Judith K. Ockene

Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement.

DESCRIPTION Update of the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for colorectal cancer. METHODS To update its recommendation, the USPSTF commissioned 2 studies: 1) a targeted systematic evidence review on 4 selected questions relating to test characteristics and benefits and harms of screening technologies, and 2) a decision analytic modeling analysis using population modeling techniques to compare the expected health outcomes and resource requirements of available screening modalities when used in a programmatic way over time. RECOMMENDATIONS The USPSTF recommends screening for colorectal cancer using fecal occult blood testing, sigmoidoscopy, or colonoscopy in adults, beginning at age 50 years and continuing until age 75 years. The risks and benefits of these screening methods vary. (A recommendation). The USPSTF recommends against routine screening for colorectal cancer in adults 76 to 85 years of age. There may be considerations that support colorectal cancer screening in an individual patient. (C recommendation). The USPSTF recommends against screening for colorectal cancer in adults older than age 85 years. (D recommendation). The USPSTF concludes that the evidence is insufficient to assess the benefits and harms of computed tomographic colonography and fecal DNA testing as screening modalities for colorectal cancer. (I statement).

Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.

IMPORTANCE Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE To report a comprehensive, integrated overview of findings from the 2 Womens Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000611.

Initial symptoms of nicotine dependence in adolescents

OBJECTIVES It has been assumed that nicotine dependence has a slow onset and occurs only after prolonged daily use of tobacco. A cohort of young adolescents was followed to determine when the first symptoms of nicotine dependence occur with respect to the duration and frequency of tobacco use. DESIGN A cohort of 681 seventh grade students (age 12–13 years) from seven schools in two small cities in central Massachusetts was followed over one year. Detailed information regarding tobacco use was obtained in individual confidential interviews conducted in school three times over the year. The latency time to the onset of symptoms of nicotine dependence was measured from the time a subject first smoked at a frequency of at least once per month. RESULTS 22% of the 95 subjects who had initiated occasional smoking reported a symptom of nicotine dependence within four weeks of initiating monthly smoking. One or more symptoms were reported by 60 (63%) of these 95 subjects. Of the 60 symptomatic subjects, 62% had reported experiencing their first symptom before smoking daily or began smoking daily only upon experiencing their first symptom. DISCUSSION The first symptoms of nicotine dependence can appear within days to weeks of the onset of occasional use, often before the onset of daily smoking. The existence of three groups of individuals—rapid onset, slower onset, and resistant—distinguishable from one another by their susceptibility to nicotine dependence, is postulated.

Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.

CONTEXT In the Womens Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported. OBJECTIVE To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009. DESIGN, SETTING, AND PARTICIPANTS A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants. MAIN OUTCOME MEASURES Invasive breast cancer incidence and breast cancer mortality. RESULTS In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group. CONCLUSIONS Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000611.

Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women

BACKGROUND Following the release of the 2002 report of the Womens Health Initiative (WHI) trial of estrogen plus progestin, the use of menopausal hormone therapy in the United States decreased substantially. Subsequently, the incidence of breast cancer also dropped, suggesting a cause-and-effect relation between hormone treatment and breast cancer. However, the cause of this decrease remains controversial. METHODS We analyzed the results of the WHI randomized clinical trial--in which one study group received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily and another group received placebo--and examined temporal trends in breast-cancer diagnoses in the WHI observational-study cohort. Risk factors for breast cancer, frequency of mammography, and time-specific incidence of breast cancer were assessed in relation to combined hormone use. RESULTS In the clinical trial, there were fewer breast-cancer diagnoses in the group receiving estrogen plus progestin than in the placebo group in the initial 2 years of the study, but the number of diagnoses increased over the course of the 5.6-year intervention period. The elevated risk decreased rapidly after both groups stopped taking the study pills, despite a similar frequency of mammography. In the observational study, the incidence of breast cancer was initially about two times as high in the group receiving menopausal hormones as in the placebo group, but this difference in incidence decreased rapidly in about 2 years, coinciding with year-to-year reductions in combined hormone use. During this period, differences in the frequency of mammography between the two groups were unchanged. CONCLUSIONS The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography.

Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Services Task Force Recommendation Statement

DESCRIPTION Update of the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation about the use of aspirin for the prevention of coronary heart disease. METHODS Review of the literature since 2002, focusing on new evidence on the benefits and harms of aspirin for the primary prevention of cardiovascular disease, including myocardial infarction and stroke. The new evidence was reviewed and synthesized according to sex. RECOMMENDATIONS Encourage men age 45 to 79 years to use aspirin when the potential benefit of a reduction in myocardial infarctions outweighs the potential harm of an increase in gastrointestinal hemorrhage. (A recommendation) Encourage women age 55 to 79 years to use aspirin when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage. (A recommendation) Evidence is insufficient to assess the balance of benefits and harms of aspirin for cardiovascular disease prevention in men and women 80 years or older. (I statement) Do not encourage aspirin use for cardiovascular disease prevention in women younger than 55 years and in men younger than 45 years. (D recommendation).

Development of symptoms of tobacco dependence in youths: 30 month follow up data from the DANDY study

Objective: To determine if there is a minimum duration, frequency or quantity of tobacco use required to develop symptoms of dependence. Design and setting: A retrospective/prospective longitudinal study of the natural history of tobacco dependence employing individual interviews conducted three times annually in two urban school systems over 30 months. Detailed histories of tobacco use were obtained including dates, duration, frequency, quantity, patterns of use, types of tobacco, and symptoms of dependence. Participants: A cohort of 679 seventh grade students (age 12–13 years). Main outcome measures: The report of any of 11 symptoms of dependence. Results: Among 332 subjects who had used tobacco, 40% reported symptoms, with a median latency from the onset of monthly smoking of 21 days for girls and 183 days for boys. The median frequency of use at the onset of symptoms was two cigarettes, one day per week. The report of one or more symptoms predicted continued smoking through the end of follow up (odds ratio (OR) 44, 95% confidence interval (CI) 17 to 114, p < 0.001). Conclusions: Symptoms of tobacco dependence commonly develop rapidly after the onset of intermittent smoking, although individuals differ widely in this regard. Girls tend to develop symptoms faster. There does not appear to be a minimum nicotine dose or duration of use as a prerequisite for symptoms to appear. The development of a single symptom strongly predicted continued use, supporting the theory that the loss of autonomy over tobacco use begins with the first symptom of dependence.

Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative

BACKGROUND This study investigates whether the incidence of new-onset diabetes mellitus (DM) is associated with statin use among postmenopausal women participating in the Womens Health Initiative (WHI). METHODS The WHI recruited 161,808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 with ongoing follow-up. The current analysis includes data through 2005. Statin use was captured at enrollment and year 3. Incident DM status was determined annually from enrollment. Cox proportional hazards models were used to estimate the risk of DM by statin use, with adjustments for propensity score and other potential confounding factors. Subgroup analyses by race/ethnicity, obesity status, and age group were conducted to uncover effect modification. RESULTS This investigation included 153,840 women without DM and no missing data at baseline. At baseline, 7.04% reported taking statin medication. There were 10,242 incident cases of self-reported DM over 1,004,466 person-years of follow-up. Statin use at baseline was associated with an increased risk of DM (hazard ratio [HR], 1.71; 95% CI, 1.61-1.83). This association remained after adjusting for other potential confounders (multivariate-adjusted HR, 1.48; 95% CI, 1.38-1.59) and was observed for all types of statin medications. Subset analyses evaluating the association of self-reported DM with longitudinal measures of statin use in 125,575 women confirmed these findings. CONCLUSIONS Statin medication use in postmenopausal women is associated with an increased risk for DM. This may be a medication class effect. Further study by statin type and dose may reveal varying risk levels for new-onset DM in this population.

Smoking and mortality--beyond established causes.

BACKGROUND Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States. However, if smoking causes additional diseases, these official estimates may significantly underestimate the number of deaths attributable to smoking. METHODS We pooled data from five contemporary U.S. cohort studies including 421,378 men and 532,651 women 55 years of age or older. Participants were followed from 2000 through 2011, and relative risks and 95% confidence intervals were estimated with the use of Cox proportional-hazards models adjusted for age, race, educational level, daily alcohol consumption, and cohort. RESULTS During the follow-up period, there were 181,377 deaths, including 16,475 among current smokers. Overall, approximately 17% of the excess mortality among current smokers was due to associations with causes that are not currently established as attributable to smoking. These included associations between current smoking and deaths from renal failure (relative risk, 2.0; 95% confidence interval [CI], 1.7 to 2.3), intestinal ischemia (relative risk, 6.0; 95% CI, 4.5 to 8.1), hypertensive heart disease (relative risk, 2.4; 95% CI, 1.9 to 3.0), infections (relative risk, 2.3; 95% CI, 2.0 to 2.7), various respiratory diseases (relative risk, 2.0; 95% CI, 1.6 to 2.4), breast cancer (relative risk, 1.3; 95% CI, 1.2 to 1.5), and prostate cancer (relative risk, 1.4; 95% CI, 1.2 to 1.7). Among former smokers, the relative risk for each of these outcomes declined as the number of years since quitting increased. CONCLUSIONS A substantial portion of the excess mortality among current smokers between 2000 and 2011 was due to associations with diseases that have not been formally established as caused by smoking. These associations should be investigated further and, when appropriate, taken into account when the mortality burden of smoking is investigated. (Funded by the American Cancer Society.).

