Genotype-phenotype relationships in an investigation of the role of proteases in abdominal aortic aneurysm expansion.

BACKGROUND: The aim of the study was to investigate the effect of functional polymorphisms in promoters of matrix metalloproteinase (MMP) 2, MMP-3, MMP-9, MMP-12 and plasminogen activator inhibitor (PAI) 1 genes on the growth rate of small abdominal aortic aneurysms (AAA). METHODS: Some 455 individuals with a small AAA (4.0-5.5 cm) were monitored for aneurysm growth by ultrasonography (mean follow-up 2.6 years). They also provided a DNA sample for analysis of the -1306 C > T, -1171 5A > 6A, -1562 C > T, -82 A > G and -675 4G > 5G alleles of MMP-2, MMP-3, MMP-9, MMP-12 and PAI-1, respectively. Mean linear AAA growth rates were calculated by flexible modelling; the sample size was sufficient to detect variants that influenced the growth rate by 25 per cent. RESULTS: For MMP-2, MMP-9 and MMP-12 genotypes, growth rates were similar to the mean linear growth rate of 3.08 mm per year. For MMP-3, growth rates were 3.05 (for 5A5A), 3.19 (for 5A6A) and 2.90 (for 6A6A) mm per year. For PAI-1, patients with 4G4G, 4G5G and 5G5G genotypes had growth rates of 3.18, 2.92 and 3.47 mm per year, respectively, for aneurysms with a baseline diameter of 45.1, 44.6 and 46.2 mm. The increased growth rate for patients with PAI-1 5G5G genotype was not statistically significant (P = 0.061), although these patients had the lowest plasma PAI-1 concentrations (P = 0.018). CONCLUSION: There was no evidence that any specific MMP polymorphism had a clinically significant effect on AAA expansion. The plasminogen system may have a small but clinically significant role in AAA development. Much larger studies would be needed to evaluate genes of smaller effect.

Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial.

OBJECTIVE: To assess whether a pragmatic policy of perioperative beta-blockade, with metoprolol, reduced the 30-day cardiovascular morbidity and mortality and reduced the length of hospital stay in average patients undergoing infrarenal vascular surgery. METHODS: This was a double-blind randomized placebo-controlled trial that occurred in vascular surgical units in four UK hospitals. Participants were 103 patients without previous myocardial infarction who had infrarenal vascular surgery between July 2001 and March 2004. Interventions were oral metoprolol (50 mg twice daily, supplemented by intravenous doses when necessary) or placebo from admission until 7 days after surgery. Holter monitors were kept in place for 72 hours after surgery. RESULTS: Eighty men and 23 women (median age, 73 years) were randomized, 55 to metoprolol and 48 to placebo, and 97 (94%) underwent surgery during the trial. The most common operations were aortic aneurysm repair (38%) and distal bypass (29%). Intraoperative inotropic support was required in 64% and 92% of patients in the placebo and metoprolol groups, respectively. Within 30 days, cardiovascular events occurred in 32 patients, including myocardial infarction (8%), unstable angina (9%), ventricular tachycardia (19%), and stroke (1%). Four (4%) deaths were reported. Cardiovascular events occurred in 15 (34%) and 17 (32%) patients in the placebo and metoprolol groups, respectively (unadjusted relative risk, 0.94; 95% confidence interval, 0.53-1.66; adjusted [for age, sex, statin use, and aortic cross-clamping] relative risk, 0.87; 95% confidence interval, 0.48-1.55). Time from operation to discharge was reduced from a median of 12 days (95% confidence interval, 9-19 days) in the placebo group to 10 days (95% confidence interval, 8-12 days) in the metoprolol group (adjusted hazard ratio, 1.71; 95% confidence interval, 1.09-2.66; P < .02). CONCLUSIONS: Myocardial ischemia was evident in a high proportion (one third) of the patients after surgery. A pragmatic regimen of perioperative beta-blockade with metoprolol did not seem to reduce 30-day cardiovascular events, but it did decrease the time from surgery to discharge.

Long-term outcomes of immediate repair compared with surveillance of small abdominal aortic aneurysms.

