Patrick McElduff

Low Paraoxonase Activity Predicts Coronary Events in the Caerphilly Prospective Study

Background—The hypothesis that paraoxonase (PON1) has a role in preventing atherosclerosis is based on experimental, transgenic, and case-control studies but has not previously been tested prospectively. Methods and Results—The Caerphilly Prospective Study is a cohort study of men aged 49 to 65 years observed for coronary heart disease (CHD) events (fatal and nonfatal myocardial infarction) over a mean period of 15 years. Serum PON1 activity toward paraoxon was measured in 1353 participants. PON1 activity was 20% lower in the 163 men who had a coronary event (P =0.039). Men in the highest quintile of PON1 activity had a decreased risk compared with those in the lowest quintile (OR 0.57 [95% CI, 0.33 to 0.96]). The inverse relationship between quintiles of serum PON1 activity and CHD risk was graded, the median change in OR across each quintile being 0.87 (0.77 to 0.98). After adjustment for all other CHD risk factors, including HDL cholesterol, this median value became 0.90 (0.78 to 1.02). PON1 was most predictive of a new CHD event in patients at highest risk by virtue of preexisting CHD (adjusted median OR for each quintile, 0.74 [0.59 to 0.93]; n=313) or the presence of other risk factors. For the highest tertile of CHD risk (n=390) calculated by the Framingham equation, adjusted median OR for each quintile was 0.84 (0.66 to 1.05); n=390. Conclusions—Low serum PON1 activity toward paraoxon is an independent risk factor for coronary events in men at high risk because of preexisting disease or other CHD risk factors.

A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke

BACKGROUND Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent. METHODS In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits). RESULTS The three treatment groups each comprised 25 patients. The mean (±SD) NIHSS score at baseline for all patients was 14.4±2.6, and the time to treatment was 2.9±0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02). CONCLUSIONS Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging. (Funded by the Australian National Health and Medical Research Council; Australia New Zealand Clinical Trials Registry number, ACTRN12608000466347.).

How much alcohol and how often? Population based case-control study of alcohol consumption and risk of a major coronary event

Abstract Objective:To quantify the effects of quantity and frequency of alcohol consumption on risk of acute myocardial infarction and coronary death. Design:Case-control study. Setting:Lower Hunter region of New South Wales, Australia, 1983-94. Subjects:Men and women aged 35-69 years. Main outcome measure:Acute myocardial infarction or coronary death. Results:Alcohol consumption patterns were compared between 11 511 cases of acute myocardial infarction or coronary death and 6077 controls randomly selected from the same study population. After adjusting for the effects of age, smoking, and medical history, men and women who consumed one or two drinks of alcohol on five or six days a week had a reduction in risk of a major coronary event compared with men and women who were non-drinkers (odds ratios: men 0.31 (95% confidence interval 0.22 to 0.45); women 0.33 (0.18 to 0.59)). A similar reduction in risk was found after excluding non-drinkers who were formerly moderate to heavy drinkers. An acute protective effect of alcohol consumption was also found for regular drinkers who consumed one or two drinks in the 24 hours preceding the onset of symptoms (odds ratios: men 0.74 (0.51 to 1.09); women 0.43 (0.20 to 0.95)). Conclusions:Frequency and quantity of alcohol consumption are important in assessing the risk of a major coronary event. Risk is lowest among men who report one to four drinks daily on five or six days a week and among women who report one or two drinks daily on five or six days a week.

Leaking urine: Prevalence and associated factors in Australian women

The Womens Health Australia project provided the opportunity to examine the prevalence of leaking urine and associated variables in three large cohorts of Australian women 18–23 years of age (“young” N = 14,761), 45–50 (“mid‐age” N = 14,070), and 70–75 (“older” N = 12,893). The proportion of women reporting leaking urine was 12.8% (95% CI: 12.2–13.3), 36.1% (35.2– 37.0), and 35% (34.1– 35.9) in each of the three cohorts, respectively. Logistic regression analysis showed significant associations between leaking urine and parity in the young and mid‐age women, and between leaking urine and constipation, other bowel symptoms, body mass index, and urine that burns or stings in all three groups. In the mid‐age and older cohorts, women who reported having both hysterectomy and prolapse repair, or prolapse repair alone, were also more likely to report leaking urine. Lower scores on the physical and mental component summary scores of the medical outcomes survey short form (36 items) questionnaire suggest lower quality of life among women who report leaking urine, compared with those who do not. Neurourol. Urodynam. 18:567–577, 1999.

