Largest Risk Reduction Research Articles

Variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment

Osteoporosis and treatment may affect both composition and nanomechanical properties and their spatial distributions within the individual trabeculae of cancellous bone at length scales that cannot be captured by bulk measurements. This study utilized 25 mature adult ewes divided into 5 treatment groups. Four treatment groups were given a dietary model for human high-turnover osteoporosis, and two of these were treated with antiresorptive drugs, either zoledronate (ZOL) or raloxifene (RAL), to examine their effects on bulk tissue properties and nanoscale tissue composition and mechanical properties within trabeculae. Treatment effects were most pronounced at the nanoscale, where RAL increased indentation modulus and hardness throughout trabeculae by 10% relative to the osteoporosis model. In comparison, ZOL increased these properties exclusively at the surfaces of trabeculae (indentation modulus +12%, hardness +16%). Nanomechanical alterations correlated with changes in tissue mineralization, carbonate substitution, crystallinity, and aligned collagen. Despite only minimal changes in bulk tissue tBMD, the nanomechanical improvements within trabeculae with both treatments greatly improved the predicted theoretical bending stiffness of individual trabeculae when idealized as cylindrical struts. Hence, small tissue-level alterations in critical locations for resisting trabecular failure could account for some of the discrepancy between the large reductions in fracture risk and the only modest changes in BMD with antiresorptive treatments.

Effectiveness of aromatase inhibitors and tamoxifen in reducing subsequent breast cancer.

Tamoxifen (TAM) has been prescribed for decades and aromatase inhibitors (AIs) have been used since the early 2000s in preventing subsequent breast cancer. However, outside of clinical trials, the effectiveness of AIs is not established. We examined the long-term risk of subsequent breast cancer among survivors treated with TAM and AIs in a large health plan. The study included 22,850 survivors, diagnosed with initial breast cancer (stages 0–IV) from 1996 to 2006, and followed 13 years maximum. We compared the risk of subsequent breast cancer in those who used TAM and/or AIs versus nonusers (the reference group). Hazard ratios (HR) adjusted for patient, tumor, treatment, and health-care characteristics were estimated using Cox models with time-dependent drug use status. Women who used TAM/AIs had a large reduction in risk of subsequent breast cancer compared with nonusers. While confidence intervals (CI) for all hormone treatment groups overlapped, women with high adherence (medication possession ratio ≥80%) who used AIs exclusively and had positive ER or PR receptor status had the greatest risk reduction (HR = 0.34, 95% CI: 0.28–0.41), followed by those who switched from TAM to AIs (HR = 0.39, 95% CI: 0.30–0.49), and those who used TAM exclusively (HR = 0.42, 95% CI: 0.36–0.47). Women with high adherence had the greatest risk reduction in subsequent breast cancer, but the results were not substantially different from women who took the drugs less regularly. Compared with nonusers, the reduction in subsequent breast cancer risk ranged from 58% to 66% across the hormone treatment groups and degree of adherence.

Physical activity and risk of breast cancer overall and by hormone receptor status: The European prospective investigation into cancer and nutrition

Physical activity is associated with reduced risks of invasive breast cancer. However, whether this holds true for breast cancer subtypes defined by the estrogen receptor (ER) and the progesterone receptor (PR) status is controversial. The study included 257,805 women from the multinational EPIC-cohort study with detailed information on occupational, recreational and household physical activity and important cofactors assessed at baseline. During 11.6 years of median follow-up, 8,034 incident invasive breast cancer cases were identified. Data on ER, PR and combined ER/PR expression were available for 6,007 (67.6%), 4,814 (54.2%) and 4,798 (53.9%) cases, respectively. Adjusted hazard ratios (HR) were estimated by proportional hazards models. Breast cancer risk was inversely associated with moderate and high levels of total physical activity (HR = 0.92, 95% confidence interval (CI): 0.86-0.99, HR = 0.87, 95%-CI: 0.79-0.97, respectively; p-trend = 0.002), compared to the lowest quartile. Among women diagnosed with breast cancer after age 50, the largest risk reduction was found with highest activity (HR = 0.86, 95%-CI: 0.77-0.97), whereas for cancers diagnosed before age 50 strongest associations were found for moderate total physical activity (HR = 0.78, 95%-CI: 0.64-0.94). Analyses by hormone receptor status suggested differential associations for total physical activity (p-heterogeneity = 0.04), with a somewhat stronger inverse relationship for ER+/PR+ breast tumors, primarily driven by PR+ tumors (p-heterogeneity < 0.01). Household physical activity was inversely associated with ER-/PR- tumors. The results of this largest prospective study on the protective effects of physical activity indicate that moderate and high physical activity are associated with modest decreased breast cancer risk. Heterogeneities by receptor status indicate hormone-related mechanisms.