Serum 25-Hydroxyvitamin D Concentrations and Risk for Hip Fractures

Context Vitamin D supplementation may help prevent fractures, but the relationship between blood vitamin D concentrations and fracture risk is unclear. Contribution These authors observed an increased risk for hip fracture among women with lower serum 25-hydroxyvitamin D [25(OH) vitamin D] concentrations that was independent of measures of frailty, body mass index, physical function, and falls. Caution The authors did not measure bone mineral density (BMD), so they could not determine whether 25(OH) vitamin D concentrations give different information about fracture risk than that offered by BMD. Implication Low serum 25(OH) vitamin D concentrations seem to be associated with a higher hip fracture risk. The Editors Vitamin D deficiency is common in older adults, especially during the winter (1) and in homebound populations (2), general medical inpatients (3), and community-dwelling women admitted to the hospital with acute hip fracture (4). A recently published evidence-based report on vitamin D and bone health (5) found the level of evidence for an association between serum 25-hydroxyvitamin D [25(OH) vitamin D] concentrations and fracture risk to be inconsistent (5). Since publication of that review, 1 prospective study (6) reported no relationship between serum 25(OH) vitamin D concentrations and fractures, whereas another (7) reported a significantly lower risk for hip fracture with 25(OH) vitamin D concentrations greater than 60 nmol/L. Vitamin D concentration could be associated with fractures in several ways. It could influence muscle strength and balance, both of which contribute to falls and disability (810). The association between 25(OH) vitamin D concentrations and fracture may also be influenced by renal function, because renal insufficiency has been linked to fracture (11) and to vitamin D deficiency (12). Several interactions between vitamin D and estrogen receptors have been described (13); hormone therapy has been shown to reverse abnormalities in vitamin D metabolism (14), and low vitamin D concentrations have also been linked to higher bone turnover (15, 16). Thus, sex-steroid hormones and bone turnover could contribute to the association between 25(OH) vitamin D concentration and fractures. We conducted a nested casecontrol study within the WHI-OS (Womens Health Initiative Observational Study) among 400 case-patients with adjudicated incident hip fracture and 400 control participants. We tested whether low serum 25(OH) vitamin D concentrations are associated with a higher risk for hip fractures in community-dwelling women and whether this relationship may be mediated by poor physical functioning, frailty, falls, sex-steroid hormones, renal function, or bone turnover. Methods Study Population Our study population came from the WHI-OS, a prospective cohort study that enrolled 93676 women between 1994 and 1998 at 40 U.S. clinical centers (age range, 50 to 79 years). Study methods are described in detail elsewhere (17). In brief, women were eligible if they were postmenopausal, were unlikely to move or die within 3 years, were not enrolled in the WHI clinical trials, and were not currently participating in any other clinical trial. The human subjects review committees from each participating institution approved the study. Follow-up and Outcome Ascertainment We sent women questionnaires annually to report any hospitalization and other outcomes, including fractures. As of August 2004, median follow-up duration was 7.1 years (range, 0.7 to 9.3 years). At that time, 3.7% of participants had withdrawn or were lost to follow-up and 5.3% had died. We reviewed medical records to verify cases of hip fracture, and blinded central adjudicators confirmed the cases (18). We excluded patients with pathologic hip fractures. Nested CaseControl Study Design The present study is a casecontrol study nested within the prospective design of WHI-OS. We excluded women who had a history of hip fracture; were receiving hormone therapy up to 1 year before enrollment; or were currently receiving androgens, selective estrogen receptor modulators, antiestrogens, or other osteoporosis treatments (bisphosphonates, calcitonin, or parathyroid hormone). We also excluded women with insufficient serum stored or of unknown ethnicity, leaving 39793 eligible participants. Of these, 404 women had a hip fracture. We randomly selected 400 of these women to form the incident hip fracture group. For each case-patient, we selected 1 control participant who was within 1 year of the case-patients age at screening, was of matching race or ethnicity, and had their blood drawn within 120 days of the case-patients blood draw date; 99% of case-patients and control participants were matched within 30 days. Baseline Clinical Variables We divided clinical centers into 3 geographic regions on the basis of latitude: northern (>40 N), middle (35 to 40 N), and southern (<35 N). We ascertained all covariates at