Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis

Context  Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear. Objective  To determine whether antibodies to EBV are elevated before the onset of MS. Design, Setting, and Participants  Nested case-control study conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood sample collection were selected. Serial samples collected before the onset of symptoms were available for 69 matched case-control sets. Main Outcome Measures  Antibodies including IgA against EBV viral capsid antigen (VCA), and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus. Results  The average time between blood collection and MS onset was 4 years (range, <1-11 years). The strongest predictors of MS were serum levels of IgG antibodies to EBNA complex or EBNA-1. Among individuals who developed MS, serum antibody titers to EBNA complex were similar to those of controls before the age of 20 years (geometric mean titers: cases = 245, controls = 265), but 2- to 3-fold higher at age 25 years and older (cases = 684, controls = 282; P<.001). The risk of MS increased with these antibody titers; the relative risk (RR) in persons with EBNA complex titers of at least 1280 compared with those with titers less than 80 was 9.4 (95% confidence interval [CI], 2.5-35.4; P for trend <.001). In longitudinal analyses, a 4-fold increase in anti-EBNA complex or anti–EBNA-1 titers during the follow-up was associated with a 3-fold increase in MS risk (EBNA complex: RR , 3.0; 95% CI, 1.3-6.5; EBNA-1: RR, 3.0; 95% CI, 1.2-7.3). No association was found between cytomegalovirus antibodies and MS. Conclusion  These results suggest an age-dependent relationship between EBV infection and development of MS.      

Long-term proton pump inhibitor therapy and risk of hip fracture

Context  Proton pump inhibitors (PPIs) may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps. Objective  To determine the association between PPI therapy and risk of hip fracture. Design, Setting, and Patients  A nested case-control study was conducted using the General Practice Research Database (1987-2003), which contains information on patients in the United Kingdom. The study cohort consisted of users of PPI therapy and nonusers of acid suppression drugs who were older than 50 years. Cases included all patients with an incident hip fracture. Controls were selected using incidence density sampling, matched for sex, index date, year of birth, and both calendar period and duration of up-to-standard follow-up before the index date. For comparison purposes, a similar nested case-control analysis for histamine 2 receptor antagonists was performed. Main Outcome Measure  The risk of hip fractures associated with PPI use. Results  There were 13 556 hip fracture cases and 135 386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80-3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15-1.30]; 2 years, 1.41 [95% CI, 1.28-1.56]; 3 years, 1.54 [95% CI, 1.37-1.73]; and 4 years, 1.59 [95% CI, 1.39-1.80]; P<.001 for all comparisons). Conclusion  Long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.      

Multiple sclerosis and Epstein-Barr virus

Context  Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear. Objective  To determine whether antibodies to EBV are elevated before the onset of MS. Design, Setting, and Population  Nested case-control study conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood sample collection were selected. Main Outcome Measures  Antibodies including IgA against EBV viral capsid antigen (VCA) and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus. Results  The average time between blood collection and MS onset was 4 years. The strongest predictors of MS were serum levels of IgG antibodies to VCA or EBNA complex. The risk of MS increased monotonically with these antibody titers; relative risk (RR) in persons in the highest category of VCA (2560) compared with those in the lowest (160) was 19.7 (95% confidence interval [CI], 2.2-174; P for trend = .004). For EBNA complex titers, the RR for those in the highest category (1280) was 33.9 (95% CI, 4.1-283; P for trend <.001) vs those in the lowest category (40). Similarly strong positive associations between EBV antibodies and risk of MS were already present in samples collected 5 or more years before MS onset. No association was found between cytomegalovirus antibodies and MS. Conclusion  These results suggest a relationship between EBV infection and development of MS.      