Statin therapy for the octogenarian?

Cardiovascular risk increases progressively with age. Statins in octogenarians may therefore potentially bring about large reductions in absolute risk. Epidemiological studies, however, show that statin prescription declines with age and is lowest in the oldest patients with the highest cardiovascular risk. Reasons for low statin utilisation in the elderly include safety concerns, doubts about the utility of statin therapy in those of advanced age and a paucity of definite trial evidence supporting statin prescription in octogenarians. Some of the more recently completed statin outcome trials have randomised patients as old as 82 years. A meta-analysis of secondary prevention, with patients aged 65-82 years at randomisation, supported statin prescription in this age group, as statin therapy was associated with relative risk reduction similar to that observed in younger patients. A Swedish registry study showed improved survival in octogenarians prescribed a statin following hospitalisation with an acute myocardial infarction. Currently there is no definite evidence that statin therapy prevents or ameliorates cognitive impairment or dementia. Statin therapy should be considered in octogenarians at high cardiovascular risk, taking into account factors such as biological vs. chronological age, life expectancy, quality of life, risk of interaction with medications taken for co-morbidities and the ability of the patient to take the statin safely.

Antivirals for Management of Herpes Zoster Including Ophthalmicus: A Systematic Review of High-Quality Randomized Controlled Trials

There is lack of consensus from randomized controlled trials on the efficacy of antivirals in the management of herpes zoster. Therefore, a systematic review and meta-analysis was undertaken to provide better understanding of effectiveness of antivirals in management of herpes zoster. A total of 12 randomized controlled trials with 7,277 patients were included in the review. Trials compared one antiviral to another (aciclovir, valaciclovir, famciclovir or brivudin) for a minimum of 7 days in immunocompetent patients presenting with herpes zoster diagnosed within 72 h of symptom onset. Primary outcome was reduction in pain. Compared with aciclovir, valaciclovir showed significant reduction in herpes-zoster-associated pain up to 112 days. The largest risk reduction in pain (36%) was seen at 21-30 days (relative risk [RR] 0.64, 95% CI 0.59, 0.70) with number needed to treat to benefit (NNT) of 3 (95% CI 2.7, 3.8). Famciclovir was also superior to aciclovir with a 46% reduction in risk of pain at 28-30 days (RR 0.54, 95% CI 0.48, 0.68) with NNT of 3 (95% CI 2, 5). Time to lesion healing and adverse effect profile was comparable. Evidence from quality trials have shown significant reduction in risk of pain with valaciclovir and famciclovir for management of herpes zoster including ophthalmicus. Valaciclovir or famciclovir should be preferred treatment options in patients with herpes zoster as they both provide significant reduction in risk of herpes-zoster-associated pain. Furthermore, the superior pharmacokinetics and more convenient dosing regimens with the use of valaciclovir and famciclovir clearly make them the preferred treatment option.

Breast Cancer Chemoprevention: Current Approachesand Future Directions

Breast cancer is the most commonly diagnosed cancer globally among women and is the leading cause of cancer death. Breast cancer prevention trials have shown up to 50% reduction in breast cancer incidence among women at increased risk for breast cancer with the use of chemopreventive agents. Despite such a large potential reduction in breast cancer risk, the uptake of these agents has been poor as compared with the use of preventive agents for other health outcomes. This review provides an update of the trials evaluating chemoprevention agents for breast cancer and highlights the populations likely to benefit from them. Healthcare providers need to be comfortable with the use of chemopreventive agents for breast cancer, as they are a real option for women at increased risk, particularly those with early precursor lesions. Work is ongoing to identify agents for estrogen receptor–negative cancer and agents with minimal toxicity for more general use.