Cold periods and coronary events: an analysis of populations worldwide.

Study objective: To investigate the association between cold periods and coronary events, and the extent to which climate, sex, age, and previous cardiac history increase risk during cold weather. Design: A hierarchical analyses of populations from the World Health Organisation’s MONICA project. Setting: Twenty four populations from the WHO’s MONICA project, a 21 country register made between 1980 and 1995. Patients: People aged 35–64 years who had a coronary event. Main results: Daily rates of coronary events were correlated with the average temperature over the current and previous three days. In cold periods, coronary event rates increased more in populations living in warm climates than in populations living in cold climates, where the increases were slight. The increase was greater in women than in men, especially in warm climates. On average, the odds for women having an event in the cold periods were 1.07 higher than the odds for men (95% posterior interval: 1.03 to 1.11). The effects of cold periods were similar in those with and without a history of a previous myocardial infarction. Conclusions: Rates of coronary events increased during comparatively cold periods, especially in warm climates. The smaller increases in colder climates suggest that some events in warmer climates are preventable. It is suggested that people living in warm climates, particularly women, should keep warm on cold days.

Pretreatment diffusion- and perfusion-MR lesion volumes have a crucial influence on clinical response to stroke thrombolysis

We hypothesized that pretreatment magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) lesion volumes may have influenced clinical response to thrombolysis in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). In 98 patients randomized to intravenous (IV) tissue plasminogen activator (tPA) or placebo 3 to 6 h after stroke onset, we examined increasing acute DWI and PWI lesion volumes (Tmax—with 2-sec delay increments), and increasing PWI/DWI mismatch ratios, on the odds of both excellent (modified Rankin Scale (mRS): 0 to 1) and poor (mRS: 5 to 6) clinical outcome. Patients with very large PWI lesions (most had internal carotid artery occlusion) had increased odds ratio (OR) of poor outcome with IV-tPA (58% versus 25% placebo; OR=4.13, P=0.032 for Tmax +2-sec volume >190 mL). Excellent outcome from tPA treatment was substantially increased in patients with DWI lesions <18 mL (77% versus 18% placebo, OR=15.0, P<0.001). Benefit from tPA was also seen with DWI lesions up to 25 mL (69% versus 29% placebo, OR=5.5, P=0.03), but not for DWI lesions >25 mL. In contrast, increasing mismatch ratios did not influence the odds of excellent outcome with tPA. Clinical responsiveness to IV-tPA, and stroke outcome, depends more on baseline DWI and PWI lesion volumes than the extent of perfusion–diffusion mismatch.

Maternal vitamin D deficiency, ethnicity and gestational diabetes

Aims  Vitamin D deficiency has been linked to impaired glucose metabolism. We determined whether serum 25‐hydroxyvitamin D (25OHD) is associated with glucose metabolism in pregnant women and the effect of ethnicity on this relationship.

Patterns of Plasma Corticotropin-Releasing Hormone, Progesterone, Estradiol, and Estriol Change and the Onset of Human Labor

