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Context: Multivitamin preparations are the most common dietary supplement, taken by at least one-third of all US adults. Observational studies have not provided evidence regarding associations of multivitamin use with total and site-specific cancer incidence or mortality.Objective: To determine whether long-term multivitamin supplementation decreases the risk of total and site-specific cancer events among men.Design, Setting, and Participants: A large-scale, randomized, double-blind, placebo controlled trial (Physicians" Health Study II) of 14 641 male US physicians initially aged 50 years or older (mean [SD] age, 64.3 [9.2] years), including 1312 men with a history of cancer at randomization, enrolled in a common multivitamin study that began in 1997 with treatment and follow-up through June 1, 2011.Intervention: Daily multivitamin or placebo.Main Outcome Measures: Total cancer (excluding nonmelanoma skin cancer), with prostate, colorectal, and other site-specific cancers among the secondary end points.Results: During a median (interquartile range) follow-up of 11.2 (10.7-13.3) years, there were 2669 men with confirmed cancer, including 1373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer (multivitamin and placebo groups, 17.0 and 18.3 events, respectively, per 1000 person-years; hazard ratio [HR], 0.92; 95% CI, 0.86-0.998; P=.04). There was no significant effect of a daily multivitamin on prostate cancer (multivitamin and placebo groups, 9.1 and 9.2 events, respectively, per 1000 person-years; HR, 0.98; 95% CI, 0.88-1.09; P=.76), colorectal cancer (multivitamin and placebo groups, 1.2 and 1.4 events, respectively, per 1000 person-years; HR, 0.89; 95% CI, 0.68-1.17; P=.39), or other site-specific cancers. There was no significant difference in the risk of cancer mortality (multivitamin and placebo groups, 4.9 and 5.6 events, respectively, per 1000 person-years; HR, 0.88; 95% CI, 0.77-1.01; P=.07). Daily multivitamin use was associated with a reduction in total cancer among 1312 men with a baseline history of cancer (HR, 0.73; 95% CI, 0.56-0.96; P=.02), but this did not differ significantly from that among 13 329 men initially without cancer (HR, 0.94; 95% CI, 0.87-1.02; P=.15; P for interaction=.07). Conclusion In this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer.Trial Registration: clinicaltrials.gov Identifier: NCT00270647. [ABSTRACT FROM AUTHOR]

Context: Many individuals take vitamins in the hopes of preventing chronic diseases such as cancer, and vitamins E and C are among the most common individual supplements. A large-scale randomized trial suggested that vitamin E may reduce risk of prostate cancer; however, few trials have been powered to address this relationship. No previous trial in men at usual risk has examined vitamin C alone in the prevention of cancer.Objective: To evaluate whether long-term vitamin E or C supplementation decreases risk of prostate and total cancer events among men.Design, Setting, and Participants: The Physicians' Health Study II is a randomized, double-blind, placebo-controlled factorial trial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31, 2007. A total of 14,641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, were enrolled.Intervention: Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily.Main Outcome Measures: Prostate and total cancer.Results: During a mean follow-up of 8.0 years, there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers. Compared with placebo, vitamin E had no effect on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5 events per 1000 person-years; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.85-1.09; P = .58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1000 person-years; HR, 1.04; 95% CI, 0.95-1.13; P = .41). There was also no significant effect of vitamin C on total cancer (active and placebo vitamin C groups, 17.6 and 17.5 events per 1000 person-years; HR, 1.01; 95% CI, 0.92-1.10; P = .86) or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1000 person-years; HR, 1.02; 95% CI, 0.90-1.15; P = .80). Neither vitamin E nor vitamin C had a significant effect on colorectal, lung, or other site-specific cancers. Adjustment for adherence and exclusion of the first 4 or 6 years of follow-up did not alter the results. Stratification by various cancer risk factors demonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk.Conclusions: In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men.Trial Registration: clinicaltrials.gov Identifier: NCT00270647. [ABSTRACT FROM AUTHOR]

Context: Basic research and observational studies suggest vitamin E or vitamin C may reduce the risk of cardiovascular disease. However, few long-term trials have evaluated men at initially low risk of cardiovascular disease, and no previous trial in men has examined vitamin C alone in the prevention of cardiovascular disease.Objective: To evaluate whether long-term vitamin E or vitamin C supplementation decreases the risk of major cardiovascular events among men.Design, Setting, and Participants: The Physicians' Health Study II was a randomized, double-blind, placebo-controlled factorial trial of vitamin E and vitamin C that began in 1997 and continued until its scheduled completion on August 31, 2007. There were 14,641 US male physicians enrolled, who were initially aged 50 years or older, including 754 men (5.1%) with prevalent cardiovascular disease at randomization.Intervention: Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily.Main Outcome Measures: A composite end point of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease death).Results: During a mean follow-up of 8 years, there were 1245 confirmed major cardiovascular events. Compared with placebo, vitamin E had no effect on the incidence of major cardiovascular events (both active and placebo vitamin E groups, 10.9 events per 1000 person-years; hazard ratio [HR], 1.01 [95% confidence interval {CI}, 0.90-1.13]; P = .86), as well as total myocardial infarction (HR, 0.90 [95% CI, 0.75-1.07]; P = .22), total stroke (HR, 1.07 [95% CI, 0.89-1.29]; P = .45), and cardiovascular mortality (HR, 1.07 [95% CI, 0.90-1.28]; P = .43). There also was no significant effect of vitamin C on major cardiovascular events (active and placebo vitamin E groups, 10.8 and 10.9 events per 1000 person-years, respectively; HR, 0.99 [95% CI, 0.89-1.11]; P = .91), as well as total myocardial infarction (HR, 1.04 [95% CI, 0.87-1.24]; P = .65), total stroke (HR, 0.89 [95% CI, 0.74-1.07]; P = .21), and cardiovascular mortality (HR, 1.02 [95% CI, 0.85-1.21]; P = .86). Neither vitamin E (HR, 1.07 [95% CI, 0.97-1.18]; P = .15) nor vitamin C (HR, 1.07 [95% CI, 0.97-1.18]; P = .16) had a significant effect on total mortality but vitamin E was associated with an increased risk of hemorrhagic stroke (HR, 1.74 [95% CI, 1.04-2.91]; P = .04).Conclusions: In this large, long-term trial of male physicians, neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events. These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men.Trial Registration: clinicaltrials.gov Identifier: NCT00270647. [ABSTRACT FROM AUTHOR]

Objectives: To examine the relationship of total cholesterol and high-density lipoprotein cholesterol (HDL-C) with coronary heart disease (CHD) mortality and with occurrence of new CHD events in persons aged 71 years and older.Design: Prospective cohort study with a median of 4.4 years of follow-up.Setting: East Boston, Mass; New Haven, Conn; and Iowa and Washington counties, Iowa.Participants: A total of 2527 women and 1377 men who completed an interview, had serum lipid determinations, and survived at least 1 year. New CHD events were evaluated in persons with no CHD history or hospitalization.Main Outcome Measures: Death due to CHD (ICD-9 codes 410 through 414 as underlying cause of death); new occurrence of CHD events (fatal CHD or hospitalization with CHD [ICD-9 codes 410 through 414]).Results: After adjustment for established CHD risk factors, the relative risk (RR) of death due to CHD for those with low HDL-C (< 0.90 mmol/L [< 35 mg/dL]) compared with the reference group (HDL-C > or = 1.55 mmol/L [> or = 60 mg/dL]) was 2.5 (95% confidence interval [CI], 1.6 to 4.0). Elevated risk was present in subgroups aged 71 through 80 years (RR, 4.1; 95% CI, 1.9 to 8.8) and over 80 years (RR, 1.8; 95% CI, 0.99 to 3.4), and in men and women. Low HDL-C predicted an increased risk of occurrence of new CHD events (RR, 1.4; 95% CI, 1.1 to 2.0), with similar but nonsignificant results in subgroups of men and women. Total cholesterol was less consistently associated with CHD mortality than HDL-C. When we compared individuals with total cholesterol of at least 6.20 mmol/L (240 mg/dL) with the reference group with total cholesterol of 4.16 to 5.19 mmol/L (161 to 199 mg/dL), a significant risk of CHD mortality was seen for women (RR 1.8; 95% CI, 1.03 to 3.0) but not for men (RR, 1.0; 95% CI, 0.5 to 2.0). In the total population, for each 1-unit increase in the total cholesterol/HDL-C ratio there was a 17% increase in the risk of CHD death that was statistically significant.Conclusions: Low HDL-C predicts CHD mortality and occurrence of new CHD events in persons older than 70 years. Elevated total cholesterol was not found to be associated with CHD mortality in older men, but may be a risk factor for CHD in older women. [ABSTRACT FROM AUTHOR]

Importance: Laboratory testing for the presence of tuberculosis, hepatitis, and other conditions before starting most systemic immunomodulatory agents is recommended in patients with chronic inflammatory skin diseases (CISD) but current testing patterns in the US are unclear., Objective: To determine the prevalence of pretreatment testing that is recommended for patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis)., Design, Setting, and Participants: This descriptive analysis of US commercial insurance claims databases from December 31, 2002, to December 31, 2020, included adult patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis) who started an immunomodulatory agent, including methotrexate, tumor necrosis factor α inhibitors, interleukin (IL)-17Ai, ustekinumab, IL-23i, dupilumab, or apremilast., Main Outcomes and Measures: The proportion of patients who underwent the screening tests as suggested by professional societies-including for tuberculosis, hepatitis, and liver function; complete blood cell counts; and lipid panels-were determined within 6 months before and during 2 years after treatment start., Results: A total of 122 308 patients with CISDs (median [IQR] age, 49 [38-58] years; 63 663 [52.1%] male) starting systemic immunomodulatory treatment in the US were included. Treatment for patients with CISDs comprised methotrexate (28 684), tumor necrosis factor α inhibitors (40 965), ustekinumab (12 841), IL-23i (6116), IL-17Ai (9799), dupilumab (7787), or apremilast (16 116). Complete blood cell count was the most common test, performed in 41% (3161/7787) to 69% (19 659/28 684) of individuals before initiation across treatments. Between 11% (889/7787) and 59% (3613/6116) of patients had tuberculosis screening within 6 months before treatment, and 3% (149/4577) to 26% (1559/6097) had updated tests 1 year later. Between 13% (1006/7787) and 41% (16 728/40 965) had hepatitis panels before treatment. Low pretreatment testing levels before apremilast (15% [2331/16 116] to 45% [7253/16 116]) persisted a year into treatment (9% [816/8496] to 36% [2999/8496]) and were similar to dupilumab (11% [850/7787] to 41% [3161/7787] vs 3% [149/4577] to 25% [1160/4577])., Conclusions and Relevance: In this descriptive analysis of patients with CISDs starting systemic immunomodulatory treatment in the US, less than 60% received the recommended pretreatment testing. Additional research is required to understand whether variations in testing affect patient outcomes.