Abstract 17917: Is Small Change Significant? Association of Small Differences in Life's Simple 7 and Mortality: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort

Background. The AHA 2020 Goal includes improving cardiovascular health, defined using a metric consisting of 7 health factors, Life's Simple 7. A central concept of the goal is that small improvements in behavior / lifestyle factors at the population level will lead to large risk reductions over the life course. We developed a simple score to quantify Life's Simple 7 and evaluated the association of small differences in this score with all-cause mortality in REGARDS, a biracial national cohort. Methods. We studied 17,820 REGARDS participants without vascular diseases; black and white men and women aged 45-98 from across the US, enrolled in 2003-7, when extensive risk factor data were measured in participants' homes. The 7 components of Life's Simple 7 (blood pressure, cholesterol, glucose, BMI, smoking, physical activity, diet) were each scored in AHA-defined categories of poor (1 point), intermediate (2 points) and ideal (3 points), and were summed to yield scores ranging from poor for all (7) to ideal for all (21). With 4.6 years follow up there were 2319 deaths. Results. The score was normally distributed with mean (SD) of 13.5 (2.6). The age, sex and race-hazard ratio (HR) of death for a 1-unit increase in Simple 7 Score was 0.86 (95% CI 0.84, 0.87). There was no impact of further adjustment for income and education. Considering only the 4 behavior/lifestyle score components (BMI, smoking, physical activity, diet), the adjusted HR per 1 unit higher score was 0.79 (95% CI 0.77, 0.81). Conclusions. A small incremental difference, corresponding to improvement of 1 category (poor to intermediate or intermediate to ideal) for 1 component of Life's Simple 7 Score was associated with substantial reduction in 4.6-year all cause mortality. The association was larger considering only the 4 behavioral/lifestyle components. Results suggest profound implications of achieving the 2020 Goal that 20% of people improve by 1 level of this metric.

HDL-C: Role as a risk modifier

Evidence that low-density lipoprotein-cholesterol (LDL-C) causes cardiovascular disease (CVD) is overwhelming. It has also been proven beyond all doubt that lowering the level of LDL-C using statins reduces CV risk. However, many people remain at high risk even when their level of LDL-C has been reduced by aggressive treatment with statins. One reason for this residual risk can be a low level of high-density lipoprotein-cholesterol (HDL-C). The concentration of HDL-C is an independent, inverse predictor for CVD. This relationship is apparent even when treatment with statins has reduced the level of LDL-C to below 1.8 mmol/L (70 mg/dL). It has therefore been suggested that raising the level of HDL-C should be considered as a therapeutic strategy for reducing the residual CV risk that persists in some people, despite aggressive LDL-C lowering with statins. HDL particles have several functions with the potential to protect against arterial disease, the best known of which relates to their ability to promote cholesterol efflux from macrophages in the artery wall. However, HDLs have several additional protective properties that are independent of their involvement in cholesterol metabolism. For example, they have properties that reduce oxidation, vascular inflammation and thrombosis, improve endothelial function, promote endothelial repair, enhance insulin sensitivity and promote insulin secretion by pancreatic beta islet cells. There is also a large and compelling body of evidence in animal models showing that interventions that increase HDL levels are profoundly anti-atherogenic. Major causes of low HDL are abdominal obesity and type 2 diabetes, the worldwide incidences of which are increasing at alarming rates. Strategies to increase the concentration of HDL should begin with lifestyle changes such as weight reduction, increased physical activity and smoking cessation. However, compliance with such measures is frequently poor and pharmacological intervention may be required. Currently available HDL-raising medications include fibrates, niacin and statins. There is indisputable evidence that lowering LDL-C levels using statins translates into a large reduction in CV risk. There is also mounting evidence that increasing the level of HDL-C using statins contributes to an additional reduction in CV risk. For example, the increase in HDL-C levels that was associated with simvastatin treatment in the 4S study was a significant predictor for the reduction in CV events. Moreover, a meta-analysis of 1,455 patients in 4 coronary intravascular ultrasound imaging trials showed that both the achieved level of LDL-C and the increase in HDL-C concentration during statin treatment were significant independent predictors for coronary atheroma progression as assessed by coronary intravascular ultrasound. In conclusion, evidence suggests that low levels of HDL-C are associated with an increased CV risk even when LDL-C is reduced to below 1.7 mmol/L (70 mg/dL) with a statin. Moreover, there is mounting evidence that increasing the level of HDL-C has the capacity to reduce CV risk. Thus, there is a compelling case for targeting both the LDL and HDL fractions to reduce CV risk in people with dyslipidemia, high CV risk and low levels of HDL-C.

Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials

SummaryBackgroundAfter breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk.MethodsWe undertook a meta-analysis of individual patient data for 10 801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease.FindingsOverall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7–17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6–6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2–17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8–5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (≥20%), intermediate (10–19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1–12·5), 1·1% (–2·0 to 4·2), and 0·1% (–7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5–27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8–15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease.InterpretationAfter breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.FundingCancer Research UK, British Heart Foundation, and UK Medical Research Council.

Risk Reduction Possibilities From Diversification Of Real Estate Portfolios

Using a macro data base not previously examined, this paper investigates the benefits of diversification in real estate portfolios. Results support the findings of Burns and Epley (1982) and Miles and McCue (1984) that large reduction in risk can be achieved by intra regional diversification. But contrary to some previous work, substantial benefits from interregional diversification are also indicated.

Acceptability of circumcision as a means of HIV prevention among men who have sex with men in China

Conclusive evidence-based research has shown that circumcision reduces the risk of HIV transmission via heterosexual intercourse, whilst ongoing studies are investigating similar effects via homosexual transmissions and the results are equivocal. Few acceptability studies regarding circumcision were conducted among men who have sex with men (MSM). In this cross-sectional study, a total of 307 MSM were recruited by snowball sampling and were interviewed anonymously by some peer field workers in Yangzhou, China. Amongst all uncircumcised participants (93.4% of all participants were uncircumcised), the willingness to be circumcised increased from 8.1% to 30.7%, before and after the participants were briefed about a hypothetical potential benefit of a 50% risk reduction of circumcision in preventing HIV transmission among MSM. In the multivariate analysis, perception of overly long foreskin (odds ratio [OR] = 6.04), unprotected sexual intercourse with male regular sex partners in the last six months (OR = 2.04), and seeing no chance for contracting HIV in the next 12 months (OR = 0.54) were significantly associated with conditional willingness for circumcision. Adjusting for these variables, other significant factors were identified by multiple logistic regression analysis, including number of perceived disadvantages for having overly long foreskin (adjusted OR = 2.60), variables that were derived from the Theory of Planned Behaviors (TPB), and having some circumcised MSM peers (adjusted OR = 0.45–4.38). Some risk compensation behaviors however, may be practiced by 15.9% of the MSM who were willing to undergo circumcision. The acceptability would increase slightly with the effect size of circumcision in protecting MSM from HIV transmission via homosexual intercourse. However, it was only around 30%, even if circumcision could result in a large (50%) risk reduction in HIV transmission among MSM. If future studies can establish efficacy of circumcision, relevant promotion programs need to guard against risk compensation, though the magnitude of risk compensation may be moderate.

