and 90 days (p < 0.001 for all). DISCUSSION: AF-associated stroke occurred in one third of all patients and was associated with a distinct profile of recurrent, severe and disabling stroke. Targeted strategies to increase anticoagulation rates may provide a substantial benefit to prevent severe disabling stroke at a population level.

A non-synonymous variant in ADH1B is strongly associated with prenatal alcohol use in a European sample of pregnant women.

Pregnant women are advised to abstain from alcohol despite insufficient evidence on the fetal consequences of moderate prenatal alcohol use. Mendelian randomization could help distinguish causal effects from artifacts due to residual confounding and measurement errors; however, polymorphisms reliably associated with alcohol phenotypes are needed. We aimed to test whether alcohol dehydrogenase (ADH) gene variants were associated with alcohol use before and during pregnancy. Ten variants in four ADH genes were genotyped in women from South-West England. Phenotypes of interest were quantity and patterns of alcohol consumption before and during pregnancy, including quitting alcohol following pregnancy recognition. We tested single-locus associations between genotypes and phenotypes with regression models. We used Bayesian models (multi-locus) to take account of linkage disequilibrium and reanalyzed the data with further exclusions following two conservative definitions of 'white ethnicity' based on the woman's reported parental ethnicity or a set of ancestry-informative genetic markers. Single-locus analyses on 7410 women of white/European background showed strong associations for rs1229984 (ADH1B). Rare allele carriers consumed less alcohol before pregnancy [odds ratio (OR) = 0.69; 95% confidence interval (CI): 0.56-0.86, P = 0.001], were less likely to have 'binged' during pregnancy (OR = 0.55, 95% CI: 0.38-0.78, P = 0.0009), and more likely to have abstained in the first trimester of gestation (adjusted OR = 1.42, 95% CI: 1.12-1.80, P = 0.004). Multi-locus models confirmed these results. Sensitivity analyses did not suggest the presence of residual population stratification. We confirmed the established association of rs1229984 with reduced alcohol consumption over the life-course, contributing new evidence of an effect before and during pregnancy.

Role of p21(WAF1/CIP1) as an attenuator of both proliferative and drug-induced apoptotic signals in BCR-ABL-transformed hematopoietic cells.

The constitutive tyrosine kinase activity of the BCR-ABL fusion protein plays a crucial role in the pathogenesis of chronic myeloid leukemia and promotes growth factor-independent survival of hematopoietic cells. In 32D cells, expression levels of retrovirally transduced BCR-ABL were positively correlated with the levels of the cell cycle regulator protein p21, and this upregulation of p21 expression depended on the kinase activity of BCR-ABL. To assess the role of p21 on BCR-ABL-positive hematopoietic cells, we compared proliferation and drug-induced apoptosis in bone marrow (BM) cells from wild-type and p21 knockout mice after retroviral transfer of the BCR-ABL fusion gene. As compared with wild-type cells, p21 knockout cells showed increased proliferation, suggesting that p21 acted as an attenuator of BCR-ABL-mediated cell proliferation. In marked contrast, deletion of p21 promoted apoptosis induction by imatinib and taxol in BCR-ABL-transformed BM cells. These findings demonstrate that p21 has a dual function in BCR-ABL-transformed murine BM cells: It attenuates the effects of two apparently opposed phenomena such as BCR-ABL-mediated cell proliferation and drug-induced apoptosis. This dual function of p21 calls for a cautious evaluation of the suitability of p21 as a secondary target in anticancer therapy.

A review of studies of adherence with antihypertensive drugs using prescription databases.