Importance: Nonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates., Objective: To emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time [PICOT]) and to quantify agreement in RCT-database study pairs., Design, Setting, and Participants: New-user cohort studies with propensity score matching using 3 US claims databases (Optum Clinformatics, MarketScan, and Medicare). Inclusion-exclusion criteria for each database study were prespecified to emulate the corresponding RCT. RCTs were explicitly selected based on feasibility, including power, key confounders, and end points more likely to be emulated with real-world data. All 32 protocols were registered on ClinicalTrials.gov before conducting analyses. Emulations were conducted from 2017 through 2022., Exposures: Therapies for multiple clinical conditions were included., Main Outcomes and Measures: Database study emulations focused on the primary outcome of the corresponding RCT. Findings of database studies were compared with RCTs using predefined metrics, including Pearson correlation coefficients and binary metrics based on statistical significance agreement, estimate agreement, and standardized difference., Results: In these highly selected RCTs, the overall observed agreement between the RCT and the database emulation results was a Pearson correlation of 0.82 (95% CI, 0.64-0.91), with 75% meeting statistical significance, 66% estimate agreement, and 75% standardized difference agreement. In a post hoc analysis limited to 16 RCTs with closer emulation of trial design and measurements, concordance was higher (Pearson r, 0.93; 95% CI, 0.79-0.97; 94% meeting statistical significance, 88% estimate agreement, 88% standardized difference agreement). Weaker concordance occurred among 16 RCTs for which close emulation of certain design elements that define the research question (PICOT) with data from insurance claims was not possible (Pearson r, 0.53; 95% CI, 0.00-0.83; 56% meeting statistical significance, 50% estimate agreement, 69% standardized difference agreement)., Conclusions and Relevance: Real-world evidence studies can reach similar conclusions as RCTs when design and measurements can be closely emulated, but this may be difficult to achieve. Concordance in results varied depending on the agreement metric. Emulation differences, chance, and residual confounding can contribute to divergence in results and are difficult to disentangle.

Importance: Psoriasis in children is increasingly treated with systemic medications, yet their risk of serious infection is not well characterized in clinical practice. Pediatric clinical trials for these medications were often small and placebo controlled., Objective: To estimate the 6-month rate of infections among children with psoriasis who started treatment with ustekinumab, etanercept, or methotrexate., Design, Setting, and Participants: This cohort study used insurance claims data from clinical practices across the US on children aged 17 years or younger with psoriasis who were receiving treatment with a topical medication for psoriasis and started new treatment with ustekinumab, etanercept, or methotrexate. The analysis was stratified by the time before pediatric labeling (2009-2015) and after pediatric approval (2016-2021). Patient follow-up started 1 day after initiating treatment and ended at 6 months., Exposures: New treatment with ustekinumab, etanercept, and methotrexate., Main Outcomes and Measures: During follow-up, the frequency of inpatient serious infections and outpatient infections requiring treatment was compared. Event rates and rate ratios were estimated after propensity score decile stratification., Results: After exclusions, we identified 2338 patients (1368 girls [57.8%]) who initiated new treatment with a targeted immunomodulating agent. In all, 379 patients started treatment with ustekinumab, 779 patients started treatment with etanercept, and 1180 patients started treatment with methotrexate from 2009 through 2021. The propensity score-adjusted incidence rate of serious infection was 18.4 per 1000 person-years (3 events) for ustekinumab users, 25.6 per 1000 person-years (9 events) for etanercept users, and 14.9 per 1000 person-years (8 events) for methotrexate users. The adjusted rate of outpatient infections was 254.9 per 1000 person-years (39 events) for ustekinumab users, 435.7 per 1000 person-years (139 events) for etanercept users, and 433.6 per 1000 person-years (209 events) for methotrexate users. The adjusted rate ratio of outpatient infections was 0.58 (95% CI, 0.41-0.83) for ustekinumab vs etanercept, 0.66 (95% CI, 0.48-0.91) for ustekinumab vs methotrexate, and 0.95 (95% CI, 0.75-1.21) for etanercept vs methotrexate. Rate ratios were similar during the off-label use era and after pediatric labeling., Conclusions and Relevance: Among children with psoriasis who started treatment with immunomodulating agents, serious infections were infrequent. This cohort study suggests that there was no increase in the risk of outpatient infections for children who started treatment with ustekinumab compared with etanercept or methotrexate.

Importance: Undertreatment of older adults with atrial fibrillation with anticoagulation therapy is an important practice gap. It has been posited that the availability of direct oral anticoagulants (DOACs) would improve oral anticoagulant (OAC) initiation in older adults with atrial fibrillation given their superior safety profile compared with warfarin., Objectives: To systematically examine trends in OAC initiation and nonadherence in older adults with atrial fibrillation and coexisting geriatric conditions., Design, Setting, and Participants: This retrospective cohort study uses administrative claims data from Optum's Clinformatics Data Mart from January 1, 2010, to December 31, 2020. Participants included beneficiaries of Medicare Advantage plans aged 65 years and older with atrial fibrillation and elevated risk of ischemic stroke. Data analysis was performed from October 2021 to October 2022., Exposures: Coexisting dementia, frailty, and anemia., Main Outcomes and Measures: The primary outcomes were OAC initiation within 12 months after the first diagnosis of atrial fibrillation per year and nonadherence with OAC per year (defined as <80% of proportion of days covered among patients newly started on OAC in each year)., Results: There were 21 603 to 51 236 patients per year (total for 2010-2020, 381 488 patients) in the OAC-eligible incident AF cohort (mean [SD] age, 77.2 [6.1] to 77.4 [6.8] years; 13 871 [51.8%] to 22 901 [49.8%] women). OAC initiation within 12 months after incident AF increased from 20.2% (5405 of 26 782 patients) in 2010 to 32.9% (7111 of 21 603 patients) in 2020. DOAC uptake increased from 1.1% (291 of 26 782 patients) to 30.9% (6678 of 21 603 patients), and warfarin initiation decreased from 19.1% (5114 of 26 782 patients) to 2.0% (436 of 21 603 patients). Older age (odds ratio [OR], 0.98; 95% CI, 0.98-0.98), dementia (OR, 0.57; 95% CI, 0.55-0.58), frailty (OR, 0.74; 95% CI, 0.72-0.76), and anemia (OR, 0.75; 95% CI, 0.74-0.77) were associated with lower odds of OAC initiation. During the study period, the median (IQR) proportion of days covered increased from 77.6% (41.0%-96.4%) to 90.2% (57.4%-98.6%), and OAC nonadherence decreased from 52.2% (2290 of 4389 patients) to 39.0% (3434 of 8798 patients)., Conclusions and Relevance: Since the introduction of DOACs, OAC initiation in older adults with has improved but remained suboptimal in 2020. Additional strategies are needed to improve stroke prophylaxis in all older adults with atrial fibrillation including those with coexisting dementia, frailty, and anemia.

