Marlene J. Egger

Randomized Secondary Prevention Trial of Azithromycin in Patients With Coronary Artery Disease and Serological Evidence for Chlamydia pneumoniae Infection The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) Study

BACKGROUND Chlamydia pneumoniae commonly causes respiratory infection, is vasotropic, causes atherosclerosis in animal models, and has been found in human atheromas. Whether it plays a causal role in clinical coronary artery disease (CAD) and is amenable to antibiotic therapy is uncertain. METHODS AND RESULTS CAD patients (n=302) who had a seropositive reaction to C pneumoniae (IgG titers >/=1:16) were randomized to receive placebo or azithromycin, 500 mg/d for 3 days, then 500 mg/wk for 3 months. Circulating markers of inflammation (C-reactive protein [CRP], interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]-alpha), C pneumoniae antibody titers, and cardiovascular events were assessed at 3 and 6 months. Treatment groups were balanced, with age averaging 64 (SD=10) years; 89% of the patients were male. Azithromycin reduced a global rank sum score of the 4 inflammatory markers at 6 (but not 3) months (P=0. 011) as well as the mean global rank sum change score: 531 (SD=201) for active drug and 587 (SD=190) for placebo (P=0.027). Specifically, change-score ranks were significantly lower for CRP (P=0.011) and IL-6 (P=0.043). Antibody titers were unchanged, and number of clinical cardiovascular events at 6 months did not differ by therapy (9 for active drug, 7 for placebo). Azithromycin decreased infections requiring antibiotics (1 versus 12 at 3 months, P=0.002) but caused more mild, primarily gastrointestinal, adverse effects (36 versus 17, P=0.003). CONCLUSIONS In CAD patients positive for C pneumoniae antibodies, global tests of 4 markers of inflammation improved at 6 months with azithromycin. However, unlike another smaller study, no differences in antibody titers and clinical events were observed. Longer-term and larger studies of antichlamydial therapy are indicated.

Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate

Methotrexate therapy has been effective in the treatment of RA with short term experience suggesting little serious adverse reactions. Our review of 168 patients receiving methotrexate has identified nine patients with probable or possible methotrexate-induced pulmonary toxicity, giving a prevalence of 5% and an incidence of 3.9 per 100 patients per year. No clinical or laboratory features showed an association that could potentially predict the development of pulmonary disease. All patients experienced complete recovery with supportive care and/or corticosteroid therapy. Clinical monitoring for this complication is warranted in all patients receiving long term methotrexate therapy for RA.

