Reduction In Overall Risk Research Articles

Effect of intensive lipid‐lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease

To examine the effect of intensive lipid-lowering therapy on a composite cardiovascular outcome (cardiovascular disease [CVD]), consisting of mortality and morbidity end points, in patients with inflammatory joint disease (rheumatoid arthritis [RA], ankylosing spondylitis [AS], or psoriatic arthritis [PsA]) by post hoc analysis of 2 prospective trials of statins with a secondary end point of CVD outcome (the Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] studies). Of the 18,889 patients participating in the 2 trials, 199 had RA, 46 had AS, and 35 had PsA. Lipid-lowering therapy consisted of an intensive regimen of atorvastatin 80 mg or a conventional/low-dose regimen of atorvastatin 10 mg or simvastatin 20-40 mg. The median duration of followup was nearly 5 years. Changes in lipid levels were examined by analyses of covariance. The effect on CVD was examined by Cox regression analyses, and heterogeneity tests were performed. Patients with RA and those with AS had lower baseline cholesterol levels than patients without inflammatory joint disease (least squares mean ± SEM 180.7 ± 2.3 mg/dl and 176.5 ± 4.7 mg/dl, respectively, versus 185.6 ± 0.2 mg/dl; P = 0.03 and P = 0.05, respectively). Statin treatment led to a comparable decrease in lipid levels and a 20% reduction in overall risk of CVD in both patients with and those without inflammatory joint disease. Our findings indicate that patients with and those without inflammatory joint disease experience comparable lipid-lowering effects and CVD risk reduction after intensive treatment with statins.

Tranexamic Acid for Routine Use in Off-Pump Coronary Artery Bypass Surgery

Tranexamic Acid for Routine Use in Off-Pump Coronary Artery Bypass Surgery

Individual risk assessment and information technology to optimise screening frequency for diabetic retinopathy by Aspelund et al. (2011) Diabetologia 54:2525–2532

Individual risk assessment and information technology to optimise screening frequency for diabetic retinopathy by Aspelund et al. (2011) Diabetologia 54:2525–2532

Advances in Stroke

Carotid artery stenting (CAS) has not been shown to be as safe as carotid endarterectomy for treatment of symptomatic extracranial carotid artery stenosis in the immediate postoperative period. However, beyond the postoperative period, data continues to support a role for CAS in selected patients. A large systematic review of 206 individual studies (54 713 total patients) undergoing CAS found the cumulative 30-day risk of stroke or death to be 7.6% in symptomatic and 3.3% in asymptomatic patients.1 Factors associated with increased risk of adverse outcomes in both groups were age 75 years (relative risk [RR] 1.88), hypertension (RR 1.86), and coronary artery disease (RR 1.41). Use of embolic protection devices significantly reduced the risk of stroke or death (RR 0.57). Although reports of adverse events vary widely in the literature, there has been a trend toward overall reduction in risk over the past several years, suggesting that use of embolic protection devices, careful patient selection, and increasing operator experience may be important factors in minimizing risk. The vast majority of these data (97%) are outside the standards of a randomized controlled trial (RCT), emphasizing the need for data from the trials that are currently enrolling patients. Among the larger studies currently enrolling patients are the Carotid Stenting for High Risk Surgical Patients (CHOICE, Abbott Vascular, target 5000 patients), Asymptomatic Carotid Surgery Trial-2 (ACST-2, target 5000 patients), and Stent-Protected Angioplasty in Asymptomatic Carotid Artery Stenosis versus Endarterectomy trial (SPACE-2, target 3640 patients). This year, we received our first update from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the largest RCT to date comparing the periprocedural safety and long-term (4 years) efficacy of CAS versus carotid endarterectomy.2 Data from the lead-in phase demonstrated an overall 30-day stroke and death rate of 4.4%. Restenosis rates in the lead-in phase were reported to be 13% with 1.2% of patients requiring repeat revascularization by 1-year follow-up. These numbers compare to restenosis rates of 10.7% and 4.6% in patients undergoing CAS and carotid endarterectomy, respectively, in the SPACE trial3 and 19% of CAS patients in the Stenting and Angioplasty with Protection in Patients at High Risk of Endarterectomy (SAPPHIRE) study. 4 The Carotid Revascularization Using Endarterectomy

