Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Transmission potential of Mayaro virus in Florida Aedes aegypti and Aedes albopictus mosquitoes.

Mayaro virus (MAYV) is an emerging mosquito-borne arbovirus present in Central and South America that causes arthralgia and febrile illness. Domestic mosquitoes Aedes aegypti (Diptera: Culicidae) and Aedes albopictus are potential vectors of MAYV that may allow for transmission to humans in urban settings. The present paper assesses susceptibility to infection, disseminated infection and transmission potential in Florida Ae. aegypti and Ae. albopictus for MAYV. Oral infection was significantly higher in Ae. albopictus (85-100%) than in Ae. aegypti (67-82%). Viral dissemination to the haemocoel in Ae. aegypti and Ae. albopictus mosquitoes was rapid and co-occurred with infection of the salivary glands. Rates of disseminated infection were generally higher in Ae. aegypti (45-85%) than in Ae. albopictus (38-76%), although the difference was significant only at 9 days after feeding on MAYV-infected blood. Both mosquito species exhibited low rates of MAYV infection in saliva expectorates. Viral titres in the bodies of mosquitoes increased in line with the number of days post-blood feeding and were higher in Ae. aegypti than in Ae. albopictus. Although Florida mosquito vectors have the potential to transmit MAYV and thus to initiate an urban cycle after having fed on higher titres of MAYV-infected blood, lower viraemia in infected humans is likely to limit transmission potential.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

Cross-sectional association of endogenous steroid hormone, sex hormone-binding globulin, and precursor steroid levels with hemostatic factor levels in postmenopausal women.

Essentials Endogenous hormone levels' influence on hemostatic factor levels is not fully characterized. We tested for associations of endogenous hormone with hemostatic factor levels in postmenopause. Estrone levels were inversely associated with the natural anticoagulant, protein S antigen. Dehydroepiandrosterone sulfate levels were inversely associated with thrombin generation. SUMMARY: Background Oral use of exogenous estrogen/progestin alters hemostatic factor levels. The influence of endogenous hormones on these levels is incompletely characterized. Objectives Our study aimed to test whether, among postmenopausal women, high levels of estradiol (E2), estrone (E1), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), and androstenedione, and low levels of sex hormone-binding globulin (SHBG), are positively associated with measures of thrombin generation (TG), a normalized activated protein C sensitivity ratio (nAPCsr), and factor VII activity (FVIIc), and negatively associated with antithrombin activity (ATc) and total protein S antigen (PSAg). Methods This Heart and Vascular Health study cross-sectional analysis included 131 postmenopausal women without a prior venous thrombosis who were not currently using hormone therapy. Adjusted mean differences in TG, nAPCsr, FVIIc, ATc and PSAg levels associated with differences in hormone levels were estimated using multiple linear regression. We measured E2, E1, total T, DHEAS, DHEA and androstenedione levels by mass spectrometry, SHBG levels by immunoassay, and calculated the level of free T. Results One picogram per milliliter higher E1 levels were associated with 0.24% lower PSAg levels (95% Confidence Interval [CI]: -0.35, -0.12) and 1 µg mL-1 higher DHEAS levels were associated with 40.8 nm lower TG peak values (95% CI: -59.5, -22.2) and 140.7 nm×min lower TG endogenous thrombin potential (ETP) (95% CI: -212.1, -69.4). After multiple comparisons correction, there was no evidence for other associations. Conclusions As hypothesized, higher E1 levels were associated with lower levels of the natural anticoagulant PSAg. Contrary to hypotheses, higher DHEAS levels were associated with differences in TG peak and ETP that suggest less generation of thrombin.

The association of statin therapy with the risk of recurrent venous thrombosis.