Variability in Physician Opinion on Limiting Pediatric Life Support

Objective. We conducted this study to investigate how physicians in a pediatric intensive care unit (ICU) currently make decisions to withdraw and withhold life support. Consultation with the patients primary caregiver often precedes decisions about withdrawal and limitation of life support in chronically ill patients. In these scenarios, the patients primary caregiver was the pediatric oncologist. To evaluate the influence of subspecialty training, we compared the attitudes of the pediatric intensivists and the oncologists using scenarios describing critically ill oncology patients. Design. Cross-sectional survey. Each physician was randomly assigned 4 of 8 potential case scenarios. Setting. A total of 29 American pediatric ICUs. Participants. Pediatric intensive care and oncology attendings and fellows. Intervention. Systematic manipulation of patient characteristics in two hypothetical case scenarios describing 6-year-old female oncology patients presenting to the ICU after the institution of mechanical ventilator support for acute respiratory failure. Cases 1 through 4 described a patient who, before admission, had a 99% projected 1-year probability of survival from her underlying cancer and suffered from severe neurologic disabilities. Cases 5 through 8 described a patient who was neurologically normal before admission and had a <1% chance of surviving longer than 1 year because of her underlying cancer. Each physician was randomly assigned 2 cases from cases 1 through 4 and 2 cases from cases 5 through 8. Within each of these case scenarios, parental preferences (withdraw or advance support or look for guidance from the caregivers) and probability of survival (5% vs 40%) were manipulated. Before distribution, the survey instrument was pilot-tested and underwent a rigorous assessment for clinical sensibility. Primary Outcome Measures. Physicians ratings of the importance of 10 factors considered in the decision to withdraw life support, and their decisions about the appropriate level of care to provide. Respondents were offered five management options representing five levels of care: 1) discontinue inotropes and mechanical ventilation but continue comfort measures; 2) discontinue inotropes and other maintenance therapy but continue mechanical ventilation and comfort measures; 3) continue with current management but add no new therapeutic intervention; 4) continue with current management, add additional inotropes, change antibiotics and the like as needed, but do not start dialysis; and 5) continue with full aggressive management and plan for dialysis if necessary. Respondents also were asked whether they would obtain an ethics consultation. Results. A total of 270 physicians responded to our survey (165 of 198 potentially eligible pediatric intensivists and 105 of 178 pediatric oncologists for response rates of 83% and 59%, respectively). The respondents considered the probability of ICU survival and the wishes of the parents regarding the aggressiveness of care most important in the decision to limit life-support interventions. No clinically important differences were found when the responses of oncologists were compared with those of intensivists. In six of eight possible scenarios, the same level of intensity of care was chosen by less than half of all respondents. In three scenarios, ≥10% of respondents chose full aggressive management as the most appropriate level of care, whereas another ≥10% chose comfort measures only when viewing the same scenario. The most significant respondent factors affecting choices were professional status (attending vs fellow) and the self-rated importance of functional neurologic status. The majority of respondents (83%) believed that the intensive care and the oncology staff were usually in agreement at their institution about the level of intervention to recommend to the parents. Respondents reporting that they were more likely to withdraw life support than their colleagues were more likely to limit life-support interventions in the scenarios than those who reported that they were less likely to withdraw life support. At least 50% of respondents would request an ethics consult when 1) the probability of acute survival was 40% and the parents wanted to withdraw support in the patient with neurologic disabilities and 2) when the probability of survival was 5% and the parents wanted to advance support in the patient with a <1 year life expectancy from her underlying cancer. Conclusions. Acute prognosis, parental wishes, and functional status are significant determinants of limitations of life support for critically ill children. However, responses to these hypothetical patient scenarios reflect marked variability in decision-making across pediatric intensivists and oncologists. The degree to which this variability in decision-making exists in actual patient care requires additional study. Variability in decision-making may lead to unnecessary suffering, lack of fairness when making decisions about neurologically handicapped individuals, and inappropriate use of scarce resources in futile cases. Increased efforts should be directed at developing clearer recommendations for limiting life support in critically ill children.

Electron arc irradiation of the postmastectomy chest wall: clinical results

Abstract Background and purpose : Since 1980 electron arc irradiation of the postmastectomy chest wall has been the preferred technique for patients with advanced breast cancer at our institution. Here we report the results of this technique in 140 consecutive patients treated from 1980 to 1993. Materials and Methods : Thoracic computerized tomography was used to determine internal mammary lymph node depth and chest wall thickness, and for computerized dosimetry calculations. Total doses of 45–50 Gy in 5 to 5 12 weeks were delivered to the chest wall and internal mammary lymph nodes via electron arc and, in most cases, supraclavicular and axillary nodes were treated with a matching photon field. Patients were assessed for acute and late radiation changes, local and distant control of disease, and survival. Patients had a minimum follow-up of 1 year after completion of radiation treatment, and a mean follow up interval of 49 months and a median of 33 months. All patients had advanced disease: T stages 1, 2, 3, and 4 represented 21%, 39%, 21% and 19% of the study population, with a mean number of positive axillary lymph nodes of 6.5 (range, 0–29). Analysis was performed according to adjuvant status (no residual disease, n = 90), residual disease (positive margin, n = 15, and primary radiation, n = 2), or recurrent disease ( n = 33). Results : Acute radiation reactions were generally mild and self limiting. A total of 26% of patients developed moist desquamation, and 32% had brisk erythema. Actuarial 5 year local-regional control, freedom from distant failure, and cause-specific survival was 91%, 64%, and 75% in the adjuvant group; 84%, 50%, and 53% in the residual disease group; and 63%, 34%, and 32% in the recurrent disease group, respectively. In univariate Cox regressions, the number of positive lymph nodes was predictive for local failure in the adjuvant group ( P = 0.037). Chronic complications were minimal with 11% of patients having arm edema, 17% hyperpigmentation, and 13% telangectasia formation. Conclusion : These data demonstrate that local-regional control with electron arc therapy of the postmastectomy chest wall is comparable to photon techniques. Acute radiation reactions are well tolerated and mostly of minor extent. A previous report demonstrated a significant reduction in the dose-volume relationship of the lung using the electron arc compared with two photon techniques. Consequently, with careful attention to treatment planning and dosimetry, electron arc therapy of the postmastectomy chest wall is safe and effective. The radiation dose to heart and lung is minimized without compromise on local control.