Importance: Limited evidence is available on the comparative effectiveness of empagliflozin vs alternative second-line glucose-lowering agents in patients with type 2 diabetes (T2D) receiving routine care who have a broad spectrum of cardiorenal risk., Objective: To evaluate the association of empagliflozin with cardiovascular outcomes relative to liraglutide and sitagliptin, stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD)., Design, Setting, and Participants: This retrospective comparative effectiveness cohort study used deidentified Medicare claims data from August 1, 2014, to September 30, 2018, with follow-up from drug initiation until treatment changes, death, or gap in Medicare enrollment (>30 days). Data analysis was performed from October 1, 2021, to April 30, 2022. Medicare fee-for-service beneficiaries older than 65 years with T2D were included. A total of 45 788 patients (22 894 propensity score-matched pairs initiating treatment with either empagliflozin or liraglutide) were included in cohort 1, and 45 624 patients (22 812 propensity score-matched pairs initiating treatment with either empagliflozin or sitagliptin) were included in cohort 2., Exposures: Empagliflozin vs liraglutide (cohort 1) or empagliflozin vs sitagliptin (cohort 2)., Main Outcomes and Measures: Primary outcomes were (1) modified major adverse cardiovascular events (MACEs), including a composite of myocardial infarction, stroke, and all-cause mortality, and (2) hospitalization for heart failure (HHF). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, adjusting for 143 baseline covariates using 1:1 propensity score matching., Results: Among 45 788 patients in cohort 1, the mean (SD) age was 71.9 (5.1) years; 23 396 patients (51.1%) were female, 22 392 (48.9%) were male, and 38 049 (83.1%) were White. Among 45 624 patients in cohort 2, the mean (SD) age was 72.1 (5.1) years; 21 418 patients (46.9%) were female, 24 206 (53.1%) were male, and 37 814 (82.9%) were White. Relative to patients initiating liraglutide, those initiating empagliflozin had a similar risk of the modified MACE outcome (HR, 0.90; 95% CI, 0.79-1.03) and a reduced risk of HHF (HR, 0.66; 95% CI, 0.52-0.82). Across subgroups, empagliflozin was associated with a lower risk of the modified MACE outcome in patients with a history of ASCVD (HR, 0.83; 95% CI, 0.71-0.98) and HF (HR, 0.77; 95% CI, 0.60-1.00) compared with liraglutide, and potential heterogeneity in estimates was observed by sex (male: HR, 0.85 [95% CI, 0.71-1.01]; female: HR, 1.16 [95% CI, 0.94-1.42]; P = .02 for homogeneity). However, reductions in the risk of HHF were observed across most subgroups (eg, ASCVD: HR, 0.66 [95% CI, 0.51-0.85]; HF: HR, 0.66 [95% CI, 0.49-0.88]). Compared with sitagliptin, empagliflozin was associated with reduced risks of the modified MACE outcome (HR, 0.68; 95% CI, 0.60-0.77) and HHF (HR, 0.45; 95% CI, 0.36-0.56), which were consistent across all subgroups. Absolute benefits of empagliflozin vs sitagliptin were larger in patients with a history of ASCVD (modified MACE: RD, -17.6 [95% CI, -24.9 to -10.4]; HHF: RD, -16.7 [95% CI, -21.7 to -11.9]), HF (modified MACE: RD, -41.1 [95% CI, -59.9 to -22.6]; HHF: RD, -50.4 [95% CI, -67.5 to -33.9]), or CKD (modified MACE: RD, -26.7 [95% CI, -41.3 to -12.3]; HHF: RD, -31.9 [95% CI, -43.5 to -20.8])., Conclusions and Relevance: In this comparative effectiveness study of older adults, empagliflozin was associated with a lower risk of HHF (relative to both liraglutide and sitagliptin) and the modified MACE outcome (relative to sitagliptin), with larger absolute benefits in patients with established cardiorenal diseases. These findings suggest that older adults with T2D might benefit more from empagliflozin vs liraglutide or sitagliptin with respect to the risk of HHF; with respect to the risk of MACEs, empagliflozin might be preferable to liraglutide only in patients with cardiovascular disease history and to sitagliptin across all patient subgroups.

Importance: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have demonstrated many cardiovascular and kidney function benefits for patients with type 2 diabetes (T2D). However, the results of SGLT-2i use in primary prevention of atrial fibrillation (AF) were inconsistent in clinical trials, and incident AF was not a prespecified end point., Objective: To examine incident AF with initiation of an SGLT-2i compared with initiation of a dipeptidyl peptidase-4 inhibitor (DPP-4i) or a glucagonlike peptide-1 receptor agonist (GLP-1RA) among older adults (aged ≥66 years) with T2D in routine clinical practice., Design, Setting, and Participants: A population-based new-user cohort study included older adults with T2D who had no history of AF and were enrolled in Medicare fee-for-service from April 1, 2013, to December 31, 2018. Data analysis was performed from June 28 to December 1, 2021., Exposures: To control for potential confounding, new users of SGLT-2i were 1:1 propensity score (PS)-matched to new users of DPP-4is or GLP-1RAs in 2 pairwise comparisons based on 138 baseline covariates., Main Outcomes and Measures: The primary outcome was incident AF, defined as an inpatient diagnosis code for AF. Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years, with their 95% CIs, were estimated in the PS-matched groups., Results: New users of SGLT-2is were 1:1 PS-matched to new users of a DPP-4i (n = 74 868) or GLP-1RA (n = 80 475). Overall, the mean (SD) age of study participants was 72 (5) years, and 165 984 were women (53.4%). The risk of incident AF was lower in the SGLT-2i group than the matched DPP-4i group (HR, 0.82; 95% CI, 0.76 to 0.89; RD, -3.7; 95% CI, -5.2 to -2.2 per 1000 person-years) or the matched GLP-1RA group (HR, 0.90; 95% CI, 0.83 to 0.98; RD, -1.8; 95% CI, -3.2 to -0.3 per 1000 person-years). Results were consistent across several sensitivity and subgroup analyses., Conclusions and Relevance: The findings of this study suggest that the initiation of an SGLT-2i was associated with a reduced risk of incident AF compared with a DPP-4i or GLP-1RA. The results may be helpful when weighing the potential risks and benefits of various glucose level-lowering agents in older adults with T2D.

Importance: Risk profiles for premature coronary heart disease (CHD) are unclear., Objective: To examine baseline risk profiles for incident CHD in women by age at onset., Design, Setting, and Participants: A prospective cohort of US female health professionals participating in the Women's Health Study was conducted; median follow-up was 21.4 years. Participants included 28 024 women aged 45 years or older without known cardiovascular disease. Baseline profiles were obtained from April 30, 1993, to January 24, 1996, and analyses were conducted from October 1, 2017, to October 1, 2020., Exposures: More than 50 clinical, lipid, inflammatory, and metabolic risk factors and biomarkers., Main Outcomes and Measures: Four age groups were examined (<55, 55 to <65, 65 to <75, and ≥75 years) for CHD onset, and adjusted hazard ratios (aHRs) were calculated using stratified Cox proportional hazard regression models with age as the time scale and adjusting for clinical factors. Women contributed to different age groups over time., Results: Of the clinical factors in the women, diabetes had the highest aHR for CHD onset at any age, ranging from 10.71 (95% CI, 5.57-20.60) at CHD onset in those younger than 55 years to 3.47 (95% CI, 2.47-4.87) at CHD onset in those 75 years or older. Risks that were also noted for CHD onset in participants younger than 55 years included metabolic syndrome (aHR, 6.09; 95% CI, 3.60-10.29), hypertension (aHR, 4.58; 95% CI, 2.76-7.60), obesity (aHR, 4.33; 95% CI, 2.31-8.11), and smoking (aHR, 3.92; 95% CI, 2.32-6.63). Myocardial infarction in a parent before age 60 years was associated with 1.5- to 2-fold risk of CHD in participants up to age 75 years. From approximately 50 biomarkers, lipoprotein insulin resistance had the highest standardized aHR: 6.40 (95% CI, 3.14-13.06) for CHD onset in women younger than 55 years, attenuating with age. In comparison, weaker but significant associations with CHD in women younger than 55 years were noted (per SD increment) for low-density lipoprotein cholesterol (aHR, 1.38; 95% CI, 1.10-1.74), non-high-density lipoprotein cholesterol (aHR, 1.67; 95% CI, 1.36-2.04), apolipoprotein B (aHR, 1.89; 95% CI, 1.52-2.35), triglycerides (aHR, 2.14; 95% CI, 1.72-2.67), and inflammatory biomarkers (1.2- to 1.8-fold)-all attenuating with age. Some biomarkers had similar CHD age associations (eg, physical inactivity, lipoprotein[a], total high-density lipoprotein particles), while a few had no association with CHD onset at any age. Most risk factors and biomarkers had associations that attenuated with increasing age at onset., Conclusions and Relevance: In this cohort study, diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of CHD. Most risk factors had attenuated relative rates at older ages.

Importance: Chronic kidney disease (CKD) is a common complication of type 2 diabetes that can lead to end-stage kidney disease and is associated with high cardiovascular risk. Few treatments are available to prevent CKD in type 2 diabetes., Objective: To test whether supplementation with vitamin D3 or omega-3 fatty acids prevents development or progression of CKD in type 2 diabetes., Design, Setting, and Participants: Randomized clinical trial with a 2 × 2 factorial design conducted among 1312 adults with type 2 diabetes recruited between November 2011 and March 2014 from all 50 US states as an ancillary study to the Vitamin D and Omega-3 Trial (VITAL), coordinated by a single center in Massachusetts. Follow-up was completed in December 2017., Interventions: Participants were randomized to receive vitamin D3 (2000 IU/d) and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; 1 g/d) (n = 370), vitamin D3 and placebo (n = 333), placebo and omega-3 fatty acids (n = 289), or 2 placebos (n = 320) for 5 years., Main Outcomes and Measures: The primary outcome was change in glomerular filtration rate estimated from serum creatinine and cystatin C (eGFR) from baseline to year 5., Results: Among 1312 participants randomized (mean age, 67.6 years; 46% women; 31% of racial or ethnic minority), 934 (71%) completed the study. Baseline mean eGFR was 85.8 (SD, 22.1) mL/min/1.73 m2. Mean change in eGFR from baseline to year 5 was -12.3 (95% CI, -13.4 to -11.2) mL/min/1.73 m2 with vitamin D3 vs -13.1 (95% CI, -14.2 to -11.9) mL/min/1.73 m2 with placebo (difference, 0.9 [95% CI, -0.7 to 2.5] mL/min/1.73 m2). Mean change in eGFR was -12.2 (95% CI, -13.3 to -11.1) mL/min/1.73 m2 with omega-3 fatty acids vs -13.1 (95% CI, -14.2 to -12.0) mL/min/1.73 m2 with placebo (difference, 0.9 [95% CI, -0.7 to 2.6] mL/min/1.73 m2). There was no significant interaction between the 2 interventions. Kidney stones occurred among 58 participants (n = 32 receiving vitamin D3 and n = 26 receiving placebo) and gastrointestinal bleeding among 45 (n = 28 receiving omega-3 fatty acids and n = 17 receiving placebo)., Conclusions and Relevance: Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years. The findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes., Trial Registration: ClinicalTrials.gov Identifier: NCT01684722.