Medicine residents' understanding of the biostatistics and results in the medical literature

Context  Physicians depend on the medical literature to keep current with clinical information. Little is known about residents' ability to understand statistical methods or how to appropriately interpret research outcomes. Objective  To evaluate residents' understanding of biostatistics and interpretation of research results. Design, Setting, and Participants  Multiprogram cross-sectional survey of internal medicine residents. Main Outcome Measure  Percentage of questions correct on a biostatistics/study design multiple-choice knowledge test. Results  The survey was completed by 277 of 367 residents (75.5%) in 11 residency programs. The overall mean percentage correct on statistical knowledge and interpretation of results was 41.4% (95% confidence interval [CI], 39.7%-43.3%) vs 71.5% (95% CI, 57.5%-85.5%) for fellows and general medicine faculty with research training (P < .001). Higher scores in residents were associated with additional advanced degrees (50.0% [95% CI, 44.5%-55.5%] vs 40.1% [95% CI, 38.3%-42.0%]; P < .001); prior biostatistics training (45.2% [95% CI, 42.7%-47.8%] vs 37.9% [95% CI, 35.4%-40.3%]; P = .001); enrollment in a university-based training program (43.0% [95% CI, 41.0%-45.1%] vs 36.3% [95% CI, 32.6%-40.0%]; P = .002); and male sex (44.0% [95% CI, 41.4%-46.7%] vs 38.8% [95% CI, 36.4%-41.1%]; P = .004). On individual knowledge questions, 81.6% correctly interpreted a relative risk. Residents were less likely to know how to interpret an adjusted odds ratio from a multivariate regression analysis (37.4%) or the results of a Kaplan-Meier analysis (10.5%). Seventy-five percent indicated they did not understand all of the statistics they encountered in journal articles, but 95% felt it was important to understand these concepts to be an intelligent reader of the literature. Conclusions  Most residents in this study lacked the knowledge in biostatistics needed to interpret many of the results in published clinical research. Residency programs should include more effective biostatistics training in their curricula to successfully prepare residents for this important lifelong learning skill.      

Prophylactic Oral Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularization, Valve Replacement, or Repair: PAPABEAR: a randomized controlled trial

Context  Atrial tachyarrhythmias after cardiac surgery are associated with adverse outcomes and increased costs. Previous trials of amiodarone prophylaxis, while promising, were relatively small and yielded conflicting results. Objective  To determine whether a brief perioperative course of oral amiodarone is an effective and safe prophylaxis for atrial tachyarrhythmias after cardiac surgery overall and in important subgroups. Design, Setting, and Patients  Double-blind randomized controlled trial of 601 patients listed for nonemergent coronary artery bypass graft (CABG) surgery and/or valve replacement/repair surgery between February 1, 1999, and September 26, 2003, at a tertiary care hospital. The patients were followed up for 1 year. Intervention  Oral amiodarone (10 mg/kg daily) or placebo administered 6 days prior to surgery through 6 days after surgery (13 days). Randomization was stratified for subgroups defined by age, type of surgery, and use of preoperative -blockers. Main Outcome Measure  Incidence of atrial tachyarrhythmias lasting 5 minutes or longer that prompted therapy by the sixth postoperative day. Results  Atrial tachyarrhythmias occurred in fewer amiodarone patients (48/299; 16.1%) than in placebo patients (89/302; 29.5%) overall (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.34-0.69; P<.001); in patients younger than 65 years (19 [11.2%] vs 36 [21.1%]; HR, 0.51 [95% CI, 0.28-0.94]; P = .02); in patients aged 65 years or older (28 [21.7%] vs 54 [41.2%]; HR, 0.45 [95% CI, 0.27-0.75]; P<.001); in patients who had CABG surgery only (22 [11.3%] vs 46 [23.6%]; HR, 0.45 [95% CI, 0.26-0.79]; P = .002); in patients who had valve replacement/repair surgery with or without CABG surgery (25 [23.8%] vs 44 [44.1%]; HR, 0.51 [95% CI, 0.31-0.84; P = .008); in patients who received preoperative -blocker therapy (27 [15.3%] vs 42 [25.0%]; HR, 0.58 [95% CI, 0.34-0.99]; P = .03); and in patients who did not receive preoperative -blocker therapy (20 [16.3%] vs 48 [35.8%]; HR, 0.40 [95% CI, 0.22-0.71]; P<.001), respectively. Postoperative sustained ventricular tachyarrhythmias occurred less frequently in amiodarone patients (1/299; 0.3%) than in placebo patients (8/302; 2.6%) (P = .04). Dosage reductions of blinded therapy were more common in amiodarone patients (34/299; 11.4%) than in placebo patients (16/302; 5.3%) (P = .008). There were no differences in serious postoperative complications, in-hospital mortality, or readmission to the hospital within 6 months of discharge or in 1-year mortality. Conclusion  Oral amiodarone prophylaxis of atrial tachyarrhythmias after cardiac surgery is effective and may be safe overall and in important patient subgroups. Clinical Trials Registration  ClinicalTrials.gov Identifier: NCT00251706      

Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis

Sonal Singh, MD, MPH; Yoon K. Loke, MBBS, MD; Curt D. Furberg, MD, PhD

JAMA. 2008;300(12):1439-1450.