Uses and abuses of analysis of covariance in clinical trials

Measurement of improvement in clinical trials in chronic diseases commonly compares baseline data to endpoint values by performing t-tests or analysis of variance (ANOVA) on raw gains or percentage changes. This procedure can be misleading and the use of an analysis of covariance (ANCOVA) should be considered. Properly used, ANCOVA increases statistical power in a clinical trial. However, its advantage over t-tests can be nullified by small numbers of patients, violations of assumptions, and incorrect application of the techniques. An evaluation of ANCOVA in chronic disease studies is given, with examples of its strengths and weaknesses as seen in several drug trials in the rheumatic diseases. Recommendations on its use and a decision tree for the nonstatistician are provided.

Can women correctly contract their pelvic floor muscles without formal instruction

Objectives It is unknown how many women presenting for primary care can appropriately contract their pelvic floor muscle (PFM) or whether this ability differs between women with or without pelvic floor disorders. We sought to describe the proportion of women who initially incorrectly contract the PFM and how many can learn after basic instruction. Methods This cross-sectional study enrolled 779 women presenting to community-based primary care practices. During PFM assessment, research nurses recorded whether women could correctly contract their PFM after a brief verbal cue. We defined pelvic organ prolapse (POP) as prolapse to or beyond the hymen and stress urinary incontinence (SUI) as a score of greater than equal 3 on the Incontinence Severity Index. Results Pelvic floor muscle contraction was done correctly on first attempt in 85.5%, 83.4%, 68.6%, and 85.8% of women with POP, SUI, both POP and SUI, and neither POP nor SUI, respectively (P=0.01 for difference between POP and SUI versus neither POP nor SUI). Of 120 women who initially incorrectly contracted the PFM, 94 women (78%) learned after brief instruction. Women with POP were less likely to learn than women with neither POP nor SUI (54.3% vs 85.7%, P=0.001). Increasing vaginal delivery and decreasing caffeine intake (but not age or other demographic factors) were associated with incorrect PFM contraction; only decreased caffeine intake remained significant on multivariable analysis. Conclusions Most women with no or mild pelvic floor disorders can correctly contract their PFM after a simple verbal cue, suggesting that population-based prevention interventions can be initiated without clinical confirmation of correct PFM technique.