Importance: Cybersecurity is an increasingly important threat to health care delivery, and email phishing is a major attack vector against hospital employees., Objective: To describe the practice of phishing simulation and the extent to which health care employees are vulnerable to phishing simulations., Design, Setting, and Participants: Retrospective, multicenter quality improvement study of a convenience sample of 6 geographically dispersed US health care institutions that ran phishing simulations from August 1, 2011, through April 10, 2018. The specific institutions are anonymized herein for security and privacy concerns., Exposures: Simulated phishing emails received by employees at US health care institutions., Main Outcomes and Measures: Date of phishing campaign, campaign number, number of emails sent, number of emails clicked, and email content. Emails were classified into 3 categories (office related, personal, or information technology related)., Results: The final study sample included 6 anonymized US health care institutions, 95 simulated phishing campaigns, and 2 971 945 emails, 422 062 of which were clicked (14.2%). The median institutional click rates for campaigns ranged from 7.4% (interquartile range [IQR], 5.8%-9.6%) to 30.7% (IQR, 25.2%-34.4%), with an overall median click rate of 16.7% (IQR, 8.3%-24.2%) across all campaigns and institutions. In the regression model, repeated phishing campaigns were associated with decreased odds of clicking on a subsequent phishing email (adjusted OR, 0.511; 95% CI, 0.382-0.685 for 6-10 campaigns; adjusted OR, 0.335; 95% CI, 0.282-0.398 for >10 campaigns)., Conclusions and Relevance: Among a sample of US health care institutions that sent phishing simulations, almost 1 in 7 simulated emails sent were clicked on by employees. Increasing campaigns were associated with decreased odds of clicking on a phishing email, suggesting a potential benefit of phishing simulation and awareness. With cyberattacks increasing against US health care systems, these click rates represent a major cybersecurity risk for hospitals.

Importance: Long-term multivitamin use had no effect on risk of cardiovascular disease (CVD) in the Physicians' Health Study II. Baseline nutritional status may have modified the lack of effect., Objective: To investigate effect modification by various baseline dietary factors on CVD risk in the Physicians' Health Study II., Design, Setting, and Participants: The Physicians' Health Study II was a randomized, double-blind, placebo-controlled trial testing multivitamin use (multivitamin [Centrum Silver] or placebo daily) among US male physicians. The Physicians' Health Study II included 14 641 male physicians 50 years or older, 13 316 of whom (91.0%) completed a baseline 116-item semiquantitative food frequency questionnaire and were included in the analyses. This study examined effect modification by baseline intake of key foods, individual nutrients, dietary patterns (Alternate Healthy Eating Index and Alternate Mediterranean Diet Score), and dietary supplement use. The study began in 1997, with continued treatment and follow-up through June 1, 2011., Interventions: Multivitamin or placebo daily., Main Outcomes and Measures: Major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and CVD mortality. Secondary outcomes included myocardial infarction, total stroke, CVD mortality, and total mortality individually., Results: In total, 13 316 male physicians (mean [SD] age at randomization, 64.0 [9.0] years in those receiving the active multivitamin and 64.0 [9.1] years in those receiving the placebo) were observed for a mean (SD) follow-up of 11.4 (2.3) years. There was no consistent evidence of effect modification by various foods, nutrients, dietary patterns, or baseline supplement use on the effect of multivitamin use on CVD end points. Statistically significant interaction effects were observed between multivitamin use and vitamin B6 intake on myocardial infarction, between multivitamin use and vitamin D intake on CVD mortality, and between multivitamin use and vitamin B12 intake on CVD mortality and total mortality. However, there were inconsistent patterns in hazard ratios across tertiles of each dietary factor that are likely explained by multiple testing., Conclusions and Relevance: The results suggest that baseline nutritional status does not influence the effect of randomized long-term multivitamin use on major CVD events. Future studies are needed to investigate the role of baseline nutritional biomarkers on the effect of multivitamin use on CVD and other outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT00270647.

Importance: Statins decrease levels of low-density lipoprotein (LDL) and triglycerides as well as cardiovascular events but increase the risk for a diagnosis of type 2 diabetes mellitus (T2DM). The risk factors associated with incident T2DM are incompletely characterized., Objective: To investigate the association of lipoprotein subclasses and size and a novel lipoprotein insulin resistance (LPIR) score (a composite of 6 lipoprotein measures) with incident T2DM among individuals randomized to a high-intensity statin or placebo., Design, Setting, and Participants: This secondary analysis of the JUPITER trial (a placebo-controlled randomized clinical trial) was conducted at 1315 sites in 26 countries and enrolled 17 802 men 50 years or older and women 60 years or older with LDL cholesterol levels less than 130 mg/dL, high-sensitivity C-reactive protein levels of at least 2 mg/L, and triglyceride levels less than 500 mg/dL. Those with T2DM were excluded. A prespecified secondary aim was to assess the effect of rosuvastatin calcium on T2DM. Incident T2DM was monitored for a median of 2.0 years. Data were collected from February 4, 2003, to August 20, 2008, and analyzed (intention-to-treat) from December 1, 2013, to January 21, 2016., Interventions: Rosuvastatin calcium, 20 mg/d, or placebo., Main Outcomes and Measures: Size and concentration of lipids, apolipoproteins, and lipoproteins at baseline (11 918 patients with evaluable plasma samples) and 12 months after randomization (9180 patients). The LPIR score, a correlate of insulin resistance, was calculated as a weighted combination of size and concentrations of LDL, very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) particles., Results: Among the 11 918 patients (4334 women [36.4%]; median [interquartile range] age, 66 [60-71] years), rosuvastatin lowered the levels of LDL particles (-39.6%; 95% CI, -49.4% to -24.6%), VLDL particles (-19.6%; 95% CI, -40.6% to 10.3%), and VLDL triglycerides (-15.2%; 95% CI, -35.9% to 11.3%) and shifted the lipoprotein subclass distribution toward smaller LDL size (-1.5%; 95% CI, -3.7% to 0.5%), larger VLDL size (2.8%; 95% CI, -5.8% to 12.7%), and lower LPIR score (-3.2%; 95% CI, -20.6% to 16.9%). In analyses adjusted for age, sex, race or ethnic origin, exercise, educational level, family history, and smoking, the hazard ratio (HR) for T2DM per SD of LPIR score in the placebo arm was 1.99 (95% CI, 1.64-2.42); in the rosuvastatin arm, 2.06 (95% CI, 1.74-2.43). After additional adjustment for systolic blood pressure, body mass index, high-sensitivity C-reactive protein, hemoglobin A1c, HDL cholesterol, LDL cholesterol, and triglycerides, the LPIR score remained associated with T2DM in the placebo arm (HR, 1.35; 95% CI, 1.03-1.76) and rosuvastatin arm (HR, 1.60; 95% CI, 1.27-2.03). Similar trends were seen at 12 months. The LPIR score improved the model likelihood ratio (χ2 = 18.23; P < .001) and categorical net reclassification index (0.039; 95% CI, 0.003-0.072)., Conclusions and Relevance: In apparently healthy people, LPIR score was positively associated with incident T2DM, including during rosuvastatin therapy., Trial Registration: clinicaltrials.gov Identifier: NCT00239681.

Importance: Osteoporosis and cardiovascular disease may share common biological pathways, with inflammation playing a role in the development of both. Although observational studies have suggested that statin use is associated with a lower risk of fractures, randomized trial data addressing this issue are scant., Objective: To determine whether statin therapy reduces the risk of fracture and, in a secondary analysis, whether baseline levels of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) are associated with the risk of fracture., Design, Setting, and Participants: The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial was an international, randomized, double-blind, placebo-controlled study enrolling 17,802 men older than 50 years and women older than 60 years with hs-CRP level of at least 2 mg/L. Participants were screened from 2003 to 2006 and observed prospectively for up to 5 years (median follow-up, 1.9 years)., Intervention: Rosuvastatin calcium, 20 mg daily, or placebo., Main Outcomes and Measures: Incident fracture was a prespecified secondary end point of JUPITER. Fractures were confirmed by radiographs, computed tomography, bone scan, or other methods. Cox proportional hazards models were used to calculate hazard ratios (HRs) and associated 95% confidence intervals for the risk of fracture according to randomized treatment assignment, as well as increasing tertiles of hs-CRP, controlling for potential confounders., Results: During the study, 431 incident fractures were reported and confirmed. Among participants allocated to rosuvastatin, 221 fractures were confirmed, compared with 210 among those allocated to placebo, such that the incidence of fracture in the rosuvastatin and placebo groups was 1.20 and 1.14 per 100 person-years, respectively (adjusted HR, 1.06 [95% CI, 0.88-1.28]; P = .53). Overall, increasing baseline hs-CRP level was not associated with an increased risk of fractures (adjusted HR for each unit increase in hs-CRP tertile, 1.06 [95% CI, 0.94-1.20]; P for trend, .34)., Conclusions and Relevance: Among men and women with elevated hs-CRP level enrolled in a large trial of rosuvastatin therapy for cardiovascular disease, statin therapy did not reduce the risk of fracture. Higher baseline hs-CRP level was not associated with an increased risk of incident fracture., Trial Registration: clinicaltrials.gov Identifier: NCT00239681.

Importance: Observational studies suggest a role for dietary nutrients such as vitamin E and selenium in cataract prevention. However, the results of randomized clinical trials of vitamin E supplements and cataract have been disappointing and are not yet available for selenium., Objective: To test whether long-term supplementation with selenium and vitamin E affects the incidence of cataract in a large cohort of men., Design, Setting, and Participants: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) Eye Endpoints Study was an ancillary study of the Southwest Oncology Group-coordinated SELECT, a randomized placebo-controlled 4-arm trial of selenium and vitamin E conducted among 35,533 men, 50 years and older for African American participants and 55 years and older for all other men, at 427 participating sites in the United States, Canada, and Puerto Rico. A total of 11,267 SELECT participants from 128 SELECT sites participated in the SELECT Eye Endpoints ancillary study., Interventions: Individual supplements of selenium (200 μg per day from L-selenomethionine) and vitamin E (400 IU per day of all rac-α-tocopheryl acetate)., Main Outcomes and Measures: Incident cataract was defined as a lens opacity, age related in origin, and responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review. Cataract extraction was defined as the surgical removal of an incident cataract., Results: During a mean (SD) of 5.6 (1.2) years of treatment and follow-up, 389 cases of cataract were documented. There were 185 cataracts in the selenium group and 204 in the no selenium group (hazard ratio, 0.91; 95 % CI, 0.75-1.11; P = .37). For vitamin E, there were 197 cases in the treated group and 192 in the placebo group (hazard ratio, 1.02; 95 % CI, 0.84-1.25; P = .81). Similar results were observed for cataract extraction., Conclusions and Relevance: These data from a large cohort of apparently healthy men indicate that long-term daily supplementation with selenium and/or vitamin E is unlikely to have a large beneficial effect on age-related cataract., Trial Registration: ClinicalTrials.gov Identifier: NCT00784225.