Context  Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown.

Objective  To ascertain the cardiovascular risks of inhaled anticholinergics,including cardiovascular death, myocardial infarction (MI), and stroke.

Data Sources  Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews,regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions.

Study Selection  Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events.

Data Extraction  The primary outcome was a composite of cardiovascular death,MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I² statistic.

Data Synthesis  After a detailed screening of 103 articles, 17 trials enrolling 14 783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7311 patients (1.2%) receiving control therapy (RR, 1.58 [95%confidence interval {CI}, 1.21-2.06]; P < .001,I² = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR, 1.53 [95% CI 1.05-2.23]; P = .03, I² = 0%) and cardiovascular death (RR, 1.80 [95% CI, 1.17-2.77]; P = .008,I² = 0%) without a statistically significant increase in the risk of stroke (RR, 1.46 [95% CI, 0.81-2.62]; P = .20, I² = 0%).All-cause mortality was reported in 149 of the patients treated with inhaled anticholinergics (2.0%) and 115 of the control patients (1.6%)(RR, 1.26 [95% CI, 0.99-1.61]; P = .06,I² = 2%). A sensitivity analysis restricted to 5 long-term trials (>6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95%CI, 1.27-2.36]; P < .001, I² = 0%).

Conclusion  Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

     

Contemporary clinical profile and outcome of prosthetic valve endocarditis

Context  Prosthetic valve endocarditis (PVE) is associated with significant mortality and morbidity. The contemporary clinical profile and outcome of PVE are not well defined. Objectives  To describe the prevalence, clinical characteristics, and outcome of PVE, with attention to health care–associated infection, and to determine prognostic factors associated with in-hospital mortality. Design, Setting, and Participants  Prospective, observational cohort study conducted at 61 medical centers in 28 countries, including 556 patients with definite PVE as defined by Duke University diagnostic criteria who were enrolled in the International Collaboration on Endocarditis-Prospective Cohort Study from June 2000 to August 2005. Main Outcome Measure  In-hospital mortality. Results  Definite PVE was present in 556 (20.1%) of 2670 patients with infective endocarditis. Staphylococcus aureus was the most common causative organism (128 patients [23.0%]), followed by coagulase-negative staphylococci (94 patients [16.9%]). Health care–associated PVE was present in 203 (36.5%) of the overall cohort. Seventy-one percent of health care–associated PVE occurred within the first year of valve implantation, and the majority of cases were diagnosed after the early (60-day) period. Surgery was performed in 272 (48.9%) patients during the index hospitalization. In-hospital death occurred in 127 (22.8%) patients and was predicted by older age, health care–associated infection (62/203 [30.5%]; adjusted odds ratio [OR], 1.62; 95% confidence interval [CI], 1.08-2.44; P = .02), S aureus infection (44/128 [34.4%]; adjusted OR, 1.73; 95% CI, 1.01-2.95; P = .05), and complications of PVE, including heart failure (60/183 [32.8%]; adjusted OR, 2.33; 95% CI, 1.62-3.34; P<.001), stroke (34/101 [33.7%]; adjusted OR, 2.25; 95% CI, 1.25-4.03; P = .007), intracardiac abscess (47/144 [32.6%]; adjusted OR, 1.86; 95% CI, 1.10-3.15; P = .02), and persistent bacteremia (27/49 [55.1%]; adjusted OR, 4.29; 95% CI, 1.99-9.22; P<.001). Conclusions  Prosthetic valve endocarditis accounts for a high percentage of all cases of infective endocarditis in many regions of the world. Staphylococcus aureus is now the leading cause of PVE. Health care–associated infection significantly influences the clinical characteristics and outcome of PVE. Complications of PVE strongly predict in-hospital mortality, which remains high despite prompt diagnosis and the frequent use of surgical intervention.      