baseline. Clinic interviewers recorded current use of prescription medications by direct inspection of medicine containers. We entered prescription names into the WHI database and assigned drug codes by using Medispan software (First DataBank, San Bruno, California). Average amounts of elemental calcium and vitamin D preparations were entered directly from supplement containers. Dietary intakes of calcium and vitamin D were assessed by using a semiquantitative food-frequency questionnaire (19). Total calcium and vitamin D intake was defined as the sum of diet and supplements. We used questionnaires to ascertain date of birth, race or ethnicity, age at menopause, history of any fracture after age 55 years, smoking, parental history of hip fracture, self-rated health status, and alcohol consumption. We classfied physical activity on the basis of frequency and duration of walking and mild, moderate, and strenuous activities in the previous week. We calculated kilocalories of energy expended in 1 week as the metabolic equivalent (kcal hours/week per kg) (20). We measured physical function by using the RAND Short Form-36 physical function scale, which comprises 10 items measuring whether health now limits physical function in moderate or vigorous activity (2 items); strength to lift, carry, stoop, bend, or stair climb (4 items); ability to walk various distances without difficulty (3 items); and self-care (1 item) (21). The scale is scored from 0 to 100, with higher scores indicating better physical function. We compared women with a score greater than 90 versus those with a score less than or equal to 90, a cutoff value corresponding to the median score. We computed a frailty score, which included self-reported muscle weakness and impaired walking speed (RAND Short Form-36 physical function scale score <75), exhaustion (RAND Short Form-36 vitality scale score <55), low physical activity (lowest quartile of physical activity), and unintended weight loss between baseline and 3 years of follow-up (22). A woman was considered frail if she reported 3 or more of these indicators. Weight was measured on a balance-beam scale with the participant dressed in indoor clothing without shoes. Height was measured by using a wall-mounted stadiometer. Body mass index was calculated as weight (in kg) divided by height (in m2). Laboratory Procedures Laboratory personnel blinded to casecontrol status obtained a 12-hour fasting blood sample at the baseline visit, which was processed and stored at 80C according to strict quality control procedures (23). Serum 25(OH) vitamin D concentrations and sex-steroid hormone levels were measured at the Reproductive Endocrine Research Laboratory at the University of Southern California. 25-Hydroxyvitamin vitamin D was measured by using a radioimmunoassay with DiaSorin reagents (DiaSorin, Stillwater, Minnesota). The sensitivity of the assay was 3.75 nmol/L. The interassay coefficients of variation were 11.7%, 10.5%, 8.6%, and 12.5% at 14.0, 56.8, 82.5, and 122.5 nmol/L, respectively. Estradiol and testosterone concentrations were quantified by using sensitive and specific radioimmunoassays after organic solvent extraction and celite column partition chromatography (2427). The intra- and interassay coefficients of variation were 7.9% and 8% to 12%, respectively, for estradiol and 6% and 10% to 12%, respectively, for testosterone. We calculated bioavailable hormone concentrations by using mass action equations (2830). We measured sex hormonebinding globulin by using a solid-phase, 2-site chemiluminescent immunoassay. The intra- and interassay coefficients of variation were 4.1% to 7.7% and 5.8% to 13%, respectively. Serum cystatin C, a marker of renal function that is independent of age and weight, was measured at Medical Research Laboratories International, Highland Heights, Kentucky, by using the Dade Behring BN-II nephelometer and Dade Behring reagents (Dade Behring, Ramsey, Minnesota) in a particle-enhanced immunonepholometric assay. Serum C-terminal telopeptide of type I collagen and aminoterminal procollagen extensions propeptide were measured by immunoassay (Synarc, Lyon, France). Statistical Analysis We used chi-square and t tests to compare baseline characteristics between case-patients with hip fracture and matched control participants. We assigned 25(OH) vitamin D concentrations to quartile categories defined on the basis of the distribution in the control participants. To further assess confounding, we compared baseline characteristics across quartiles of 25(OH) vitamin D concentrations in case-patients and control participants combined. We calculated the P values for trend by using logistic regression and coding the variable of interest as a continuous variable. We assessed the association between serum 25(OH) vitamin D concentrations and incident hip fracture in conditional logistic regression models that retained the matched casecontrol design. We first examined the unadjusted associations and then adjusted for age, b