UNLABELLED: Essentials A lowered risk of recurrent venous thrombosis (VT) with statin treatment is controversial. Among observational inception cohort of 2,798 adults with incident VT, 457 had recurrent VT. Time-to-event models with time-varying statin use and adjustment for potential confounders was used for analysis. Compared to nonuse, current statin use was associated with 26% lower risk of recurrent VT. Click to hear Prof. Büller's perspective on Anticoagulant Therapy in the Treatment of Venous Thromboembolism SUMMARY: Background Meta-analyses of randomized controlled trials suggest that treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) lowers the risk of incident venous thrombosis (VT), particularly among those without prevalent clinical cardiovascular disease (CVD). Whether this is true for the prevention of recurrent VT is debated. We used an observational inception cohort to estimate the association of current statin use with the risk of recurrent VT. Methods and Results The study setting was a large healthcare organization with detailed medical record and pharmacy information at cohort entry and throughout follow-up. We followed 2798 subjects 18-89 years of age who experienced a validated incident VT between January 1, 2002, and December 31, 2010, for a first recurrent VT, validated by medical record review. During follow-up, 457 (16%) developed a first recurrent VT. In time-to-event models incorporating time-varying statin use and adjusting for potential confounders, current statin use was associated with a 26% lower risk of recurrent VT: hazard ratio 0.74, 95% confidence interval 0.59-0.94. Among cohort members free of CVD (n = 2134), current statin use was also associated with a lower risk (38%) of recurrent VT: hazard ratio 0.62, 95% confidence interval 0.45-0.85. We found similar results when restricting to new users of statins and in subgroups of different statin types and doses. Conclusions In a population-based cohort of subjects who had experienced an incident VT, statin use, compared with nonuse, was associated with a clinically relevant lower risk of recurrent VT. These findings suggest a potential secondary benefit of statins among patients who have experienced an incident VT.

Case-control study of second-line therapies for type 2 diabetes in combination with metformin and the comparative risks of myocardial infarction and stroke.

We conducted a population-based case-control study to assess the myocardial infarction (MI) and stroke risks associated with sulphonylureas and insulin when used in combination with metformin. Cases had type 2 diabetes and used metformin + insulin or metformin + sulphonylureas at the time of a first MI or first stroke between 1995 and 2010; controls used the same treatment combinations and were randomly sampled from the same population. MI and stroke diagnoses and potential confounders were validated by medical record reviews. Compared with metformin + sulphonylurea, metformin + insulin was associated with similar risks of MI or stroke [odds ratio 0.98 (95% confidence interval 0.63-1.52)]. Meta-analysis with another observational study improved the precision of the risk estimate [relative risk 0.92 (95% confidence interval 0.69-1.24)]. Current evidence suggests that there may not be large differences in cardiovascular risk associated with the use of insulin or sulphonylureas when used in combination with metformin.

Differential associations of oral estradiol and conjugated equine estrogen with hemostatic biomarkers.

BACKGROUND: The risk of venous thrombosis (VT) associated with oral hormone therapy (HT) may differ by type of estrogen compound. OBJECTIVE: To compare the thrombotic profile of women using oral conjugated equine estrogens (CEE) with that of women using oral estradiol (E2). METHODS: In postmenopausal, female, health maintenance organization (HMO) members with no history of VT, we measured thrombin generation, levels of factor VII activity, antithrombin activity and total protein S antigen. Mean levels of hemostasis biomarkers were cross-sectionally compared by use and type of estrogen using multiple linear regressions. The type of estrogen used was determined primarily by the HMO formulary, which changed its preferred estrogen from CEE to E2 during the study period. RESULTS: The sample included 92 E2 users and 48 CEE users, with a mean age of 64.1 years and mean BMI of 29.1 kg m(-2) . Twenty-seven per cent of HT contained medroxyprogesterone acetate. Compared with E2 users, CEE users had greater thrombin generation peak values and endogenous thrombin potential, and lower total protein S (multivariate adjusted differences of 49.8 nm (95% CI, 21.0, 78.6), 175.0 nm × Min (95% CI, 54.4, 295.7) and -13.4% (95% CI, -19.8, -6.9), respectively). Factor VII and antithrombin levels were not different between E2 and CEE users. Results were similar in subgroups of users of unopposed HT, opposed HT, low-dose estrogen and standard dose estrogen. CONCLUSION: The hemostatic profile of women using CEE is more prothrombotic than that of women using E2. These findings provide further evidence for a different thrombotic risk for oral CEE and oral E2.