Hepatitis C and progression of HIV disease

Context  Conflicting reports exist regarding the effect of hepatitis C virus(HCV) on the progression of human immunodeficiency virus (HIV) disease. Objective  To assess the effect of HCV infection on clinical and immunologic progressionof HIV disease and immunologic response to highly active antiretroviral therapy(HAART). Design  Prospective cohort study. Setting  University-based, urban HIV clinic in the United States. Patients  There were 1955 patients enrolled between January 1995 and January 2001who were eligible for analysis because of having at least 1 return visit tothe clinic and being free of acquired immunodeficiency syndrome (AIDS) atenrollment. Median (interquartile range) length of follow-up was 2.19 (1.00-3.50)years for HCV-infected and 2.00 (1.00-3.00) years for HCV-uninfected patients. Main Outcome Measures  Progression to an AIDS-defining illness, survival, and progression toa CD4 cell count below 200/µL; CD4 cell count change following initiationof effective HAART (resulting in a viral load of <400 copies/mL recordedat 75% of measurements). Results  No difference was detected in the risk of acquiring an AIDS-definingillness (HCV-infected patients, 231 events [26.4%] and HCV-uninfected patients,264 events [24.4%]; relative hazard [RH], 1.03; 95% confidence interval [CI],0.86-1.23) or in the risk of death (HCV-infected patients, 153 deaths [17.5%]and HCV-uninfected patients, 168 deaths [15.5%]; RH, 1.05; 95% CI, 0.85 -1.30).Although an increased risk of death was detected in the subgroup of 429 HCV-infectedpatients with a baseline CD4 cell count of 50/µL through 200/µL(RH, 1.51; 95% CI, 1.01-2.27), after adjustment for exposure to HAART andits effectiveness in a multivariate Cox regression analysis, death was notindependently associated with HCV infection in this subgroup (RH, 1.01; 95%CI, 0.65-1.56). Similarly, in those receiving effective HAART (n = 208), therewas no difference in the increase in CD4 cell count or CD4 percentage duringHAART in HCV-infected compared with HCV-uninfected patients. Conclusions  Among patients in this urban US cohort, we did not detect evidence thatHCV infection substantially alters the risk of dying, developing AIDS, orresponding immunologically to HAART, especially after accounting for differencesin its administration and effectiveness.      

Risk factors for parvovirus B19 infection in pregnancy

Context  Parvovirus B19 infection during pregnancy has been associated with fetal death. However, the incidence of and risk factors for infection in pregnant women have not been well studied. Objectives  To estimate a pregnant woman's risk of infection with parvovirus B19 in epidemic and endemic situations and to study risk factors for infection. Design  Population-based cohort study conducted between November 1992 and June 1994. Setting  Three regions in Denmark. Participants  A total of 30,946 pregnant women from a consecutive and population-based screening. Main Outcome Measures  Specific IgG antibodies in serum samples obtained in the first trimester of pregnancy and from the newborn infant to assess past infection and seroconversion. Information on family structure, educational background, socioeconomic status, and pregnancy outcome was obtained from national registers. Results  Based on 30,946 serum samples, 65.0% of pregnant women had evidence of past infection. Annual seroconversion rates among susceptible women during endemic and epidemic periods were 1.5% (95% confidence interval [CI], 0.2%-1.9%) and 13.0% (95% CI, 8.7%-23.1%), respectively. Baseline seropositivity was significantly correlated with increasing number of siblings, having a sibling of the same age, number of own children, and occupational exposure to children. Risk of acute infection increased with the number of children in the household as follows: 0 children odds ratio (OR), 1 (reference); 1 child OR, 3.17 (95% CI, 2.24-4.49); 2 children OR, 5.47 (95% CI, 3.55-8.45); 3 or more children OR, 7.54 (95% CI, 3.80-14.94). Having children aged 6 to 7 years resulted in the highest rate of seroconversion among mothers (6.8%; OR, 4.07; 95% CI, 1.89-8.73). Compared with other pregnant women, nursery school teachers had a 3-fold increased risk of acute infection (OR, 3.09; 95% CI, 1.62-5.89). Population-attributable risk of seroconversion was 55.4% for number of own children and 6.0% for occupational exposure. Conclusions  The risk of infection is high for susceptible pregnant women during epidemics and associated with the level of contact with children. Nursery school teachers have the highest occupational risk, but most infections seem to be the result of exposure to the woman's own children.