CONTEXT Clinical prediction of preterm delivery is largely ineffective, and the mechanism mediating progesterone (P) withdrawal and estrogen activation at the onset of human labor is unclear. OBJECTIVES Our objectives were to determine associations of rates of change of circulating maternal CRH in midpregnancy with preterm delivery, CRH with estriol (E3) concentrations in late pregnancy, and predelivery changes in the ratios of E3, estradiol (E2), and P. DESIGN AND SETTING A cohort of 500 pregnant women was followed from first antenatal visits to delivery during the period 2000-2004 at John Hunter Hospital, New South Wales, Australia, a tertiary care obstetric hospital. PATIENTS Unselected subjects were recruited (including women with multiple gestations) and serial blood samples obtained. MAIN OUTCOME MEASURES CRH daily percentage change in term and preterm singletons at 26 wk, ratios E3/E2, P/E3, and P/E2 and the association between E3 and CRH concentrations in the last month of pregnancy (with spontaneous labor onset) were assessed. RESULTS CRH percentage daily change was significantly higher in preterm than term singletons at 26 wk (medians 3.09 and 2.73; P = 0.003). In late pregnancy, CRH and E3 concentrations were significantly positively associated (P = 0.003). E3/E2 increased, P/E3 decreased, and P/E2 was unchanged in the month before delivery (medians: E3/E2, 7.04 and 10.59, P < 0.001; P/E3, 1.55 and 0.98, P < 0.001; P/E2, 11.78 and 10.79, P = 0.07). CONCLUSIONS The very rapid rise of CRH in late pregnancy is associated with an E3 surge and critically altered P/E3 and E3/E2 ratios that create an estrogenic environment at the onset of labor. Our evidence provides a rationale for the use of CRH in predicting preterm birth and informs approaches to delaying labor using P supplementation.

Defining the Extent of Irreversible Brain Ischemia Using Perfusion Computed Tomography

Background: Perfusion computed tomography (PCT) shows promise in acute stroke assessment. However, the accuracy of CT perfusion thresholds in defining the acute infarct core remains uncertain. Method: Concurrent PCT and MRI-DWI performed 3–6 h after symptoms onset were assessed in 57 ischemic stroke patients. PCT was compared to DWI images to define the infarct core using a pixel-based receiver operating characteristic curve analysis to calculate the area under the curve (AUC) for thresholds from PCT maps that were coregistered with the DWI slice location. Results: A relative cerebral blood flow (CBF) of 45% of the contralateral hemisphere was found to be the most accurate threshold for describing the infarct core (AUC 0.788), and it was also by far the most frequent threshold with the highest AUC across patients. Conclusion: CBF thresholds on PCT define the acute infarct core more accurately than do other PCT thresholds, including a cerebral blood volume of 2 ml/100 g.

Effects of restricting pub closing times on night-time assaults in an Australian city

Aims In March 2008 the New South Wales judiciary restricted pub closing times to 3 a.m., and later 3.30 a.m., in the central business district (CBD) of Newcastle, Australia. We sought to determine whether the restriction reduced the incidence of assault. Design Non-equivalent control group design with before and after observations. Setting Newcastle, a city of 530 000 people. Participants People apprehended for assault in the CBD and nearby Hamilton, an area with a similar night-time economy but where no restriction was imposed. Measurements Police-recorded assaults in the CBD before and after the restriction were compared with those in Hamilton. Cases were assaults occurring from 10 p.m.–6 a.m. from January 2001–March 2008, with April 2008–September 2009 as the post-restriction period. We also examined changes in assault incidence by time of night. Negative binomial regression with time, area, time × area interaction terms and terms for secular trend and seasonal effects was used to analyse the data. Autocorrelation was examined using generalized estimating equations. Findings In the CBD, recorded assaults fell from 99.0 per quarter before the restriction to 67.7 per quarter afterward [incidence rate ratio (IRR): 0.66, 95% confidence interval (CI): 0.55–0.80]. In the same periods in Hamilton, assault rates were 23.4 and 25.5 per quarter, respectively (IRR: 1.02, 95% CI: 0.79–1.31). The relative reduction attributable to the intervention was 37% (IRR = 0.63, 95% CI: 0.47–0.81) and approximately 33 assault incidents were prevented per quarter. Conclusion This study indicates that a restriction in pub closing times to 3/3.30 a.m. in Newcastle, NSW, produced a large relative reduction in assault incidence of 37% in comparison to a control locality.