The association of smoking with venous thrombosis in women. A population-based, case-control study.

The evidence for an association between smoking and venous thrombosis (VT) is inconsistent, and its mediation pathways remain to be fully elucidated. A population-based, case-control study was conducted in a large, integrated healthcare system in Washington State, USA. Cases were women aged 18-90 years who experienced a validated incident deep-vein thrombosis or pulmonary embolism between January 1, 1995, and December 31, 2009. Controls were randomly selected from members of the healthcare system. Smoking status (current, former, never) was assessed from medical records review and, for a subset, also by telephone interview. Multivariable logistic regression was used to estimate odds ratios (OR) associated with smoking status. We identified 2,278 cases and 5,927 controls. Subjects comprised mostly postmenopausal white women with a mean age of 66 years and a current smoking prevalence of 10%. Compared to never-smokers, current and former smokers were at higher risk of VT (adjusted OR 1.21, 95% confidence interval [CI] 1.02-1.44 and OR 1.15, 95%CI 1.03-1.29, respectively). These associations were attenuated with further adjustment for potential mediators (cardiovascular disease, congestive heart failure, cancer, recent hospitalisations and physical activity): OR 1.02 (95%CI 0.83-1.25) and 0.95 (95%CI 0.83-1.08), respectively. In conclusion, the modestly increased risk of VT in women who are current or former smokers might be explained by the occurrence of smoking-related diseases and decreased physical activity. Our results do not support a direct biological effect of smoking on the risk of VT that is clinically relevant.

Raman spectroscopy and microspectrophotometry of reactive dyes on cotton fibres: analysis and detection limits.

A collaborative study on Raman spectroscopy and microspectrophotometry (MSP) was carried out by members of the ENFSI (European Network of Forensic Science Institutes) European Fibres Group (EFG) on different dyed cotton fabrics. The detection limits of the two methods were tested on two cotton sets with a dye concentration ranging from 0.5 to 0.005% (w/w). This survey shows that it is possible to detect the presence of dye in fibres with concentrations below that detectable by the traditional methods of light microscopy and microspectrophotometry (MSP). The MSP detection limit for the dyes used in this study was found to be a concentration of 0.5% (w/w). At this concentration, the fibres appear colourless with light microscopy. Raman spectroscopy clearly shows a higher potential to detect concentrations of dyes as low as 0.05% for the yellow dye RY145 and 0.005% for the blue dye RB221. This detection limit was found to depend both on the chemical composition of the dye itself and on the analytical conditions, particularly the laser wavelength. Furthermore, analysis of binary mixtures of dyes showed that while the minor dye was detected at 1.5% (w/w) (30% of the total dye concentration) using microspectrophotometry, it was detected at a level as low as 0.05% (w/w) (10% of the total dye concentration) using Raman spectroscopy. This work also highlights the importance of a flexible Raman instrument equipped with several lasers at different wavelengths for the analysis of dyed fibres. The operator and the set up of the analytical conditions are also of prime importance in order to obtain high quality spectra. Changing the laser wavelength is important to detect different dyes in a mixture.

A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.

An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8.

The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial.

Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.

Ciprofloxacin-sensitive and ciprofloxacin-resistant Campylobacter jejuni are equally susceptible to natural orange oil-based antimicrobials.