Importance: This study adds to the evidence that elevated levels of high-sensitivity C-reactive protein (hsCRP) predict future risk of age-related macular degeneration (AMD). This information might shed light on underlying pathological mechanisms involving inflammation and could be of clinical utility in the identification of persons at high risk of AMD who may benefit from increased adherence to lifestyle recommendations, eye examination schedules, and therapeutic protocols., Objective: To investigate the relationship between hsCRP and future risk of AMD in US men and women., Design: Pooled analysis of prospective nested case-control data from the Women's Health Study and 4 other cohorts, the Physicians' Health Study, Women's Antioxidant and Folic Acid Cardiovascular Study, Nurses' Health Study, and Health Professionals Follow-up Study., Setting: A prospective nested case-control study within 5 large cohorts., Participants: Patients were initially free of AMD. We prospectively identified 647 incident cases of AMD and selected age- and sex-matched controls for each AMD case (2 controls for each case with dry AMD or 3 controls for each case of neovascular AMD). MAIN OUTCOME MEASURES We measured hsCRP in baseline blood samples. We used conditional logistic regression models to examine the relationship between hsCRP and AMD and pooled findings using meta-analytic techniques., Results: After adjusting for cigarette smoking status, participants with high (>3 mg/L) compared with low (<1 mg/L) hsCRP levels had cohort-specific odds ratios (ORs) for incident AMD ranging from 0.94 (95% CI, 0.58-1.51) in the Physicians' Health Study to 2.59 (95% CI, 0.58-11.67) in the Women's Antioxidant and Folic Acid Cardiovascular Study. After testing for heterogeneity between studies (Q = 5.61; P = .23), we pooled findings across cohorts and observed a significantly increased risk of incident AMD for high vs low hsCRP levels (OR, 1.49; 95% CI, 1.06-2.08). Risk of neovascular AMD was also increased among those with high hsCRP levels (OR, 1.84; 95% CI, 1.14-2.98)., Conclusions and Relevance: Overall, these pooled findings from 5 prospective cohorts add further evidence that elevated levels of hsCRP predict greater future risk of AMD. This information might shed light on underlying mechanisms and could be of clinical utility in the identification of persons at high risk of AMD who may benefit from increased adherence to lifestyle recommendations, eye examination schedules, and therapeutic protocols.

Context: Although multivitamins are used to prevent vitamin and mineral deficiency, there is a perception that multivitamins may prevent cardiovascular disease (CVD). Observational studies have shown inconsistent associations between regular multivitamin use and CVD, with no long-term clinical trials of multivitamin use., Objective: To determine whether long-term multivitamin supplementation decreases the risk of major cardiovascular events among men., Design, Setting, and Participants: The Physicians' Health Study II, a randomized, double-blind, placebo-controlled trial of a common daily multivitamin, began in 1997 with continued treatment and follow-up through June 1, 2011. A total of 14,641 male US physicians initially aged 50 years or older (mean, 64.3 [SD, 9.2] years), including 754 men with a history of CVD at randomization, were enrolled., Intervention: Daily multivitamin or placebo., Main Outcome Measures: Composite end point of major cardiovascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, and CVD mortality. Secondary outcomes included MI and stroke individually., Results: During a median follow-up of 11.2 (interquartile range, 10.7-13.3) years, there were 1732 confirmed major cardiovascular events. Compared with placebo, there was no significant effect of a daily multivitamin on major cardiovascular events (11.0 and 10.8 events per 1000 person-years for multivitamin vs placebo, respectively; hazard ratio [HR], 1.01; 95% CI, 0.91-1.10; P = .91). Further, a daily multivitamin had no effect on total MI (3.9 and 4.2 events per 1000 person-years; HR, 0.93; 95% CI, 0.80-1.09; P = .39), total stroke (4.1 and 3.9 events per 1000 person-years; HR, 1.06; 95% CI, 0.91-1.23; P = .48), or CVD mortality (5.0 and 5.1 events per 1000 person-years; HR, 0.95; 95% CI, 0.83-1.09; P = .47). A daily multivitamin was also not significantly associated with total mortality (HR, 0.94; 95% CI, 0.88-1.02; P = .13). The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD (P = .62 for interaction)., Conclusion: Among this population of US male physicians, taking a daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up., Trial Registration: clinicaltrials.gov Identifier: NCT00270647.

Objective: To examine whether intake of ω-3 fatty acids and fish affects incidence of age-related macular degeneration (AMD) in women., Design: A detailed food-frequency questionnaire was administered at baseline among 39 876 female health professionals (mean [SD] age: 54.6 [7.0] years). A total of 38 022 women completed the questionnaire and were free of a diagnosis of AMD. The main outcome measure was incident AMD responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review., Results: A total of 235 cases of AMD, most characterized by some combination of drusen and retinal pigment epithelial changes, were confirmed during an average of 10 years of follow-up. Women in the highest tertile of intake for docosahexaenoic acid, compared with those in the lowest, had a multivariate-adjusted relative risk of AMD of 0.62 (95% confidence interval, 0.44-0.87). For eicosapentaenoic acid, women in the highest tertile of intake had a relative risk of 0.66 (95% confidence interval, 0.48-0.92). Consistent with the findings for docosahexaenoic acid and eicosapentaenoic acid, women who consumed 1 or more servings of fish per week, compared with those who consumed less than 1 serving per month, had a relative risk of AMD of 0.58 (95% confidence interval, 0.38-0.87)., Conclusion: These prospective data from a large cohort of female health professionals without a diagnosis of AMD at baseline indicate that regular consumption of docosahexaenoic acid and eicosapentaenoic acid and fish was associated with a significantly decreased risk of incident AMD and may be of benefit in primary prevention of AMD.

Context: The risks associated with new-onset atrial fibrillation (AF) among middle-aged women and populations with a low comorbidity burden are poorly defined., Objectives: To examine the association between incident AF and mortality in initially healthy women and to evaluate the influence of associated cardiovascular comorbidities on risk., Design, Setting, and Participants: Between 1993 and March 16, 2010, 34,722 women participating in the Women's Health Study underwent prospective follow-up. Participants were 95% white, older than 45 years (median, 53 [interquartile range {IQR}, 49-59] years), and free of AF and cardiovascular disease at baseline. Cox proportional hazards models with time-varying covariates were used to determine the risk of events among women with incident AF. Secondary analyses were performed among women with paroxysmal AF., Main Outcome Measures: Primary outcomes included all-cause, cardiovascular, and noncardiovascular mortality. Secondary outcomes included stroke, congestive heart failure, and myocardial infarction., Results: During a median follow-up of 15.4 (IQR, 14.7-15.8) years, 1011 women developed AF. Incidence rates per 1000 person-years among women with and without AF were 10.8 (95% confidence interval [CI], 8.1-13.5) and 3.1 (95% CI, 2.9-3.2) for all-cause mortality, 4.3 (95% CI, 2.6-6.0) and 0.57 (95% CI, 0.5-0.6) for cardiovascular mortality, and 6.5 (95% CI, 4.4-8.6) and 2.5 (95% CI, 2.4-2.6) for noncardiovascular mortality, respectively. In multivariable models, hazard ratios (HRs) of new-onset AF for all-cause, cardiovascular, and noncardiovascular mortality were 2.14 (95% CI, 1.64-2.77), 4.18 (95% CI, 2.69-6.51), and 1.66 (95% CI, 1.19-2.30), respectively. Adjustment for nonfatal cardiovascular events potentially on the causal pathway to death attenuated these risks, but incident AF remained associated with all mortality components (all-cause: HR, 1.70 [95% CI, 1.30-2.22]; cardiovascular: HR, 2.57 [95% CI, 1.63-4.07]; and noncardiovascular: HR, 1.42 [95% CI, 1.02-1.98]). Among women with paroxysmal AF (n = 656), the increase in mortality risk was limited to cardiovascular causes (HR, 2.94; 95% CI, 1.55-5.59)., Conclusion: Among a group of healthy women, new-onset AF was independently associated with all-cause, cardiovascular, and noncardiovascular mortality, with some of the risk potentially explained by nonfatal cardiovascular events.

Objective: To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of age-related cataract in a large cohort of men., Methods: In a randomized, double-masked, placebo-controlled trial, 11,545 apparently healthy US male physicians 50 years or older without a diagnosis of cataract at baseline were randomly assigned to receive 400 IU of vitamin E or placebo on alternate days and 500 mg of vitamin C or placebo daily., Main Outcome Measure: Incident cataract responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review., Application to Clinical Practice: Long-term use of vitamin E and C supplements has no appreciable effect on cataract., Results: After 8 years of treatment and follow-up, 1174 incident cataracts were confirmed. There were 579 cataracts in the vitamin E-treated group and 595 in the vitamin E placebo group (hazard ratio, 0.99; 95% confidence interval, 0.88-1.11). For vitamin C, there were 593 cataracts in the treated group and 581 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14)., Conclusion: Long-term alternate-day use of 400 IU of vitamin E and daily use of 500 mg of vitamin C had no notable beneficial or harmful effect on the risk of cataract., Trial Registration: clinicaltrials.gov Identifier: NCT00270647.