Association between statin treatment and outcome in relation to renal function in survivors of myocardial infarction

As statins are recommended at discharge to all patients following myocardial infarction (MI), we studied their use and efficacy in renal disease by analyzing the data, in the nationwide SWEDEHEART registry, of 42,814 consecutive survivors of MI with available creatinine/dialysis data but without statin therapy on admission. The estimated glomerular filtration rate (eGFR) was determined by the Modification of Diet in Renal Disease Study formula and the patients classified into the five traditional stages of kidney disease. The 1-year survival in relation to prescription of statin at discharge was assessed in a Cox regression analysis adjusted by a propensity score that described each individual's likelihood of being treated with a statin, established by 36 baseline characteristics and in-hospital therapies. Statin use at discharge decreased with increased renal impairment from 81% in eGFR stage 1 to 31% in eGFR stage 5. After adjusting for the propensity score and discharge medication, statin use was associated with a significant reduction in overall risk of death (hazard ratio 0.63), with a statistically significant interaction between statin therapy and the stage of renal function. Thus, statin use at discharge was associated with improved 1-year survival of patients in stages 2-4 (mild-to-severe) of renal insufficiency. This effect appears attenuated in those with stage 5 renal failure.

Accident management following loss-of-coolant accidents during cooldown in a Westinghouse two-loop PWR

Operation of pressurised water reactors involves shutdown periods for refuelling and maintenance. In preparation for this, the reactor system is cooled down, depressurised and partially drained. Although reactor coolant pressure is lower than during full-power operation, there remains the possibility of a loss-of-coolant accident (LOCA), with a certain but low probability. While the decay heat to be removed is lower than that from a LOCA at full power, the reduced availability of safety systems implies a risk of failing to maintain core cooling, and hence of core damage. This is recognised though probabilistic safety analyses (PSA), which identify low but non-negligible contributions to core damage frequency from accidents during cooldown and shutdown. Analyses are made for a typical two-loop Westinghouse PWR of the consequences of a range of LOCAs during hot and intermediate shutdown, 4 and 5 h after reactor shutdown respectively. The accumulators are isolated, while power to some of the pumped safety injection systems (SIs) is racked out. The study assesses the effectiveness of the nominally assumed SIs in restoring coolant inventory and preventing core damage, and the margin against core damage where their actuation is delayed. The calculations use the engineering-level MELCOR1.8.5 code, supplemented by the SCDAPSIM and SCDAP/RELAP5 codes, which provide a more detailed treatment of coolant system thermal hydraulics and core behaviour. Both treatments show that the core is readily quenched, without damage, by the nominal SI which assumes operation of only one pump. Margins against additional scenario and model uncertainties are assessed by assuming a delay of 900 s (the time needed to actuate the remaining pumps) and a variety of assumptions regarding models and the number of pumps available in conjunction with both MELCOR and versions of SCDAP. Overall, the study provides confidence in the inherent robustness of the plant design with respect to LOCA during cooldown to cold shutdown, and in the validity of a two-tier calculational method. The results have been directly used in updating the plant shutdown PSA, by changing the success criteria for core cooling during cooldown of the plant and showing a reduction in overall risk.

Recreational physical activity and risk of epithelial ovarian cancer

Physical activity may influence ovarian cancer risk through hormonal, inflammatory, or immune-mediated processes or by suppressing ovulation. In a population-based case-control study of epithelial ovarian cancer, we assessed risk associated with recreational physical activity with a focus on characterizing risk within histologic subtypes. Information was collected during in-person interviews with 812 women with ovarian cancer diagnosed in western Washington State from 2002-2005 and 1,313 controls. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Exercise was assessed according to the average hours and metabolic equivalent (MET)-hours per week and the number of years in which regular recreational activity occurred. Relative to women who reported no regular exercise throughout adulthood, the overall risk of invasive, but not borderline, ovarian cancer was reduced among more active women. Reductions in risk of invasive disease were most evident among women with the greatest frequency of high-intensity activity during adulthood. For serous invasive cancer, women in the uppermost category of MET-hours per week of recreational activity in adulthood had 60% the risk of inactive women (95% CI 0.4-0.9), whereas this level of activity was associated with more than a doubling in risk of endometrioid and clear cell invasive tumors. Our findings are compatible with an overall reduction in risk of invasive epithelial ovarian cancer associated with recreational activity but suggest that this association may differ in women with different histologic types of disease. Inconsistent findings across studies that have considered histologic type indicate that this issue is not yet resolved.