Poor adherence with antihypertensive therapies is a major factor in the low rates of blood pressure control among people with hypertension. Patient adherence is influenced by a large number of interacting factors but their exact impact is not well understood, partly because it is difficult to measure adherence. Longitudinal prescription data can be used as a measure of drug supply and are particularly useful to identify interruptions and changes of treatment. Obtaining a medicine does not ensure its use; however, it has been established that continuous collection of prescription medications is a useful marker of adherence. We found 20 studies published in the last 10 years that used large prescription databases to investigate adherence with antihypertensive therapies. These were assessed in terms of patient selection, the definition of the adherence outcome(s), and statistical modeling. There was large variation between studies, limiting their comparability. Particular methodological problems included: the failure to identify an inception cohort, which ensures baseline comparability, in four studies; the exclusion of patients who could not be followed up, which results in a selection bias, in 17 studies; failure to validate outcome definitions; and failure to model the discrete-time structure of the data in all the studies we examined. Although the data give repeated measurements on patients, none of the studies attempted to model patient-level variability. Studies of such observational data have inherent limitations, but their potential has not been fully realized in the modeling of adherence with antihypertensive drugs. Many of the studies we reviewed found high rates of nonadherence to antihypertensive therapies despite differences in populations and methods used. Adherence rates from one database ranged from 34% to 78% at 1 year. Some studies found women had better adherence than men, while others found the reverse. Novel approaches to analyzing data from such databases are required to use the information available appropriately and avoid the problems of bias.

Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases.

The leukemogenic tyrosine kinase Bcr-Abl contains a highly conserved inhibitor-binding pocket (IBP), which serves as a binding site for imatinib mesylate. Mutations at the IBP may lead to resistance of the Abl kinase against imatinib mesylate. To examine the mechanisms of imatinib mesylate binding and resistance in more detail, we created several point mutations at amino acid positions 315 and 380 of Abl, blocking the access to the IBP and rendering Bcr-Abl imatinib mesylate-resistant. Moreover, introduction of a mutation destabilizing the inactive conformation of Abl (Asp276Ser/Glu279Ser) also led to imatinib mesylate resistance, suggesting that the inhibitor required inactivation of the kinase prior to binding. These Bcr-Abl mutants were then used to evaluate the binding mode and specificity of 2 compounds, PP1 and CGP76030, originally characterized as Src kinase inhibitors. Both compounds inhibited Bcr-Abl in a concentration-dependent manner by overlapping binding modes. However, in contrast to imatinib mesylate, PP1 and CGP76030 blocked cell growth and survival in cells expressing various inhibitor-resistant Abl mutants. Studies on the potential signaling mechanisms demonstrated that in cells expressing inhibitor-resistant Bcr-Abl mutants, PP1 and CGP76030 inhibited the activity of Src family tyrosine kinases and Akt but not signal transducer and activator of transcription-5 (STAT5) and JUN kinase (Jnk). The results suggest that the use of Src kinase inhibitors is a potential strategy to prevent or overcome clonal evolution of imatinib mesylate resistance in Bcr-Abl(+) leukemia.

The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate.

The clinical progression of chronic myeloid leukemia (CML) from chronic phase to blast crisis is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes. This study was undertaken to investigate the influence of Bcr-Abl and of the small molecule Abl tyrosine-kinase inhibitor imatinib mesylate on granulocyte colony-stimulating factor (G-CSF)-induced neutrophilic differentiation. We show that differentiation of 32Dcl3 cells into mature granulocytes is accompanied by the increased expression of the antigens macrophage adhesion molecule-1 (Mac-1) and Gr-1, of the G-CSF receptor (G-CSFR), of myeloid transcription factors (CCAAT/enhancer-binding protein-alpha [C/EBPalpha], C/EBPepsilon, and PU.1), and of the cyclin-dependent kinase inhibitor p27(Kip1). In 32Dcl3 cells transfected with the bcr-abl gene (32D(Bcr-Abl)), G-CSF did not trigger either granulocytic differentiation or the up-regulation of C/EBPalpha, C/EBPepsilon, and the G-CSFR. This could be correlated to a defect in c-Myc down-regulation. In contrast, the up-regulation of PU.1 and p27(Kip1) by G-CSF was not affected by Bcr-Abl. Importantly, incubation of 32D(Bcr-Ablwt) cells with the kinase inhibitor imatinib mesylate prior to G-CSF stimulation completely neutralized the effects of Bcr-Abl on granulocytic differentiation and on C/EBPalpha and C/EBPepsilon expression. Taken together, the results suggest that the Bcr-Abl kinase induces a reversible block of the granulocytic differentiation program in myeloid cells by disturbing regulation of hematopoietic transcription factors such as C/EBPalpha and C/EBPepsilon.