Misclassification of exposure in a case-control study : the effects of different types of exposure and different proxy respondents in a study of pancreatic cancer

This investigation addressed three questions about misclassification in a case-control study of risk factors for pancreatic cancer in which all exposure data were obtained from proxy respondents. These questions were: (1) To what degree was misclassification dependent on the type of exposure? (2) To what degree did misclassification vary by the type of proxy? (3) What was the magnitude of the effect of proxy misclassification on odds ratios measured across several levels of exposure? To answer these questions. we interviewed 163 control (index) subjects and next-of-kin (proxy) respondent pairs. Each of the controls and their respective proxies reported the controls use of coffee, cigarettes, and alcohol and weekly exposure to beef, milk, bacon, fruits, and vegetables. Nonspouse proxies misclassified exposures more than spouse proxies with the exception of cigarettes. Cigarette use was the most accurately reported exposure, followed by alcohol, coffee, and foods. For nondifferential misclassification between cases and controls, the slope of a dose-response curve was decreased from 6.6% to 100% depending on the exposure and the type of proxy respondent. Investigators conducting studies using proxy respondents need to recognize that misclassification is a function of multiple factors, including both the type of exposures under study and the type of proxies available. (Epidemiology 1992;3:223-231)

Adverse drug events in trauma patients.

BACKGROUND Adverse drug events (ADEs) are noxious and unintended results of drug therapy. ADEs have been shown to be a risk to hospitalized patients. The purpose of this study was to determine the rate and nature of ADEs in trauma patients and to characterize the population at risk. METHODS An electronic medical record, a hospital wide computerized surveillance program, and a clinical pharmacist prospectively investigated ADEs in 4,320 trauma patients from 1996 through 1999. RESULTS The rate of ADEs in trauma patients (98/4320, 2.3%) was twice that of non-trauma hospital patients (1,111/96,218, 1.2%, p < 0.001). Traumatized females had ADEs 1.5 times more often than traumatized males (2.7% versus 1.8%, p = 0.052). The medication class most often associated with ADEs was analgesics with 54% involving morphine and 20% involving meperidine. The most common ADEs were nausea, vomiting, and itching. Only one ADE was directly attributed to a medical error. CONCLUSIONS Trauma patients are at double the risk for ADEs. Analgesics are particularly associated with ADEs and use should be carefully monitored.

Dose volume histogram analysis of lung radiation from chest wall treatment: Comparison of electron arc and tangential photon beam techniques

The technique of electron arc irradiation of the post-mastectomy chest wall was developed to improve dose uniformity and to reduce lung irradiation in comparison to that seen with standard chest wall tangent photon beam methods. Because of the cephalocaudal variation in chest wall shape and thickness, electron arc treatment planning requires anatomical detail provided by multiple axial CT images of the thorax. To compare the fixed beam and rotational techniques, computer simulated beams covering the chest wall and internal mammary lymphatics were retrospectively applied to the CT-derived contours obtained during treatment planning for 12 consecutive patients receiving adjuvant chest wall treatment by electron arc. The lung dose distribution for each technique was calculated using heterogeneity corrections. The multiplanar 2-dimensional isodose distributions were summed to provide estimated 3-dimensional dose distributions of integral histograms. These reveal that for most of these patients a modest to large improvement in volume-dose relationship occurs with the electron arc technique.

Intra-abdominal pressures during activity in women using an intra-vaginal pressure transducer

Abstract Strenuous physical activity has been linked to pelvic floor disorders in women. Using a novel wireless intra-vaginal pressure transducer, intra-abdominal pressure was measured during diverse activities in a laboratory. Fifty-seven women performed a prescribed protocol using the intra-vaginal pressure transducer. We calculated maximal, area under the curve and first moment of the area intra-abdominal pressure for each activity. Planned comparisons of pressure were made between levels of walking and cycling and between activities with reported high pressure in the literature. Findings indicate variability in intra-abdominal pressure amongst individuals doing the same activity, especially in activities that required regulation of effort. There were statistically significant differences in maximal pressure between levels of walking, cycling and high pressure activities. Results for area under the curve and first moment of the area were not always consistent with maximal pressure. Coughing had the highest maximal pressure, but had lower area under the curve and first moment of the area compared to most activities. Our data reflect novel findings of maximal, area under the curve and first moment of the area measures of intra-abdominal pressure, which may have clinical relevance for how physical activity relates to pelvic floor dysfunction.