BACKGROUND: Two clinical trials, one British and one American, have shown that early, prophylactic elective surgery does not improve five-year survival among patients with small abdominal aortic aneurysms. We report long-term outcomes in the United Kingdom Small Aneurysm Trial. METHODS: We randomly assigned 1090 patients, 60 to 76 years of age, with small abdominal aortic aneurysms (diameter, 4.0 to 5.5 cm) to one of two groups: 563 were assigned to undergo early elective surgery, and 527 were assigned to undergo surveillance by ultrasonography. Patients were followed in the trial until June 1998 and thereafter until August 2001; the mean duration of follow-up was 8 years (range, 6 to 10). RESULTS: The mean duration of survival was 6.5 years among patients in the surveillance group, as compared with 6.7 years among patients in the early-surgery group (P=0.29). The adjusted hazard ratio for death from any cause in the early-surgery group as compared with the surveillance group was 0.83 (95 percent confidence interval, 0.69 to 1.00; P=0.05). The 30-day operative mortality in the early-surgery group (5.5 percent) led to an early disadvantage in terms of survival. The survival curves crossed at three years, and at eight years, mortality in the early-surgery group was 7.2 percentage points lower than that in the surveillance group (P=0.03). There was no evidence that age, sex, or the initial size of the aneurysm modified the hazard ratio or that delayed surgery in the surveillance group increased 30-day postoperative mortality. Death was attributable to a ruptured aneurysm in 19 of the 411 men who died (5 percent) and in 12 of the 85 women who died (14 percent) (P=0.001). The rate of early cessation of smoking was higher in the early-surgery group than in the surveillance group. CONCLUSIONS: Among patients with a small abdominal aortic aneurysm, we found no long-term difference in mean survival between the early-surgery and surveillance groups, although after eight years, total mortality was lower in the early-surgery group. This difference may be attributed in part to beneficial changes in lifestyle adopted by members of the early-surgery group.

Characteristics of those who repeatedly acquire sexually transmitted infections: a retrospective cohort study of attendees at three urban sexually transmitted disease clinics in England.

BACKGROUND: Individuals who repeatedly acquire sexually transmitted infections (STIs) may facilitate the persistence of disease at endemic levels. Identifying those most likely to become reinfected with an STI would help in the development of targeted interventions. GOAL: To investigate the demographic and behavior characteristics of sexually transmitted disease (STD) clinic patients most likely to reattend with an STI. STUDY DESIGN: The proportion of patients attending three STD clinics in England between 1994 and 1998 who reattended for treatment of acute STI within 1 year was estimated from Kaplan-Meier failure curves. A Cox proportional hazard model was used to investigate the relation between rate of reattendance with an acute STI and patient characteristics. RESULTS: Of the 17,466 patients presenting at an STD clinic with an acute STI, 14% reattended for treatment of an STI within 1 year. Important determinants of reinfection were age, sexual orientation, and ethnicity: 20% of 12- to 15-year-old females (adjusted hazard ratio [HR], 1.90; CI, 1.13-3.18, compared with 20- to 24-year-old females), 22% of homosexual men (adjusted HR, 1.30; CI, 1.07-1.58, compared with heterosexual men), and 25% of black Caribbean attendees (adjusted HR, 1.87; CI, 1.63-2.13, compared with whites) reattended for treatment of acute STI within 1 year. In addition, 21% of those with a history of STI (adjusted HR, 1.42; CI, 1.28-1.59, compared with those with no history of STI) and 17% of individuals reporting three or more partners in the recent past (adjusted HR, 1.53; CI, 1.34-1.73, compared with those with one partner) reattended for treatment of an acute STI within 1 year. CONCLUSIONS: In this STD clinic population, teenage females, homosexual men, black Caribbean attendees, individuals with a history of STI, and those reporting high rates of sexual partner change repeatedly re-presented with acute STIs. Directing enhanced STD clinic-based interventions at these groups may be an effective strategy for STI control.

Aortic aneurysm diameter and risk of cardiovascular mortality.

After successful surgical repair of an abdominal aortic aneurysm, patients have for many years an increased risk of death from cardiovascular causes. We have tested the hypothesis that for patients with abdominal aortic aneurysms, the risk of nonaneurysm cardiovascular mortality before and after surgery increased with aneurysm diameter. Records of aneurysm repair or rupture and mortality were available from 2305 patients entered into the UK Small Aneurysm Trial and Study. Two hundred fifty-nine deaths occurred before aneurysm repair or rupture (mean follow-up 1.7 years), and 325 occurred after surgical repair (mean follow-up 3.6 years). The risk of nonaneurysm-related mortality and cardiovascular death before and after surgery increased with aneurysm diameter at baseline, even after adjustment for other known risk factors. The adjusted hazard ratios for cardiovascular mortality, per standard deviation (0.8-cm) increase in aneurysm diameter, were 1.34 (95% CI 1.01 to 1.79) and 1.31 (95% CI 1.06 to 1.63) in the periods before aneurysm repair or rupture and after aneurysm repair, respectively. The significant association between aortic diameter and cardiovascular mortality, excluding aneurysm-related deaths, suggests that aneurysm diameter is an independent marker of cardiovascular disease risk.