Objective: To examine in prospective data the relation between dietary intake of carotenoids and vitamins C and E and the risk of cataract in women., Design: Dietary intake was assessed at baseline in 39,876 female health professionals by using a detailed food frequency questionnaire. A total of 35,551 women provided detailed information on antioxidant nutrient intake from food and supplements and were free of a diagnosis of cataract. The main outcome measure was cataract, defined as an incident, age-related lens opacity responsible for a reduction in best-corrected visual acuity in the worse eye to 20/30 or worse based on self-report confirmed by medical record review., Results: A total of 2031 cases of incident cataract were confirmed during a mean of 10 years of follow-up. Comparing women in the extreme quintiles, the multivariate relative risk of cataract was 0.82 (95% confidence interval, 0.71-0.95; test for trend, P = .04) for lutein/zeaxanthin and 0.86 (95% confidence interval, 0.74-1.00; test for trend, P = .03) for vitamin E from food and supplements., Conclusion: In these prospective observational data from a large cohort of female health professionals, higher dietary intakes of lutein/zeaxanthin and vitamin E from food and supplements were associated with significantly decreased risks of cataract.

Objective: To investigate whether high-sensitivity C-reactive protein (hsCRP) and other biomarkers of inflammation predict age-related macular degeneration (AMD)., Methods: We measured hsCRP, soluble intercellular adhesion molecule-1 (sICAM-1), and fibrinogen levels in baseline plasma samples from 27 687 participants with a mean age of 54.6 years and initially free of AMD in the Women's Health Study. We prospectively ascertained 150 cases of AMD with vision loss of 20/30 or worse in the affected eye by self-report confirmed with review of medical records during 275 852 person-years of follow-up (mean = 10 years) and used proportional hazards models to examine the relationship between these biomarkers and AMD., Results: After adjustment for multiple risk factors, the hazard ratio (HR) (95% confidence interval [CI]) of AMD, contrasting the highest vs lowest quintile of hsCRP, was 3.09 (1.39-6.88) (P trend = .02). In similar models, the HR (95% CI) for sICAM-1 was 1.87 (0.97-3.58) (P trend = .07). The relationship between fibrinogen and AMD was J-shaped, with an HR (95% CI) of 2.01 (1.07-3.75) for women in the highest fifth vs second fifth., Conclusion: Elevated circulating levels of hsCRP, sICAM-1, and fibrinogen precede the development of visually significant AMD in women, providing further support for the hypothesis that inflammation may play a role in AMD.

Objective: To test whether beta carotene supplementation affects the incidence of age-related maculopathy (ARM) in a large-scale randomized trial., Design: Randomized, double-masked, placebo-controlled trial among 22 071 apparently healthy US male physicians aged 40 to 84 years. Participants were randomly assigned to receive beta carotene (50 mg every other day) or placebo. Main Outcome Measure Incident ARM responsible for a reduction in best-corrected visual acuity to 20/30 or worse., Results: After 12 years of treatment and follow-up, there were 162 cases of ARM in the beta carotene group vs 170 cases in the placebo group (relative risk [RR], 0.96; 95% confidence interval [CI], 0.78-1.20). The results were similar for the secondary end points of ARM with or without vision loss (275 vs 274 cases; RR, 1.01; 95% CI, 0.86-1.20) and advanced ARM (63 vs 66 cases; RR, 0.97; 95% CI, 0.69-1.37)., Conclusions: These randomized data relative to 12 years of treatment among a large population of apparently healthy men indicate that beta carotene supplementation has no beneficial or harmful effect on the incidence of ARM. Long-term supplemental use of beta carotene neither decreases nor increases the risk of ARM.

Objective: To examine the development of age-related cataract in a trial of beta carotene supplementation in men., Design: Randomized, double-masked, placebo-controlled trial., Methods: Male US physicians aged 40 to 84 years (n = 22 071) were randomly assigned to receive either beta carotene (50 mg on alternate days) or placebo for 12 years., Main Outcome Measures: Age-related cataract and extraction of age-related cataract, defined as an incident, age-related lens opacity, responsible for a reduction in best-corrected visual acuity to 20/30 or worse, based on self-report confirmed by medical record review., Results: There was no difference between the beta carotene and placebo groups in the overall incidence of cataract (998 cases vs 1017 cases; relative risk [RR], 1.00; 95% confidence interval [CI], 0.91-1.09) or cataract extraction (584 vs 593; RR, 1.00; 95% CI, 0.89-1.12). In subgroup analyses, the effect of beta carotene supplementation appeared to be modified by smoking status at baseline (P =.02). Among current smokers, there were 108 cases of cataract in the beta carotene group and 133 in the placebo group (RR, 0.74; 95% CI, 0.57-0.95). Among current nonsmokers, there was no significant difference in the number of cases in the 2 treatment groups (884 vs 881; RR, 1.03; 95% CI, 0.94-1.13). The results for cataract extraction appeared to be similarly modified by baseline smoking status (P =.05)., Conclusions: Randomized trial data from a large population of healthy men indicate no overall benefit or harm of 12 years of beta carotene supplementation on cataract or cataract extraction. However, among current smokers at baseline, beta carotene appeared to attenuate their excess risk of cataract by about one fourth.

Context: Knowledge of long-term persistence with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy is limited because previous studies have observed patients for short periods of time, in closely monitored clinical trials, or in other unrepresentative settings., Objective: To describe the patterns and predictors of long-term persistence with statin therapy in an elderly US population., Design, Setting, and Patients: Retrospective cohort study including 34 501 enrollees in the New Jersey Medicaid and Pharmaceutical Assistance to the Aged and Disabled programs who were 65 years of age and older, initiated statin treatment between 1990 and 1998, and who were followed up until death, disenrollment, or December 31, 1999., Main Outcome Measures: Proportion of days covered (PDC) by a statin in each quarter during the first year of therapy and every 6 months thereafter; predictors of suboptimal persistence during each interval (PDC <80%) were identified using generalized linear models for repeated measures., Results: The mean PDC was 79% in the first 3 months of treatment, 56% in the second quarter, and 42% after 120 months. Only 1 patient in 4 maintained a PDC of at least 80% after 5 years. The proportion of patients with a PDC less than 80% increased in a log-linear manner, comprising 40%, 61%, and 68% of the cohort after 3, 12, and 120 months, respectively. Independent predictors of poor long-term persistence included nonwhite race, lower income, older age, less cardiovascular morbidity at initiation of therapy, depression, dementia, and occurrence of coronary heart disease events after starting treatment. Patients who initiated therapy between 1996-1998 were 21% to 25% more likely to have a PDC of at least 80% than those who started in 1990., Conclusions: Persistence with statin therapy in older patients declines substantially over time, with the greatest drop occurring in the first 6 months of treatment. Despite slightly better persistence among patients who began treatment in recent years, long-term use remains low. Interventions are needed early in treatment and among high-risk groups, including those who experience coronary heart disease events after initiating treatment.

Background: Reports have suggested relationships of body weight with age-related maculopathy (ARM), particularly its nonneovascular (dry) forms, but results are inconsistent and prospective data are scarce., Objective: To examine prospectively relationships of body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) with visually significant dry and neovascular ARM during an average of 14.5 years of follow-up., Methods: Incident ARM was assessed by medical record confirmation of self-reported ARM among the 21 121 men participating in the Physicians' Health Study who (1) were followed up for at least 7 years, (2) were free of visually significant ARM at baseline, and (3) had information on BMI and cigarette smoking. We used proportional hazards regression models to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for visually significant dry ARM (256 cases) and neovascular ARM (84 cases) within 4 categories of BMI: lean (< 22.0), normal (22.0-24.9), overweight (25.0-29.9), and obese (> or = 30.0)., Results: Adjusting for age, randomized aspirin and beta carotene assignments, and cigarette smoking, the incidence for visually significant dry ARM was lowest in men with a normal BMI. Compared with these men, the RRs (95% CIs) were as follows: 1.43 (1.01-2.04) for lean, 1.24 (0.93-1.66) for overweight, and 2.15 (1.35-3.45) for obese men. Although there was no significant relationship of BMI with the diagnosis of neovascular ARM, due to the small number of cases these analyses could not rule out an important relationship., Conclusions: Obesity is a risk factor for visually significant ARM in men, in particular for dry ARM. However, the relationship of BMI with dry ARM appears to be J-shaped, and the leanest individuals also appear to be at increased risk.

Objective: To examine the development of age-related maculopathy (ARM) in a large-scale trial of low-dose aspirin treatment., Methods: The Physicians' Health Study I was a randomized, double-masked, placebo-controlled trial of low-dose aspirin (325 mg every other day) and beta carotene (50 mg every other day) in the prevention of cardiovascular disease and cancer conducted among 22 071 US male physicians aged 40 to 84 years in 1982. A total of 21 216 participants did not report ARM at baseline, were followed up for at least 7 years, and are included in this analysis., Main Outcome Measures: Total ARM, defined as a self-report confirmed by medical record evidence of an initial diagnosis subsequent to randomization, and ARM with vision loss, defined as total ARM but with vision loss to 20/30 or worse attributable to ARM., Results: Early termination of the randomized aspirin component of the Physicians' Health Study I, after an average of 60.2 months of treatment and follow-up due to a statistically extreme 44% reduced risk of first myocardial infarction, resulted in a far lower number of incident cases of ARM during the aspirin treatment period than would have accrued without early termination. Thus, during an average of 60.2 months of follow-up, a total of 117 cases of ARM were confirmed, including 57 cases responsible for vision loss to 20/30 or worse. There were 51 cases of ARM in the aspirin group and 66 in the placebo group (relative risk, 0.77; 95% confidence interval, 0.54-1.11). For ARM with vision loss, there were 25 cases in the aspirin group and 32 in the placebo group (relative risk, 0.78; 95% confidence interval, 0.46-1.32)., Conclusions: These randomized trial data tend to exclude any large beneficial effect of 5 years of low-dose aspirin treatment on ARM. However, a smaller, but potentially important, beneficial effect cannot be ruled out and would require testing in randomized trials of adequate size and duration.