The UK Prospective Diabetes Study (UKPDS): Its legacy for type 2 diabetes management

subjects (> 120% ideal body weight) randomised primarily to metformin, there was a substantial risk reduction for MI (39%, p=0.01) and all-cause mortality (36%, p=0.011). The blood pressure control part of the UKPDS, known as the Hypertension in Diabetes Study (HDS), demonstrated that tight blood pressure control over nine years (mean fall of 160/94 to 144/82 mmHg), with either atenolol or captopril, compared to a less tight blood pressure control group (mean fall of 161/94 to 154/87 mmHg) – a difference of 10/5 mmHg, sustained over the nine years – resulted in significant benefit. There was a reduction in overall risk of microvascular complications by 37% (p=0.0092), diabetes-related deaths by 32% (p=0.0046) but no significant effect was seen in all-cause mortality. After 6 years, 29% of the diabetic subjects required three or more drugs to achieve tight blood pressure control.

Pill Use Is Associated with Reductions in Overall Risk of Cancer and in Risk of Main Gynecologic Cancers

Ever-use of the pill had no adverse effect on the overall risk of cancer in the large cohort of British women participating in the Royal College of General Practitioners oral contraception study. Rather analyses of data reflecting as much as 36 years of observation indicate that ever-users of oral contraceptives had a 12% reduction in the risk of developing any cancer and a 29% reduction in the risk of developing cervical uterine or ovarian cancer. (Analyses of data from a subset of the cohort however revealed no association between ever-use and the risk of any cancer.) Long-term pill use was associated with elevated risks of some cancers and with reduced risks of others. Analyses of data from the U.S. Nurses Health Study another long-term cohort study confirm the inverse association between pill use and ovarian cancer risk; they also show that the risk of this disease is reduced among sterilized women and elevated among women who have used an IUD or are infertile. (excerpt)

Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women

Background: B vitamins such as folate, vitamin B-6, and vitamin B-12 are coenzymes that are important for DNA integrity and stability. Deficiency in these B vitamins may promote tumor carcinogenesis.Objective: We prospectively evaluated plasma concentrations of folate, pyridoxal 5-phosphate (PLP; the principal active form of vitamin B-6), and vitamin B-12 in relation to breast cancer risk.Design: We included 848 incident cases of invasive breast cancer identified as of 31 March 2004, and 848 individually matched control subjects from 28 345 women in the Women's Health Study aged ≥45 y who provided blood samples and had no history of cancer and cardiovascular disease at baseline in 1993. Logistic regression controlling for matching factors and other risk factors for breast cancer was used to estimate relative risks (RRs) and 95% CIs. All statistical tests were 2 sided.Results: Plasma concentrations of folate, PLP, and vitamin B-12 were not associated with overall risk of breast cancer. Women in the highest quintile group relative to those in the lowest quintile had multivariate RRs of 1.42 (95% CI: 1.00, 2.02) for plasma folate (P for trend = 0.21), 0.91 (95% CI: 0.63, 1.30) for plasma PLP (P for trend = 0.48), and 1.29 (95% CI: 0.92, 1.82) for plasma vitamin B-12 (P for trend = 0.18). However, higher plasma folate concentrations were moderately associated with an increased risk of developing premenopausal breast cancer (P for trend = 0.04) and for developing estrogen receptor (ER)–positive or progesterone receptor (PR)–positive breast tumors (P for trend ≤ 0.06). Conversely, an inverse association was seen between plasma PLP and postmenopausal breast cancer (P for trend = 0.04).Conclusions: Data from this study suggest that B vitamins, including folate, vitamin B-6, and vitamin B-12, may confer little or no reduction in overall risk of developing breast cancer. The observed positive associations of folate status with risk of developing premenopausal breast cancer and ER-positive or PR-positive tumors are unexpected. Additional research is needed to elucidate the role of folate in breast cancer development.