A total of 10 ciprofloxacin-sensitive (ciprofloxacin minimum inhibitory concentration, MIC < 0.5 micro g/ml) and 10 ciprofloxacin-resistant (MIC 16 to 32 micro g/ml) presumptive C. jejuni were further characterized and evaluated for their inhibition by natural orange oil fractions. Partial species identification was performed by using a hippuricase gene-based polymerase chain reaction (PCR) assay. One of the isolates appeared to be atypical and failed to hydrolyze hippurate. Of the ciprofloxacin-resistant C. jejuni isolates tested, six were found to have their quinolone resistance determined by a C --> T mutation in codon 86 of gyrA. Both groups of ciprofloxacin-sensitive and -resistant C. jejuni isolates were most susceptible to cold-pressed terpeneless Valencia orange oil (C4) which yielded inhibition zones from 44.0 +/- 1.4 to 80 +/- 0.0 mm. Less inhibitory responses were recorded for 5-fold concentrated Valencia orange oil (C3) and distilled d-limonene (C7) which exerted similar effects on both ciprofloxacin-sensitive and -resistant C. jejuni isolates. In general, ciprofloxacin-resistant and -sensitive C. jejuni isolates were equally susceptible to the respective orange oil fractions.

ABO genotype and risk of thrombotic events and hemorrhagic stroke.

BACKGROUND: The non-O alleles of the ABO genotype have been associated with an increased risk of thrombosis. Risk associated with the specific A(1), A(2) or B alleles is not well defined. OBJECTIVES: To examine the association of the ABO genotype with myocardial infarction (MI), ischemic stroke, hemorrhagic stroke, and venous thrombosis (VT). PATIENTS AND METHODS: We used data from two ongoing population-based case-control studies of MI, stroke, and VT. Cases included hypertensive adults and postmenopausal women with incident non-fatal MI (n = 1063), ischemic stroke (n = 469), and hemorrhagic stroke (n = 91), and postmenopausal women with incident non-fatal VT (n = 504). Controls were frequency matched to cases on age, sex, hypertension status, and year of identification. ABO genotypes were determined using single-nucleotide polymorphisms, and subjects were grouped by diplotype according to the presence of O(1), O(2), A(11), A(2) and B alleles. Logistic regression was used to test the association of diplotypes with risk of each outcome. RESULTS: As compared with the O(1)O(1) group, the A(11) allele was associated with an increased risk of VT [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.41-2.26] and MI (OR 1.23; 95% CI 1.05-1.44). The B allele was associated with an increased risk of VT (OR 1.82; 95% CI 1.29-2.57) and ischemic stroke (OR 1.59; 95% CI 1.17-2.17). The AB diplotype category was associated with a 2.7-fold risk of VT (OR 2.70; 95% CI 1.73-4.21). No other associations reached significance. CONCLUSIONS: The VT and MI findings are confirmatory, and the ischemic stroke finding with the B allele is a novel finding and needs replication.

Treatment for peritoneal dialysis-associated peritonitis.

BACKGROUND: Peritonitis is a common complication of peritoneal dialysis (PD) and is associated with significant morbidity. Adequate treatment is essential to reduce morbidity and recurrence. OBJECTIVES: To evaluate the benefits and harms of treatments for PD-associated peritonitis. SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE and reference lists without language restriction. Date of search: February 2005 SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs assessing the treatment of peritonitis in peritoneal dialysis patients (adults and children) evaluating: administration of an antibiotic(s) by different routes (e.g. oral, intraperitoneal, intravenous); dose of an antibiotic agent(s); different schedules of administration of antimicrobial agents; comparisons of different regimens of antimicrobial agents; any other intervention including fibrinolytic agents, peritoneal lavage and early catheter removal were included. DATA COLLECTION AND ANALYSIS: Two authors extracted data on study quality and outcomes. Statistical analyses were performed using the random effects model and the dichotomous results were expressed as relative risk (RR) with 95% confidence intervals (CI) and continuous outcomes as mean difference (WMD) with 95% CI. MAIN RESULTS: We identified 36 studies (2089 patients): antimicrobial agents (30); urokinase (4), peritoneal lavage (1) intraperitoneal (IP) immunoglobulin (1). No superior antibiotic agent or combination of agents were identified. Primary response and relapse rates did not differ between IP glycopeptide-based regimens compared to first generation cephalosporin regimens, although glycopeptide regimens were more likely to achieve a complete cure (3 studies, 370 episodes: RR 1.66, 95% CI 1.01 to 3.58). For relapsing or persistent peritonitis, simultaneous catheter removal/replacement was superior to urokinase at reducing treatment failure rates (1 study, 37 patients: RR 2.35, 95% CI 1.13 to 4.91). Continuous IP and intermittent IP antibiotic dosing had similar treatment failure and relapse rates. IP antibiotics were superior to IV antibiotics in reducing treatment failure (1 study, 75 patients: RR 3.52, 95% CI 1.26 to 9.81). The methodological quality of most included studies was suboptimal and outcome definitions were often inconsistent. There were no RCTs regarding duration of antibiotics or timing of catheter removal. AUTHORS' CONCLUSIONS: Based on one study, IP administration of antibiotics is superior to IV dosing for treating PD peritonitis. Intermittent and continuous dosing of antibiotics are equally efficacious. There is no role shown for routine peritoneal lavage or use of urokinase. No interventions were found to be associated with significant harm.