Context: Several case-control studies suggest an association between analgesic use and increased risk of chronic renal disease, but few cohort studies have examined this association., Objective: To determine whether analgesic use is associated with risk of renal dysfunction., Design and Setting: Cohort study of analgesic use data from the Physicians' Health Study, which lasted 14 years from September 1982 to December 1995 with annual follow-up., Participants: A total of 11 032 initially healthy men who provided blood samples and self-report of analgesic use., Main Outcome Measures: Elevated creatinine level defined as 1.5 mg/dL (133 micromol/L) or higher and a reduced creatinine clearance defined as 55 mL/min (0.9 mL/s) or less, and self-reported use of acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs (never [<12 pills]; 12-1499 pills; 1500-2499 pills; and >/=2500 pills)., Results: A total of 460 men had elevated creatinine levels (4.2%) and 1258 had reduced creatinine clearance (11.4%). Mean creatinine levels and creatinine clearances were similar among men who did not use analgesics and those who did, even at total intakes of 2500 or more pills. In multivariable analyses adjusted for age; body mass index; history of hypertension, elevated cholesterol, and diabetes; occurrence of cardiovascular disease; physical activity; and use of other analgesics, the relative risks of elevated creatinine level associated with intake of 2500 or more pills were 0.83 (95% confidence interval [CI], 0.50-1.39; P for trend =.05) for acetaminophen, 0.98 (95% CI, 0.53-1.81; P for trend =.96) for aspirin, and 1.07 (95% CI, 0.71-1.64; P for trend =.86) for other nonsteroidal anti-inflammatory drugs. No association was observed between analgesic use and reduced creatinine clearance., Conclusions: Moderate analgesic use in this cohort study of initially healthy men was not associated with increased risk of renal dysfunction.

Background: In Physicians' Health Study I, randomized trial results indicated no major beneficial effect of 5 years of low-dose aspirin treatment on total cataract (relative risk [RR], 0.94; 95% confidence interval [CI], 0.79-1.13) or cataract extraction (RR, 0.81; 95% CI, 0.65-1.01) during the period of treatment., Objective: To examine the effect of assigned aspirin treatment and posttrial, self-selected aspirin use on the risk of age-related cataract over the 15 years of follow-up of Physicians' Health Study I., Methods: Participants were 20 968 US male physicians enrolled in Physicians' Health Study I who did not report cataract at baseline. At 7 years, after termination of the randomized aspirin component of the trial, self-selected aspirin use was computed from annual questionnaires. The main outcome measures were age-related cataract and extraction of age-related cataract, defined as an incident, age-related lens opacity responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review., Results: During a median of 14.9 years of follow-up, there were 2081 cataracts and 1198 cataract extractions. Overall, the age- and beta carotene-adjusted RR of cataract in men assigned to aspirin compared with those assigned to placebo was 1.09 (95% CI, 1.00-1.18). For cataract extraction, the RR was 1.09 (95% CI, 0.98-1.22). During a median posttrial follow-up of 7.9 years, a total of 1225 incident cataracts and 635 cataract extractions were documented. The multivariate RR of cataract in men who reported using aspirin frequently (>/=180 days per year) at 7 years compared with nonusers (0-13 days per year) was 1.20 (95% CI, 1.03-1.40). For cataract extraction, the multivariate RR was 1.22 (95% CI, 0.98-1.51). Results for diagnosis and extraction of cataract subtypes were similar., Conclusions: Analyses based on randomized aspirin assignment indicated no long-term benefit of 5 years of low-dose aspirin treatment on total cataract or cataract extraction. Posttrial, observational data also indicated no decreased risk of cataract in aspirin users and suggested a small increased risk of cataract in aspirin users. Further randomized trial data to investigate the effect of longer term treatment with low-dose aspirin are being collected as part of the ongoing Women's Health Study, a randomized trial of low-dose aspirin and vitamin E among 39 876 apparently healthy, postmenopausal US female health professionals.

Context: Although cigarette smoking has been shown to be a risk factor for age-related cataract, data are inconclusive on the risk of cataract in individuals who quit smoking., Objective: To examine the association between smoking cessation and incidence of age-related cataract., Design: Prospective cohort study conducted from 1982 through 1997, with an average follow-up of 13.6 years., Setting and Participants: A total of 20,907 US male physicians participating in the Physicians' Health Study I who did not have a diagnosis of age-related cataract at baseline and had reported their level of smoking at baseline., Main Outcome Measures: Incident age-related cataract defined as self-report confirmed by medical record review, diagnosed after study randomization and responsible for vision loss to 20/30 or worse, and surgical extraction of incident age-related cataract, in relation to smoking status and years since quitting smoking., Results: At baseline, 11% were current smokers, 39% were past smokers, and 50% were never smokers. Average reported cumulative dose of smoking at baseline was approximately 2-fold greater in current than in past smokers (35.8 vs 20.5 pack-years). Two thousand seventy-four incident cases of age-related cataract and 1193 cataract extractions were confirmed during follow-up. Compared with current smokers, multivariate relative risks (RRs) of cataract in past smokers who quit smoking fewer than 10 years, 10 to fewer than 20 years, and 20 or more years before the study were 0.79 (95% confidence interval [CI], 0.64-0.98), 0.73 (95% CI, 0.61-0.88), and 0.74 (95% CI, 0.63-0.87), respectively, after adjustment for other risk factors for cataract and age at smoking inception. The RR for never smokers was 0.64 (95% CI, 0.54-0.76). The reduced risk in past smokers was principally due to a lower total cumulative dose (RR of cataract for increase of 10 pack-years of smoking, 1.07; 95% CI, 1.04-1.10). A benefit of stopping smoking independent of cumulative dose was suggested in some analyses. Results for cataract extraction were similar., Conclusion: These prospective data indicate that while some smoking-related damage to the lens may be reversible, smoking cessation reduces the risk of cataract primarily by limiting total dose-related damage to the lens. JAMA. 2000;284:713-716

Context: Arterial stiffness increases with age. Thus, pulse pressure, an index of arterial stiffening, may predict congestive heart failure (CHF) in the elderly., Objective: To study prospectively the association between pulse pressure and risk of CHF., Design: Prospective cohort study., Setting: The community-based East Boston Senior Health Project, East Boston, Mass., Patients: A total of 1621 men and women (mean [SD] age, 77.9 [5.0] years) free of CHF who had blood pressure measurements taken in 1988-1989 and were followed up for 3.8 years., Main Outcome Measure: Incidence of CHF as ascertained by hospital discharge diagnosis (n = 208) and death certificates (n = 13)., Results: After controlling for age, sex, mean arterial pressure, history of coronary heart disease, diabetes mellitus, atrial fibrillation, valvular heart disease, and antihypertensive medication use, pulse pressure was an independent predictor of CHF. For each 10-mm Hg elevation in pulse pressure, there was a 14% increase in risk of CHF (95% confidence interval, 1.05-1.24; P = .003). Those in the highest tertile of pulse pressure (>67 mm Hg) had a 55% increased risk of CHF (P=.02) compared with those in the lowest (<54 mm Hg). Pulse pressure was more predictive than systolic blood pressure alone and was independent of diastolic blood pressure., Conclusion: Pulse pressure, an easily measurable correlate of pulsatile hemodynamic load, is an independent predictor of risk of CHF in this elderly cohort.

Context: Previous studies raise the possibility that blood pressure (BP) in middle age predicts later cognitive decline., Objective: To examine prospectively the relationship of BP with level of and change in cognitive function in the elderly., Design: Longitudinal, population-based study comprising subjects enrolled in the East Boston component of the Established Populations for the Epidemiologic Study of the Elderly (EPESE) (1982-1983) and the Hypertension Detection and Follow-Up Program (HDFP) (1973-1974)., Setting: East Boston, Mass., Participants: Of the 3657 participants in the EPESE with baseline BP measurements, 2068 also participated in the HDFP. Subjects were aged 65 to 102 years at baseline in the EPESE and had mental status and memory assessed at baseline and 3 and 6 years., Main Outcome Measures: Numbers of errors on the Short Portable Mental Status Questionnaire and the East Boston Memory Test and rates of change in these numbers of errors. Subjects had BP measured both at baseline in the EPESE and 9 years before, as part of the HDFP., Results: In analyses adjusted for age, sex, and education, there was no strong linear association between BP and cognition. The associations found were fairly small in magnitude, and varied according to which test was used to measure cognition. There was little evidence for an effect of BP on change in cognitive function with either test, or for an effect on level of function on the memory test. In analyses of level of mental status questionnaire performance, however, elevated systolic BP (> or =160 mm Hg) 9 years before baseline was associated with a 14% (95% confidence interval [CI], 4%-25%) increase in error rate, relative to the referent (130-139 mm Hg). Baseline systolic BP had a U-shaped association with the number of errors; error rates were 9% higher compared with the referent group among those with systolic BP lower than 130 mm Hg (95% CI, 1%-17%) and 7% greater (95% CI, 0%-15%) among those with elevated systolic BP. Diastolic BP 9 years before baseline also had a U-shaped association with errors on the mental status questionnaire., Conclusion: The findings do not suggest a linear association of BP with cognitive decline, but they are consistent with a more complex relationship between BP and cognition than previously appreciated.

Objective: To examine the association between cigarette smoking and the incidence of age-related macular degeneration (AMD) in men., Design: Prospective cohort study with average person-years of follow-up for AMD of 12.2 years., Participants: A total of 21 157 US male physicians participating in the Physicians' Health Study who did not have a diagnosis of AMD at baseline, were followed for at least 7 years, and had known levels of baseline smoking. Based on information reported at baseline, 11% were current smokers, 39% were past smokers, and 50% were never smokers., Main Outcome Measure: Incident AMD, defined as a self-report that was confirmed by medical record, review, first diagnosed after randomization, and responsible for vision loss to 20/30 or worse., Results: A total of 268 incident cases of AMD with vision loss were confirmed. In multivariate analysis, current smokers of 20 or more cigarettes per day, compared with never smokers, had an increased risk of AMD (relative risk [RR], 2.46; 95% confidence interval [CI], 1.60-3.79). Past smokers had a modest elevation in risk of AMD (RR, 1.30; 95% CI, 0.99-1.70). For current smokers of fewer than 20 cigarettes per day, there was a nonsignificant 26% increased risk of AMD (RR, 1.26; 95% CI, 0.61-2.59)., Conclusions: These prospective data provide support for the hypothesis that cigarette smoking increases the risk of developing AMD.