Are we ignoring the importance of ankle pressures in patients with abdominal aortic aneurysm?

BACKGROUND AND PURPOSE: the ankle/brachial pressure index (ABPI) has been shown to be a reliable marker of cardiovascular risk in population studies. We investigated whether the ABPI was a useful prognostic index for patients with abdominal aortic aneurysm. METHODS: patients entered into the U.K. Small Aneurysm Trial and Study had their ABPI measured in both legs at baseline (mean ABPI reported) and were followed up until 30 June 1998, with information about cause of death being obtained from the Office of National Statistics. This study focussed on cardiovascular and all-cause mortality. RESULTS: a total of 1827 men and 478 women, mean age 69 years, median aneurysm diameter 4.4 cm, were followed up for a median of 5.7 years. A total of 829 deaths were reported (rate 8.1 per 100 person-years), 546 (66%) from cardiovascular causes. The all-cause mortality risk increased as the ABPI decreased, hazard ratio 1.25 per 0.2 unit decrease in ABPI (95% CI 1.17 to 1.34, p<0.001). For patients in the lowest tertile group (ABPI <0.87) there were 11.6 deaths per 100 person-years. This increased risk persisted after adjustment for age, sex, evidence of ischaemia on resting ECG and initial aneurysm diameter, adjusted hazard ratio 1.17 per 0.2 unit decrease in ABPI (95% CI 1.07 to 1.28, p<0.001). CONCLUSION: the ankle/brachial pressure index is an important prognostic indicator for patients with abdominal aortic aneurysm. Patients with an ABPI below 0.87 (limit of lowest tertile) have the highest mortality risk and best clinical practice demands that attention is focussed on active treatment to minimise their cardiovascular risk factors.

Comparison of risk factors for four sexually transmitted infections: results from a study of attenders at three genitourinary medicine clinics in England.

OBJECTIVE: To compare the risk factors for four common sexually transmitted infections (STIs) in attenders at three large urban genitourinary medicine (GUM) clinics in England. METHODS: Clinical, demographic, and behavioural data on attenders at two clinics in London and one in Sheffield were collected. Risk factors associated with first episodes of genital warts and genital herpes simplex virus (HSV), and uncomplicated gonorrhoea and chlamydia were investigated using the presence of each of these STIs as the outcome variable in separate multiple logistic regression analyses. RESULTS: Using data on the first attendance of the 18,238 patients attending the clinics in 1996, the risk of a gonorrhoea or chlamydia diagnosis was strongly associated with teenagers compared with those aged over 34, with black Caribbeans and black Africans compared with whites, and increased with the number of sexual partners. The risk of genital warts or HSV diagnosis was lowest in black Caribbeans and black Africans compared with whites and was not associated with the number of sexual partners. While genital warts were associated with younger age, odds ratios were much lower compared with those for the bacterial infections. Genital HSV diagnoses were not associated with age. CONCLUSIONS: This study of GUM clinic attenders suggests a reduction in the incidence of bacterial STIs may be achievable through targeted sexual health promotion focusing particularly on black ethnic minorities, teenagers, and those with multiple sexual partnerships. Viral STIs were less clearly associated with population subgroups and a broader population based approach to sexual health promotion may be more effective in controlling these infections.

CD4 cell counts in adults with newly diagnosed HIV infection: results of surveillance in England and Wales, 1990-1998. CD4 Surveillance Scheme Advisory Group.

OBJECTIVES: To describe the distribution and changes in CD4 cell counts (both initial and subsequent) in HIV-infected persons over time and determine the factors influencing these counts. DESIGN: Reports were requested from laboratories measuring CD4 cell counts in England and Wales. Initial counts were analysed and median counts were followed over time. METHODS: Time trends and the relationship between initial CD4 cell count and age, sex, and HIV risk category were studied using quantile regression methods or chi-square tests. RESULTS: Between 1990 and 1998, 9553 adults were newly diagnosed with HIV infection and had a CD4 cell count within 6 months of HIV diagnosis. Over 50% of initial CD4 cell counts in each major risk category were below 350 cells/mm3. Older age (P < 0.001), male sex (P < 0.013) and heterosexual risk (P < 0.001) were independently associated with lower initial CD4 cell counts. For heterosexually infected adults, the median initial CD4 cell count was significantly negatively associated with the year of diagnosis (P = 0.03) and the median age increased through the time period examined (P < 0.001), whereas for men who have sex with men (MSM), there was no significant change in these values over time. For each year cohort of newly diagnosed individuals, the median CD4 cell count in subsequent years decreased until 1996 and then increased thereafter, consistent with a treatment effect. CONCLUSION: Across all major risk groups, a large proportion of HIV-infected adults are being diagnosed late in the course of HIV disease. For the heterosexually infected, the data suggest an ageing cohort effect, whereas for MSM the data are consistent with continuing transmission.