DASH-Style Diet and 24-Hour Urine Composition

We previously observed associations between a Dietary Approaches to Stop Hypertension (DASH)-style diet and large reductions in kidney stone risk. This study examined associations between a DASH-style diet and 24-hour excretions of urinary lithogenic factors. We studied 3426 participants with and without nephrolithiasis in the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Studies (NHS) I and II. A dietary DASH score was based on seven components: high intake of fruits, vegetables, nuts and legumes, dairy products, and whole grains and low intake of sweetened beverages and red and processed meats. We used analysis of covariance to adjust for age, stone history, body size, and other factors. Comparing participants in the highest to lowest quintiles of DASH score, multivariate-adjusted urinary calcium excretion was 3% greater in HPFS (P trend 0.12), 10% greater in NHS I (P trend <0.01), and 12% greater in NHS II (P trend 0.05). Urinary oxalate was 4% to 18% greater (P trend all ≤0.03), urinary citrate was 11% to 16% greater (P trend all <0.01), and urinary volume was 16% to 32% greater (P trend all <0.001). Higher DASH score was associated with higher urine potassium, magnesium, phosphate, and pH, and lower relative supersaturations (RSS) of calcium oxalate (women only) and uric acid. A DASH-style diet may reduce stone risk by increasing urinary citrate and volume. The small associations between higher DASH score and lower RSS suggest unidentified stone inhibitors in dairy products and/or plants.

Effects of ethnicity on diabetes incidence and prevention: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial

Risk of Type 2 diabetes varies by ethnicity, but whether ethnicity remains important among those who have impaired glucose tolerance or impaired fasting glucose is uncertain. Whether the effect of thiazolidinedione treatment on diabetes prevention in persons with non-diabetic dysglycaemia varies by ethnicity is also not known. We addressed these questions using data collected in the DREAM trial. A 2-by-2 factorial double-blind randomized controlled trial to compare the effects of rosiglitazone and ramipril on the primary outcome of diabetes or death in persons meeting criteria for impaired glucose tolerance or impaired fasting glucose. The effect of these interventions by ethnicity was estimated using Cox regression analysis. Of 5269 adults, 2365 were randomly assigned to rosiglitzone and 2634 to placebo. South Asians showed a higher hazard for the primary outcome compared with Europeans (hazard ratio, 95% confidence interval 2.21, 1.41-3.47) adjusted for age, gender, BMI, waist-hip ratio and geographic region. A lesser increase in risk was seen in Black people (1.37, 1.04-1.81). A significant reduction in risk of the primary outcome with rosiglitazone treatment assignment was seen in all ethnic groups, but the treatment effect significantly differed by ethnicity (P=0.0242), with South Asians experiencing a smaller, and Latinos a larger preventive effect. Ethnicity is an important risk factor for Type 2 diabetes in dysglycaemic persons. All ethnic groups experienced a large significant reduction in diabetes risk because of rosiglitazone. The magnitude of this reduction differed by ethnicity. Given the post hoc nature of this analysis, further confirmation of these findings is needed.

Abstract 5728: HIV tropism and decreased risk of breast cancer among women in the United States