PGD gender selection for non-Mendelian disorders with unequal sex incidence

Preimplantation genetic diagnosis (PGD) was originally developed for couples whose potential offspring were at risk of severe Mendelian disorders, but has since been extended to other indications. One possible use of PGD is to perform gender selection for couples whose offspring are at increased risk of disorders that do not follow Mendelian inheritance, but which are substantially more common in one sex than another (unequal sex incidence). Here, we examine the clinical and ethical issues to be considered prior to offering PGD gender selection to reduce the risk of a child being affected by a non-Mendelian condition with unequal sex incidence. Factors to be considered include: the risk that a child of either sex will be affected by the condition; the overall reduction in risk provided by gender selection and the potential harms of the procedure. Consideration should also be given to the interests of the family and the child to be born, the seriousness of the condition and the couple's procreative autonomy. To illustrate these issues we use the example of autism, a non-Mendelian disorder that is considerably more common in males than in females.

Wine Consumption and Epithelial Ovarian Cancer

Wine Consumption and Epithelial Ovarian Cancer

Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women.

Treatment with alendronate, a potent and specific inhibitor of bone resorption, is known to significantly reduce fracture risk among women with postmenopausal osteoporosis. The purpose of this meta-analysis was to assess the consistency of the effect of alendronate in reducing the risk of hip fracture among different studies and populations. Data from completed, randomized, treatment studies were pooled in a meta-analysis. The duration of the studies ranged from 1-4.5 years. The dose of alendronate ranged from 5-20 mg/day, with over 95% of patients receiving either 5 or 10 mg/day during the trials. In patients with a T-score of less than or equal to -2.0, or with a vertebral fracture, the effect on hip fracture risk consistently favored patients receiving alendronate therapy, with an overall reduction in risk of hip fracture of 45% [95% confidence interval (CI) 16% to 64%, P=0.007]. For patients who met the criteria of osteoporosis, as defined by the World Health Organization (WHO), the overall risk reduction was 55% (95% CI 29% to 72%, P=0.0008). In both analyses we performed a sensitivity analysis by removing one study at a time. The strength of the evidence was not dependent on any one study. We conclude that therapy with alendronate is associated with significant and clinically important reductions in the incidence of hip fracture in women with postmenopausal osteoporosis. The overall reduction is consistent among different patient populations.

A functional polymorphism in RGS6 modulates the risk of bladder cancer.

RGS proteins negatively regulate heterotrimeric G protein signaling. Recent reports have shown that RGS proteins modulate neuronal, cardiovascular, and lymphocytic activity, yet their role in carcinogenesis has not been explored. In an epidemiologic study of 477 bladder cancer patients and 446 matched controls, three noncoding single-nucleotide polymorphisms (SNPs) in RGS2 and RGS6 were each associated with a statistically significant reduction in bladder cancer risk. The risk of bladder cancer was reduced by 74% in those individuals with the variant genotype at all three SNPs (odds ratio, 0.26; 95% confidence interval, 0.09-0.71). When the SNPs were analyzed separately, the RGS6-rs2074647 (C-->T) polymorphism conferred the greatest overall reduction in risk of bladder cancer (odds ratio, 0.66; 95% confidence interval, 0.46-0.95). These reductions in risk were more pronounced in ever smokers, suggesting a gene-environment interaction. In transfection assays, the RGS6-rs2074647 (C-->T) polymorphism increased the activity of a luciferase-RGS fusion protein by 2.9-fold, suggesting that this SNP is functionally significant. Finally, we demonstrate that RGS2 transcripts and several splice variants of RGS6 are expressed in bladder cancer cells. These data provide the first evidence that RGS proteins may be important modulators of cancer risk and validate RGS6 as a target for further study.