Risk factors for postoperative death following elective surgical repair of abdominal aortic aneurysm: results from the UK Small Aneurysm Trial. On behalf of the UK Small Aneurysm Trial participants.

BACKGROUND: In regional and population studies, the mortality rate within 30 days of elective surgical repair of abdominal aortic aneurysm is approximately 8 per cent. Identification of preoperative factors associated with this mortality risk is important for informing surgical policy and may suggest suitable preoperative interventions. METHODS: In the UK Small Aneurysm Trial, 820 patients aged 60-80 years underwent elective open surgical repair of an abdominal aortic aneurysm. The relationship between 30-day mortality rate and 13 prespecified potential prognostic factors was investigated. The value of a published clinical prediction rule was also evaluated. RESULTS: The postoperative mortality rate was 5.6 per cent overall (46 deaths in 820 patients). Postoperative mortality risk was significantly associated with older age (P = 0. 03), higher serum creatinine level (P = 0.002) and lower forced expiratory volume in 1 s (FEV1) (P = 0.003) in univariate analyses. Evidence of a relationship between age and postoperative death was weakened (P = 0.08) after adjustment for creatinine level and FEV1. The predicted postoperative mortality risk ranged from 2.7 per cent in younger patients with below average creatinine levels and above average FEV1, to 7.8 per cent in older patients with above average creatinine levels and below average FEV1. The published clinical prediction rule did not validate well on these data; observed risk did not correlate with predicted risk except for a small group of high-risk patients. CONCLUSION: Poor preoperative lung and renal function was strongly associated with postoperative death. Age was less important once these two important prognostic factors had been taken into account. The potential for preoperative improvement in lung and renal function to reduce postoperative mortality rates should be addressed in future studies.

The Vein Graft Surveillance Trial: rationale, design and methods. VGST participants.

OBJECTIVES: to compare the amputation rates, quality of life and health care costs in patients receiving duplex ultrasound scanning against clinical surveillance following femoropopliteal and femorocrural vein bypass. DESIGN: multi-centre, prospective, randomised controlled trial. METHODS: 1200 patients with a patent vein graft at 30 days postoperatively will be randomised to either clinical or duplex follow-up. All patients are seen in an out-patient clinic at 6 weeks, then 3, 6, 9, 12 and 18 months postoperatively. At each appointment patients are examined clinically; palpable pulses in the graft and crural vessels, presenting symptoms and their ankle-branchial pressure indices (ABPIs) measured. In the duplex group only, the results of the scan are monitored. The incidence of radiological and/or surgical interventions throughout the follow-up period are also noted. Quality of life is measured using the SF-36 and EuroQol questionnaires at the 6 and 18 month appointments. Hospital stays and resource use are documented for health economic analysis. RESULTS: the primary endpoint of this study is amputation or death from vascular causes; however, graft patency rates will also be compared between the groups. Quality of life and health economic data will be used to determine if there is any benefit in either arm in these outcomes between follow-up strategies. CONCLUSIONS: this large, randomised-controlled trial will hopefully provide direct evidence on the benefit of duplex surveillance for vein grafts in terms of limb salvage, quality of life of the patients and cost-benefit to the purchaser.

Epidemiology and detection of HIV-1 among pregnant women in the United Kingdom: results from national surveillance 1988-96.