Abstract Objective: Envelope (env) of X4 strains of HIV binds exclusively to the CXCR4 chemokine receptor, which is commonly and highly expressed on neoplastic breast duct cells. Binding of X4-env protein, but not R5-env protein, can induce apoptosis of neoplastic breast cells. We postulated that HIV viral tropism, specifically strains that use CXCR4, may account for the &amp;gt;30% reduction in breast cancer incidence observed in HIV-infected women in the USA before effective antiretroviral therapy was available. Methods: A retrospective case-control study of women who developed breast cancer during 1993-2008 in the WIHS and HERS longitudinal studies. Cases were HIV-infected women who had stored plasma samples within 24 months (before or after) of a confirmed breast adenocarcinoma diagnosis and who had HIV viral load ≥500 copies/mL. Three HIV-infected women controls, without breast cancer, were matched to each case based on age (±2 yrs) and date of plasma specimen collection. The Monogram Biosciences Trofile assay was used to classify women who had X4-tropic (including X4/R5-tropic) versus exclusively R5-tropic HIV. Unadjusted and adjusted conditional logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for breast cancer associated with tropism, contemporaneous HIV viral load and CD4 count, antiretroviral therapy, and classical breast cancer risk factors from questionnaires. Results: 22 breast cancer cases and 66 matched controls met the inclusion criteria and had valid HIV tropism results. Only 2 (9.1%) breast cancer cases had CXCR4-using HIV, compared to 19 (28.8%) of the matched controls (OR=0.20, 95% CI 0.04-1.0). In univariate analysis of 19 variables, breast cancer was inversely associated with CXCR4-using HIV (P=0.05), and marginally associated with menstrual status (P=0.10). In multivariate conditional regression analysis adjusted for CXCR4-using HIV and menstruation in the past 12 months, both variables were significantly associated with reduced odds of breast cancer (CXCR4-using HIV ORadj=0.10, 95% CI 0.01-0.93; menstruation in the past 12 months ORadj=0.07, 95% CI 0.005-0.92). Other classical breast cancer risk factors, HIV viral load, CD4 cell count, antiretroviral therapy, and race/ethnicity had no detectable impact on these associations. Our results imply that CXCR4-using HIV may account for a 24-27% reduction in breast cancer incidence, assuming our population is representative of HIV-infected women in the USA. Conclusion: These results support the hypothesis that the low breast cancer incidence observed in women with HIV/AIDS is specifically tied to circulating variants of HIV that bind to and signal through CXCR4, a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells. If confirmed, these findings of a large risk reduction, suggest that pharmacologic therapy directed at CXCR4 might reduce breast cancer risk for women in general. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5728.

99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: Farm lifestyles and the hygiene hypothesis

About 15 years have gone by since Strachan first proposed the idea that infections and unhygienic contact may confer protection from the development of allergic illnesses. The so-called 'hygiene hypothesis' has since undergone numerous modifications in the field of epidemiology, clinical science and immunology. Three main areas of research have been brought forward: to explore the role of overt viral and bacterial infections for the inception of allergic diseases; to investigate the significance of environmental exposure to microbial compounds on the development of allergies; and to study the effect of both exposures on underlying innate and adaptive immune responses. A concept unifying these various aspects has not been found, but various pieces of a complex interplay between immune responses of the host, characteristics of the invading microorganism, the level and variety of the environmental exposure and the interactions between an exposed subject's genetic background and the environmental exposures becomes apparent. A natural experiment relating to the hygiene hypothesis is the recurrent observation of a protective effect of growing up on a farm for asthma and allergies. This has been shown in a large number of epidemiological studies across the world among children and adults. The timing and duration of exposure are likely to play a critical role. The largest reduction in risk has been demonstrated for those exposed prenatally and continuously thereafter until adulthood. The protective factors in these farming environments have not been unravelled completely. Findings from various studies suggest that the contact with farm animals, at least in childhood, confers protection. Also the consumption of unprocessed cow's milk directly from the farm has been shown to protect from childhood asthma and allergies. Increased levels of microbial substances may, at least in part, contribute to the 'farm effect'. However, only few studies have measured microbial exposures in these environments and the results obtained so far suggest that the underlying protective microbial exposure(s) have not been identified, but a number of studies using metagenomic approaches are currently under way. The mechanisms by which such environmental exposures confer protection from respiratory allergies are also not well understood. There is good evidence for the involvement of innate immune responses, but translation into protective mechanisms for asthma and allergies is lacking. Furthermore, a number of gene x environment interactions have been observed.

Number Needed to Treat With Rosuvastatin to Prevent First Cardiovascular Events and Death Among Men and Women With Low Low-Density Lipoprotein Cholesterol and Elevated High-Sensitivity C-Reactive Protein