Suicidal risk during treatment with clozapine: a meta-analysis

Objective Suicide remains a major cause of premature mortality among patients with schizophrenia. Evidence of reduced suicidal risk with available psychiatric treatments is limited, but emerging data suggest such an effect of clozapine in chronically psychotic patients, leading us to compile the reported evidence. Method We searched for published studies with contrasting rates of suicides or attempts by psychotic patients treated with clozapine vs. other agents. Results Among six such studies, random-effects meta-analysis indicated a substantially lower overall risk of suicidal behaviors with clozapine vs. other treatments (risk-ratio 3.3; 95% confidence interval [CI] 1.7–6.3; p<0.0001). For completed suicides, the risk ratio (RR) was 2.9 ([CI 1.5–5.7]; p=0.002). Conclusion Long-term treatment with clozapine was associated with three-fold overall reduction of risk of suicidal behaviors. However, available findings are quantitatively inconsistent, well-designed studies remain rare, and the only randomized trial did not find reduced risk of completed suicide. Additional randomized comparisons among modern treatments for psychotic disorders are required to clarify their impact on mortality.

Evaluation of a national eye care programme: re-survey after 10 years

AIMTo re-survey the Gambia after an interval of 10 years to assess the impact of a national eye care programme (NECP) on the prevalence of blindness and low vision.METHODComparison of...

Improvements in pelvic exenteration: factors responsible for reducing morbidity and mortality.

Since pelvic exenteration for the treatment of recurrent gynecologic malignancy first was described, reported rates of morbidity and mortality have declined steadily. However, the factors responsible for this decline have never been clearly delineated. We reviewed the charts of 154 patients who underwent pelvic exenteration for gynecologic malignancy between 1954 and 1994. Charts were abstracted for details of the surgical procedure, pathologic findings, postoperative management, short- and long-term complications, time to recurrence, and overall survival. Seventy-two patients (47%) experienced 95 identifiable postoperative complications, resulting in death in 22 patients (14%). The rate of infectious complications declined to a statistically significant degree between the first two decades and latter two decades of the study (odds ratio [OR] 0.28. 95% CI 0.11-0.69). The use of routine prophylactic antibiotics was associated with this decline in infectious complications (OR 0.25, 95% CI 0.07-0.83). The use of preoperative subcutaneous heparin was associated with a reduction in thrombotic complications from 5 of 100 patients to 0 of 54 patients (P = .11), as well as a significant reduction in overall risk of complications (OR 0.53, 95% CI 0.33-0.85) and risk of postoperative mortality (OR 0.19, 95% CI 0.05-0.80). There was a significant reduction in overall risk of postoperative complications with both intensive care unit monitoring postoperatively (OR 0.65, 95% CI 0.43-0.99) and routine postoperative monitoring with a pulmonary artery catheter (OR 0.61, 95% CI 0.38-0.98). Routine use of prophylactic antibiotics, prophylactic subcutaneous heparin, and intensive postoperative monitoring appear to have reduced morbidity from pelvic exenteration.

Incidence of second primary cancers in three Italian population-based cancer registries.