Variation in 24 hemostatic genes and associations with non-fatal myocardial infarction and ischemic stroke.

BACKGROUND: Arterial thrombosis involves platelet aggregation and clot formation, yet little is known about the contribution of genetic variation in fibrin-based hemostatic factors to arterial clotting risk. We hypothesized that common variation in 24 coagulation-fibrinolysis genes would contribute to risk of incident myocardial infarction (MI) or ischemic stroke (IS). METHODS: We conducted a population-based, case-control study. Subjects were hypertensive adults and postmenopausal women 30-79 years of age, who sustained a first MI (n = 856) or IS (n = 368) between 1995 and 2002, and controls matched on age, hypertension status, and calendar year (n = 2,689). We investigated the risk of MI and IS associated with (i) global variation within each gene as measured by common haplotypes and (ii) individual haplotypes and single nucleotide polymorphisms (SNPs). Significance was assessed using a 0.2 threshold of the false discovery rate q-value, which accounts for multiple testing. RESULTS: After accounting for multiple testing, global genetic variation in factor (F) VIII was associated with IS risk. Two haplotypes in FVIII and one in FXIIIa1 were significantly associated with increased IS risk (all q-values < 0.2). A plasminogen gene SNP was associated with MI risk. All are new discoveries not previously reported. Another 24 tests had P-values < 0.05 and q-values > 0.2 in MI and IS analyses, 23 of which are new and hypothesis generating. CONCLUSIONS: Apart from the association of FVIII variation with IS, we found little evidence that common variation in the 24 candidate fibrin-based hemostasis genes strongly influences arterial thrombotic risk, but our results cannot rule out small effects.

Identifying a suitable mounting medium for use in forensic fibre examination.

As the result of a previous study many laboratories have used XAM neutral medium-improved white mounting medium in textile fibre examination for more than 20 years. Due to European Directive 98/79/EC, XAM is no longer available and an alternative needed to be found. A list of desirable properties was formulated and a number of mounting media were tested against this. Entellan New was identified as the best mounting medium, and performed similarly to XAM in all aspects.

An investigation into the use of calculating the first derivative of absorbance spectra as a tool for forensic fibre analysis.

A range of fibre samples was measured using J&M MSP400 and J&M MSP800 microspectrophotometers across the visible and UV/visible wavelength ranges respectively. The first derivative of the absorbance spectra was then calculated and studied. When the absorbance spectra produced for some samples were broad and featureless, the first derivative spectra provided more points of comparison that facilitated discrimination. For many of the samples, calculating the first derivative did not result in any additional discrimination due to the high number of points of comparison present in the absorbance spectra. However, for the samples that exhibited a high level of intra-sample colour variation (e.g. through uneven dye uptake common in cotton and wool, etc.), which was evident in the absorbance spectra, the associated first derivative spectra highlighted this variation between the fibres and could potentially have resulted in false exclusions. The results show that whilst calculating first derivative can be a useful aid in the comparison of spectra, a high degree of caution is required when applying this method to fibres which exhibit a large intra-sample variation in colour.