As recently demonstrated, random allocation to rosuvastatin results in large relative risk reductions for first cardiovascular events among apparently healthy men and women with low levels of low-density lipoprotein cholesterol but elevated levels of high-sensitivity C-reactive protein. However, whether the absolute risk reduction among such individuals justifies wide application of statin therapy in primary prevention is a controversial issue with broad policy and public health implications. Absolute risk reductions and consequent number needed to treat (NNT) values were calculated across a range of end points, timeframes, and subgroups using data from Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), a randomized evaluation of rosuvastatin 20 mg versus placebo conducted among 17 802 apparently healthy men and women with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein >or=2 mg/L. Sensitivity analyses were also performed to address the potential impact that alternative statin regimens might have on a similar primary prevention population. For the end point of myocardial infarction, stroke, revascularization, or death, the 5-year NNT within JUPITER was 20 (95% CI, 14 to 34). All subgroups had 5-year NNT values for this end point below 50; as examples, 5-year NNT values were 17 for men and 31 for women, 21 for whites and 19 for nonwhites, 18 for those with body mass index <or=25 kg/m(2) and 21 for those with body mass index greater than 25 kg/m(2), 9 and 26 for those with and without a family history of coronary disease, 19 and 22 for those with and without metabolic syndrome, and 14 and 37 for those with estimated Framingham risks greater or less than 10%. For the net vascular benefit end point that additionally included venous thromboembolism, the 5-year NNT was 18 (95% CI, 13 to 29). For the restricted "hard" end point of myocardial infarction, stroke, or death, the 5-year NNT was 29 (95% CI, 19 to 56). In sensitivity analyses addressing the theoretical utility of alternative agents, 5-year NNT values of 38 and 57 were estimated for statin regimens that deliver 75% and 50% of the relative benefit observed in JUPITER, respectively. All of these calculations compare favorably to 5-year NNT values previously reported in primary prevention for the use of statins among hyperlipidemic men (5-year NNT, 40 to 70), for antihypertensive therapy (5-year NNT, 80 to 160), or for aspirin (5-year NNT, >300). Absolute risk reductions and consequent NNT values associated with statin therapy among those with elevated high-sensitivity C-reactive protein and low low-density lipoprotein cholesterol are comparable if not superior to published NNT values for several widely accepted interventions for primary cardiovascular prevention, including the use of statin therapy among those with overt hyperlipidemia. clinicaltrials.gov. Identifier NCT00239681.

Antiplatelet Polypharmacy in Primary Percutaneous Coronary Intervention

Timely and sustained reperfusion in the ST-elevation myocardial infarction setting improves mortality, and primary percutaneous coronary intervention (PCI) is the guideline-favored revascularization strategy.1 Primary PCI requires pharmacological support with antiplatelet and antithrombin therapy, and many drugs and combinations are established for this purpose. Likewise, patients with ST-elevation myocardial infarction are at risk for subsequent ischemic events in the weeks to months after their index event, and long-term antiplatelet therapy is needed. Aspirin alone provides an inadequate effect on a substantial number of patients with atherosclerotic plaque rupture, whether the vascular disruption occurs as part of an acute coronary syndrome (ACS) or a PCI procedure. Indeed, patients with concomitant spontaneous plaque rupture (ie, troponin-positive ACS) and subsequent disruption from PCI have a particularly high rate of ischemic events with aspirin therapy alone and a notably large risk reduction with antiplatelet adjuncts, such as thienopyridines and glycoprotein IIb/IIIa inhibitors. Article see p 3207 Platelet glycoprotein IIb/IIIa inhibitors have been studied in many placebo-controlled primary PCI trials. De Luca and colleagues performed a meta-analysis of such trials testing abciximab on 3949 patients. They reported an ≈30% reduction in mortality at 6 to 12 months.2 When these studies were performed, procedural thienopyridine use was infrequent, and appropriate loading doses had not been established. Of the 8 primary PCI trials in the meta-analysis, only 2 described administration of a thienopyridine loading dose, and maintenance therapy was continued for only several weeks. Since then, clopidogrel use has become commonplace, yet for a variety of reasons a placebo-controlled trial testing procedural clopidogrel in primary PCI was never performed. In the most recent scientific society guidelines, clopidogrel was given a class I recommendation for use in ST-elevation myocardial infarction1 and …