OBJECTIVE: To describe the epidemiology of HIV-1 infection in pregnant women in the United Kingdom. DESIGN: Serial unlinked serosurveillance for HIV-1 in neonatal specimens and surveillance through registers of diagnosed maternal and paediatric infections from reporting by obstetricians, paediatricians, and microbiologists. SETTING: United Kingdom, 1988-96. SUBJECTS: Pregnant women proceeding to live births and their children. MAIN OUTCOME MEASURES: Time trends in prevalence of HIV-1 seropositivity in newborn infants (as a proxy for infection in mothers); the proportions of mothers with diagnosed HIV-1 infections, and their characteristics. RESULTS: HIV-1 prevalence among mothers in London rose sixfold between 1988 and 1996 (0.19% of women tested; 1 in 520 in 1996). Apart from in Edinburgh and Dundee, levels remained low in Scotland (0.025%; 1 in 3970) and elsewhere in the United Kingdom (0.016%; 1 in 1930). Over a third of births to infected mothers in 1996 occurred outside London. In London the reported infections were predominantly among black African women, whereas in Scotland most were associated with drug injecting. The contribution of reported infection among African women increased over time as that of drug injecting declined. In Scotland 51% of mothers' infections were diagnosed before the birth. In England, despite a national policy initiative in 1992 to increase the antenatal detection rate of HIV, no improvement in detection was observed, and in 1996 only 15% of previously unrecognised HIV infections were diagnosed during pregnancy. CONCLUSIONS: HIV-1 infection affects mothers throughout the United Kingdom but is most common in London. Levels of diagnosis in pregnant women have not improved. Surveillance data can monitor effectively the impact of initiatives to reduce preventable HIV-1 infections in children.

The Health of the Nation target on syringe sharing: a role for routine surveillance in assessing progress and targeting interventions.

The Health of the Nation initiative in the United Kingdom includes a target aimed at reducing the proportion of current injecting drug users who share syringes. The PHLS Collaborative Survey of Salivary Antibodies to HIV and Hepatitis B core in injecting drug users is a comprehensive and national surveillance mechanism which routinely collects data that can be used to monitor progress toward this target. Nineteen per cent of injecting drug users (353/1876) in 1992 and 18% (375/2138) in 1993 shared previously used injecting equipment (difference of -1.3%, 95% Cl -3.7%, 1.1%). Only with further years of data collection will it be possible to tell if this decline represents a real change in behaviour. There was a substantial reduction in the proportion of sharers who received previously used needles and syringes from more than one person, from 45% (138/305) in 1992 to 27% (81/298) in 1993 (fall of 18%, 95% Cl 11%, 26%). This decline could indicate a real reduction in risk behaviour that is not reflected in the target. Monitoring this aspect of sharing could be an important supplementary measure. Women were more likely to have share (adjusted OR = 1.87, 95% Cl 1.53, 2.28) and the likelihood of sharing declined with age (adjusted OR of each 5-year age band = 0.75, 95% Cl 0.72, 0.79). Particular attention should be given to interventions which aim to reduce sharing among women and young people. Clients of agencies at which the main service provided was syringe exchange were less likely to have shared than attenders of other types of agencies (adjusted OR = 0.69, 95% Cl 0.51, 0.93). This suggests that syringe exchange schemes play a role in reducing the transmission of HIV infection.

HIV infection in injecting drug users attending centres in England and Wales, 1990-1991.

OBJECTIVE: To monitor trends in HIV infection and associated risk behaviours in injecting drug users (IDU) in England and Wales. DESIGN: Ongoing voluntary unlinked anonymous cross-sectional survey. METHOD: IDU attending centres in 1990 and 1991 were invited to complete a brief questionnaire requesting demographic and behavioural information, and to provide a saliva sample to be tested for antibodies to HIV and to the core antigen of hepatitis B virus (HBV). RESULTS: In 1990, 1.2% (19 out of 1543) of samples from 33 centres, and in 1991 1.8% (25 out of 1417) of samples from 37 centres contained antibody to HIV. Antibody t9 HBV core-antigen was found in 33 and 31% of IDU in 1990 and 1991, respectively. The prevalence of HIV infection in IDU attending centres in London (4.2%) was higher than in those attending centres elsewhere (0.8%). The prevalence of HIV infection in 1991 varied between individual centres from 0 to 10.6%, and at many centres outside London no IDU were infected with HIV. In the same year the prevalence of past infection with HBV varied from 14 to 54%, and IDU who had evidence of HBV infection were found among attenders in nearly all centres. The prevalences of sharing injecting equipment and risky sexual behaviour were high at many centres. The prevalence of HIV infection was higher in IDU who had started to inject in 1985 or earlier, than in those who started injecting later. In each year, approximately half the IDU surveyed reported having had a voluntary confidential HIV-antibody test, and the prevalence of HIV infection was five times higher in those tested than in those who had not been tested. CONCLUSIONS: HIV prevalence in IDU attending centres in England and Wales was low in 1990-1991. There is some indication that IDU have modified their injecting or sexual behaviour, but even at existing reduced levels of risk behaviour, transmission can occur in HIV is introduced into previously unexposed groups.