Objective: To examine whether body mass index is an independent predictor of cataract. (Body mass index is a standardized measure defined as weight in kilograms divided by the square of the height in meters.), Design: Prospective cohort study, with 5 years of follow-up., Participants: A total of 17,764 US male physicians participating in the Physicians' Health Study, aged 40 to 84 years, who were free of cataract, myocardial infarction, stroke, and cancer at baseline and reported complete information about body mass index and other cataract risk factors., Main Outcome Measure: Incident cataract, defined as a self-report, confirmed by medical record review, first diagnosed after randomization, age-related in origin, and responsible for a decrease in best corrected visual acuity to 20/30 or worse., Results: Incident cataract occurred during follow-up in 370 participants. In proportional hazards models that adjusted for potential confounding variables, body mass index had a strong, graded relationship with risk of cataract. Relative to those with body mass index less than 22, relative risks (95% confidence intervals) associated with body mass index of 22 to less than 25, 25 to less than 27.8, and 27.8 or more were 1.54 (1.04 to 2.27), 1.46 (0.98 to 2.20), and 2.10 (1.35 to 3.25), respectively. Relative to any given level of body mass index, a 2-unit higher level predicted a 12% increase in risk of cataract (95% confidence interval, 5% to 19%). Higher body mass index was especially strongly related to risk of posterior subcapsular and nuclear sclerotic cataracts and was also significantly related to risk of cataract extraction., Conclusions: In a prospective cohort study of apparently healthy men, higher body mass index, a potentially modifiable risk factor, was a determinant of cataract. The leanest men had the lowest rates, consistent with experimental evidence that restriction of energy intake slows development of cataract. Although precise mechanisms are unclear, the effect of body mass index on cataractogenesis is apparently independent of other risk factors, including age, smoking, and diagnosed diabetes.

Objective: To assess whether an association exists between moderate alcohol consumption and plasma concentration of endogenous tissue-type plasminogen activator (t-PA), a serine protease that plays a central role in the regulation of intravascular fibrinolysis., Design: Survey of self-reported alcohol consumption and plasma fibrinolytic capacity, controlled for lipid and nonlipid cardiac risk factors., Setting: Participants in the Physicians' Health Study., Participants: A total of 631 apparently healthy male physicians aged 40 to 84 years with no history of myocardial infarction, stroke, or transient cerebral ischemia., Main Outcome Measure: Plasma concentration of t-PA antigen., Results: A direct association was found between alcohol consumption and plasma level of t-PA antigen, such that mean plasma levels of t-PA antigen for daily, weekly, monthly, and rare or never drinkers were 10.9, 9.7, 9.1, and 8.1 ng/mL, respectively (P trend = .0002). The relation between alcohol consumption and t-PA antigen level was not materially changed in analyses that adjusted for total cholesterol and high-density lipoprotein cholesterol or nonlipid cardiovascular risk factors including age, body mass index, parental history of coronary heart disease, exercise frequency, and systolic and diastolic blood pressure., Conclusions: These data indicate a positive association between moderate alcohol intake and plasma level of endogenous t-PA antigen that is independent of high-density lipoprotein cholesterol. This finding supports the hypothesis that changes in fibrinolytic potential may be an important mechanism whereby moderate alcohol consumption decreases risk of heart disease.

Objective: To determine whether there is an increased risk for the initiation of antihypertensive therapy in older persons prescribed nonaspirin, nonsteroidal anti-inflammatory drugs (NSAIDs)., Design: Case-control study., Setting: New Jersey Medicaid program., Patients: Medicaid enrollees aged 65 years and older. The 9411 case patients were newly started on an antihypertensive medication between November 1981 and February 1990. A similar number of controls were randomly selected among other enrollees., Main Outcome Measures: We used logistic regression to determine the odds ratio for the initiation of antihypertensive therapy in patients using NSAIDs relative to nonusers, after adjusting for age, sex, race, nursing home residence, number of prescriptions filled, intensity of physician utilization, and days hospitalized., Results: The adjusted odds ratio for the initiation of antihypertensive therapy for recent NSAID users compared with nonusers was 1.66 (95% confidence interval, 1.54 to 1.80). The odds ratio increased with increasing daily NSAID dose: the adjusted odds ratio for users of low average daily doses relative to nonusers was 1.55 (95% CI, 1.38 to 1.74), that for medium-dose users was 1.64 (95% CI, 1.44 to 1.87), and that for high-dose users was 1.82 (95% CI, 1.62 to 2.05)., Conclusions: Use of NSAIDs may increase the risk for initiation of antihypertensive therapy in older persons. Given the high prevalence of NSAID use by elderly persons, this association may have important public health implications for the management of hypertension in the older population.

Objective: To determine the effect of regular intake of cranberry juice beverage on bacteriuria and pyuria in elderly women., Design: Randomized, double-blind, placebo-controlled trial., Subjects: Volunteer sample of 153 elderly women (mean age, 78.5 years)., Intervention: Subjects were randomly assigned to consume 300 mL per day of a commercially available standard cranberry beverage or a specially prepared synthetic placebo drink that was indistinguishable in taste, appearance, and vitamin C content but lacked cranberry content., Outcome Measures: A baseline urine sample and six clean-voided study urine samples were collected at approximately 1-month intervals and tested quantitatively for bacteriuria and the presence of white blood cells., Results: Subjects randomized to the cranberry beverage had odds of bacteriuria (defined as organisms numbering > or = 10(5)/mL) with pyuria that were only 42% of the odds in the control group (P = .004). Their odds of remaining bacteriuric-pyuric, given that they were bacteriuric-pyuric in the previous month, were only 27% of the odds in the control group (P = .006)., Conclusions: These findings suggest that use of a cranberry beverage reduces the frequency of bacteriuria with pyuria in older women. Prevalent beliefs about the effects of cranberry juice on the urinary tract may have microbiologic justification.

Objective: To determine the course of visual functions in patients with Bardet-Biedl syndrome., Patients and Methods: The 21 patients with Bardet-Biedl syndrome seen at Children's Hospital, Boston, Mass, had optotype and grating acuities and dark-adapted thresholds measured over time. Their ages at first visit ranged from 2 weeks to 23 years (median age, 6 years). The courses of the visual functions were analyzed with a random-effects model., Results: Substantial declines in visual functions were found. On average, grating and optotype acuities declined 0.09 log units (roughly 1 line) per year, and thresholds increased about 0.19 log units per year. The rates at which these visual functions were lost and the predicted level of the visual functions at ages 11 to 12 years (the mean ages of measurement) varied among individuals., Conclusions: The visual prognosis for children with Bardet-Biedl syndrome is poor. The course of both central and peripheral visual functions is variable.

Objective: To examine the association between cigarette smoking and the incidence of cataract., Design, Setting, and Participants: The design was a prospective cohort study using data from the Physicians' Health Study, a randomized trial of aspirin and beta carotene among 22,071 US male physicians aged 40 to 84 years that began in 1982. This analysis includes the 17,824 physicians who did not report cataract at baseline and did provide complete risk factor information. Based on information reported at baseline, 10% were current smokers, 39% were past smokers, and 51% were never smokers., Main Outcome Measure: An incident cataract was defined as a self-report confirmed by medical record review to have been first diagnosed after randomization, age-related in origin, and responsible for a decrease in best corrected visual acuity to 20/30 or worse., Main Results: During 60 months of follow-up, 557 incident cataracts among 371 participants were confirmed. Compared with never smokers, current smokers of 20 or more cigarettes per day had a statistically significant increase in the risk of cataract (relative risk [RR], 2.16; 95% confidence interval [Cl], 1.46 to 3.20; P less than .001). Similar results were obtained after simultaneously controlling for other potential cataract risk factors in a logistic regression model (RR, 2.05; 95% Cl, 1.38 to 3.05; P less than .001). Among the 557 eyes with cataract, nuclear sclerotic changes were present in 442 while posterior subcapsular changes were present in 204. After controlling for other potential cataract risk factors, current smokers of 20 or more cigarettes per day had statistically significant increases in nuclear sclerosis (RR, 2.24; 95% Cl, 1.47 to 3.41; P less than .001) and posterior subcapsular (RR, 3.17; 95% Cl, 1.81 to 5.53; P less than .001) cataract. Past smokers had an elevated risk of posterior subcapsular (RR, 1.44; 95% Cl, 0.97 to 2.13; P = .07) but not nuclear sclerosis cataract. For current smokers of fewer than 20 cigarettes per day, no increased risks were observed of total, nuclear sclerosis, or posterior subcapsular cataract., Conclusions: These data provide support for the hypothesis that cigarette smoking increases the risk of developing both nuclear sclerosis and posterior subcapsular cataract.

We evaluated visual outcome and risk of metastases in patients who underwent cataract extraction after protonbeam irradiation of a uveal melanoma. A total of 84 patients underwent cataract extraction between 2 months and 11 years after irradiation. One year after cataract extraction, approximately half of the patients had visual acuity of 20/100 or better, and approximately one third had an acuity of 20/40 or better. Larger tumor size was highly correlated with poor visual outcome 1 year after extraction. Six patients underwent enucleation after cataract removal, five due to blind, painful eyes and one due to continued growth of a previously undiagnosed ring melanoma. The rate of metastases was not higher among patients who underwent cataract extraction (adjusted rate ratio, 0.83). Results suggest that cataract extraction offers improvement of vision in selected eyes previously irradiated for a uveal melanoma, without adding to the risk of metastases among patients undergoing the procedure.