Menopausal Hormone Therapy and Risk of Colorectal Cancer

We evaluated colorectal cancer risk associated with the duration and recency of specific menopausal hormone therapy formulations (i.e., unopposed estrogen versus estrogen plus progestin) and regimens (i.e., sequential versus continuous estrogen plus progestin use) among 56,733 postmenopausal women participating in the Breast Cancer Detection Demonstration Project follow-up study. Hormone therapy use and other risk factors were ascertained through telephone interviews and mailed questionnaires from 1979 to 1998. The final cancer group included 960 women who were identified from self-report, medical records, state registry data, and the National Death Index. Poisson regression was used to generate multivariable rate ratios (RR) and 95% confidence intervals (95% CI). We observed a decreased risk of colorectal cancer among ever users of unopposed estrogen therapy (RR, 0.83; 95% CI, 0.70-0.99). Among estrogen users, the largest reduced risk was observed for current users (RR, 0.75; 95% CI, 0.54-1.05) and users of >or=ten years duration (RR, 0.74; 95% CI, 0.56-0.96). We found a reduced risk among users of estrogen plus progestin therapy (RR, 0.78; 95% CI, 0.60-1.02), with sequential regimen users (progestin <15 days per cycle) having the largest risk reduction (RR, 0.64; 95% CI, 0.43-0.95). Past users of >or=5 years ago (RR, 0.55; 95% CI, 0.32-0.98) had the largest risk reduction. In this study, estrogen plus progestin use, especially sequential regimen use, was associated with the largest overall reduction of colorectal cancer risk.

Exercise, Vascular Wall and Cardiovascular Diseases

There is much evidence extolling the virtues of physical activity on cardiovascular disease (CVD). The evidence derives from different population groups where leisure time physical activity reduced the risk of coronary heart disease and cardiovascular mortality in both men and women. Recent meta-analyses have shown that large risk reductions for both ischaemic and haemorrhagic stroke can be achieved by moderate or intense physical activity. There are many data from human and animal studies confirming a beneficial role for exercise in the prevention and treatment of CVD. Physical inactivity and obesity/overweight are not only associated with a number of health-related risk factors, but are considered to be independent risk factors for CVD, type 2 diabetes mellitus and hypertension. Clinical trials confirm that lifestyle interventions (dietary modification and increased physical activity) reduce the risk of progressing from impaired glucose tolerance to type 2 diabetes. Moreover, epidemiological studies indicate that the risk of hypertension increases by being overweight. Modest increases in exercise intensity and frequency have hypotensive effects in sedentary hypertensive patients. Long-term training improves endothelium-dependent dilatation in the aorta and resistance arteries of the heart, whereas short-term training increases endothelial function in coronary conduit arteries. Overall, more scientific evidence will undoubtedly encourage the widespread advocacy of the clinical benefits of exercise therapy in the prevention and treatment of CVD.

Coffee, glucose homeostasis, and insulin resistance: physiological mechanisms and mediators

Epidemiological studies show coffee consumption to be correlated to large risk reductions in the prevalence of type 2 diabetes (T2D). Such correlations are seen with decaffeinated and caffeinated coffee, and occur regardless of gender, method of brewing, or geography. They also exist despite clear evidence showing that caffeine causes acute postprandial hyperglycemia and lower whole-body insulin sensitivity. As the beneficial effects of coffee consumption exist for both decaffeinated and caffeinated coffee, a component of coffee other than caffeine must be responsible. This review examines the specific coffee compounds responsible for coffee's effects on T2D, and their potential physiological mechanisms of action. Being plant-derived, coffee contains many beneficial compounds found in fruits and vegetables, including antioxidants. In fact, coffee is the largest source of dietary antioxidants in industrialized nations. When green coffee is roasted at high temperatures, Maillard reactions create a number of unique compounds. Roasting causes a portion of the antioxidant, chlorogenic acid, to be transformed into quinides, compounds known to alter blood glucose levels. Coffee consumption may also mediate levels of gut peptides (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1), hormones intimately involved in the regulation of satiety and insulin secretion. Finally, coffee may have prebiotic-like properties, altering gut flora and ultimately digestion. In summary, it is evident that a better understanding of the role of coffee in the development and prevention of T2D has the potential to uncover novel therapeutic targets and nutraceutical formulations for the disease.