This is the first population-based study carried out in a southern European region to evaluate the risk of a cohort of cancer patients for developing further cancers. The Tuscany Tumour Registry, the Ragusa Cancer Registry and the Cancer Registry of Romagna, three of the 14 population-based cancer registries active in Italy, were involved in the present study. Overall, 19,252 incident cases of cancer of the female breast, and of the colon, rectum, lung and stomach were followed-up for 48 358.3 person-years. Only second metachronous cancers were considered. Controlateral breast cancers were analysed separately. Multiple primaries (MPs) were defined according to the IACR-IACR rules. The observed (O) numbers of MPs were compared with those expected (E) from age-, sex- and registry-specific incidence rates. Overall, 463 MPs were diagnosed (O/E = 0.87, P < 0.001). The O/E ratios for cancers of the colon (O/E = 0.66), rectum (O/E = 0.72) and all sites combined (O/E = 0.78) in males were significantly lower than expected. The deficit of observed MPs was significant during the first period (2-12 months) and increased over time. Patients over 65 years of age had a significant lower risk of MP, whereas young cancer patients had significantly higher risks for all cancers and for female breast cancer. Male lung cancer patients had a significantly reduced O/E ratio for stomach cancer (O/E = 0.21). Rectal cancer patients had reduced risks of developing stomach cancer and tumours of all sites combined and a 3-fold increased risk of kidney cancers. Colon cancer patients had an overall reduction in risk of MPs, but female colon cancer patients had a significantly increased risk for tumours of the ovary and small intestine; no significant results were found for primary stomach cancers. Female breast cancer patients had a significantly increased risk of rectal cancer (O/E = 1.97), and when synchronous and bilateral breast cancers were considered, significant overall increases in risk were seen for all cancer sites (O/E = 1.6) and for rectal (O/E = 2), and especially for breast cancers (O/E = 3). The cohort analysed had a lower risk of developing further independent tumours than the general population. Several artefacts may have biased these results: the exclusion of synchronous cancers greatly reduced the overall MP risk, and the age-related differences may have been due to reduced medical surveillance and diagnostic aggressiveness. We have confirmed the increased risk for kidney cancers in rectal cancer patients and the association between cancers of the colon and ovary. The significantly increased risk for rectal cancer in female breast cancer patients is probably due to hormonal and dietary factors. For female breast cancer patients, controlateral breast cancer represented the highest risk. The increased risk of cancer of the small intestine in patients with colon cancer may be due to overdiagnosis within increased medical surveillance.

Effects of Calcium Supplementation on Pregnancy-Induced Hypertension

<h3>To the Editor.</h3> —The meta-analysis of calcium supplementation and pregnancy-induced hypertension and preeclampsia by Bucher et al¹is the fourth to be performed in recent years using the same basic data and indicating a large overall reduction in risk due to calcium supplementation.^1-4Although these optimistic results are useful for generating hypotheses and for assessing the available evidence, inferences about treatment may be misleading. Two of the 9 studies in the recent meta-analysis¹were not peer reviewed and are difficult to evaluate since 1 was published as an abstract and a brief submission to a conference proceedings (Montanaro et al, 1987 and 1990), another as a letter to the editor (Lopez-Jaramillo et al, 1990). A third trial (Villar et al, 1987) was cited by the meta-analysis both for preeclampsia and gestational hypertension with identical odds ratios and confidence intervals for each. Even most of the full-length publications do not specify whether

Oral Ganciclovir for the Prevention of Cytomegalovirus Disease in Persons with AIDS

In the advanced stages of the acquired immunodeficiency syndrome (AIDS), cytomegalovirus (CMV) disease, particularly vision-damaging retinitis due to CMV is common. We evaluated prophylactic treatment with orally administered ganciclovir as a way to prevent CMV disease. We conducted a prospective, randomized, double-blind, placebo-controlled study of CMV infected persons with AIDS with either CD4+ lymphocyte counts of < or = 50 per cubic millimeter or counts of < or = 100 per cubic millimeter in those with a history of an AIDS defining opportunistic infection. Patients were randomly assigned, in a 2:1 ratio, to receive either oral ganciclovir (1000 mg three times daily) or placebo. The study was stopped after a median 367 days of follow-up. In an intention-to-treat analysis, the twelve month cumulative rates of confirmed CMV disease were 26 percent in the placebo group (n = 239) and 14 percent in the ganciclovir group (n = 486), representing an overall reduction in risk of 49 percent in the ganciclovir group (P < 0.001). The incidence of CMV retinitis after 12 months was 24 percent in the placebo group and 12 percent in the ganciclovir group (P < 0.0001). The prevalence of CMV-positive urine cultures at base line was 42 percent; after two months it was 43 percent in the placebo group and 10 percent in the ganciclovir group (P < 0.0001). The one year mortality rate was 26 percent in the placebo group and 21 percent in the ganciclovir group (P = 0.14). Therapy with granulocyte colony stimulating factor was more frequent in the ganciclovir group (24 percent) than in the placebo group (9 percent). In persons with advanced AIDS, phophylactic oral ganciclovir significantly reduces the risk of CMV disease.