Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml.

In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

Pervasive emotion recognition deficit common to alexithymia and the repressive coping style.

OBJECTIVE: Previous research has demonstrated a deficit in the ability to recognize emotions in alexithymic individuals. The repressive coping style is thought to preferentially impair the detection of unpleasant compared with pleasant emotions, and the degree of deficit is typically thought to be less severe than in alexithymia. We compared emotion recognition ability in both individuals with alexithymia and those with the repressive coping style. METHODS: Three hundred seventy-nine subjects completed the 20-item Toronto Alexithymia Scale, the Levels of Emotional Awareness Scale, the Marlowe-Crowne Scale (a measure of repressive defensiveness), the Bendig Short Form of the Taylor Manifest Anxiety Scale, and the Perception of Affect Task. The Perception of Affect Task consists of four 35-item emotion recognition subtasks: matching sentences and words, faces and words, sentences and faces, and faces and photographs of scenes. The stimuli in each subtask consist of seven emotions (happiness, sadness, anger, fear, disgust, surprise, and neutral) depicted five times each. Recognition accuracy results were collapsed across subtasks within each emotion category. RESULTS: Highly alexithymic subjects (for all, p<.01) and those with low emotional awareness (for all, p<.001) were consistently less accurate in emotion recognition in all seven categories. Highly defensive subjects (including repressors) were less accurate in the detection of anger, sadness, fear, and happiness (for all, p<.05). Furthermore, scores on the Levels of Emotional Awareness Scale accounted for significantly more variance in performance on the Perception of Affect Task than scores on the Marlowe-Crowne Scale (p<.01). CONCLUSIONS: The results indicate that alexithymia and the repressive coping style are each associated with impairments in the recognition of both pleasant and unpleasant emotions and that the two styles of emotional self-regulation differ more in the magnitude than in the quality of these impairments.

Stress management in medical education: a review of the literature.

PURPOSE: To review systematically clinical studies providing empirical data on stress-management programs in medical training. METHOD: The authors searched Medline and PSYCHINFO from 1966 to 1999. Studies were included if they evaluated stress-management programs for medical trainees (medical students, interns, or residents); reported empirical data; and had been conducted at allopathic medical schools. RESULTS: Although the search yielded over 600 articles discussing the importance of addressing the stress of medical education, only 24 studies reported intervention programs, and only six of those used rigorous scientific method. Results revealed that medical trainees participating in stress-management programs demonstrated (1) improved immunologic functioning, (2) decreases in depression and anxiety, (3) increased spirituality and empathy, (4) enhanced knowledge of alternative therapies for future referrals, (5) improved knowledge of the effects of stress, (6) greater use of positive coping skills, and (7) the ability to resolve role conflicts. Despite these promising results, the studies had many limitations. CONCLUSION: The following considerations should be incorporated into future research: (1) rigorous study design, including randomization and control (comparison) groups, (2) measurement of moderator variables to determine which intervention works best for whom, (3) specificity of outcome measures, and (4) follow-up assessment, including effectiveness of future patient care.

Exposure of the anterior spine: technique and experience with 66 patients.

PURPOSE: Anterior spinal fusion has become an increasingly popular technique used by orthopedic surgeons for a variety of lower spine pathology. At our institution urologists have assisted as retroperitoneal surgeons in achieving exposure of the appropriate spinal disk space. We report our experience with anterior spinal fusion in 66 patients. MATERIALS AND METHODS: Since 1991 we have performed 66 exposures using the flank, modified Gibson, thoracoabdominal, paramedian and midline transperitoneal approaches. Exposure of each level has subtle technical issues which are reviewed. RESULTS: During the study 34 men and 32 women 24 to 74 years old (mean age 43.8) underwent discectomy and anterior fusion of the spine. Access from T12 through L5-S1 interspace was required, and exposure of multiple spinal levels was necessary in 27. There was 1 death from massive pulmonary embolism in a patient with widely metastatic lung cancer. Retrograde ejaculation was reported by 2 men. There have been no episodes of deep or superficial wound infection and no ureteral or major vascular injuries. CONCLUSIONS: As surgeons of the retroperitoneum urologists have an important role in providing our orthopedic colleagues with safe, adequate exposure to the anterior surface of the spine during discectomy and anterior fusion.

Diagnostic tests: distinguishing good tests from bad and even ugly ones.

This article focuses on the selection and interpretation of diagnostic tests, emphasizing the importance of understanding how their mathematical parameters affect the information they provide in various settings. The utility and limitations of sensitivity, specificity, predictive value, and receiver operating characteristic (ROC) curves are discussed using catheter-related bloodstream infections as an example. ROC curves have been used for selecting optimal cutoff values for a positive result and for selecting among several alternative diagnostic tests. For example, 16 different tests have been proposed for diagnosis of catheter-related bloodstream infection; ROC analysis provides an effective way to determine which test offers the best overall performance.

Risk factors for perinatal human immunodeficiency virus transmission in patients receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group protocol 076 Study Group.

OBJECTIVE: To identify modifiable obstetric factors associated with the failure of zidovudine chemoprophylaxis to prevent perinatal human immunodeficiency virus type 1 (HIV-1) transmission. METHODS: We analyzed data from Pediatric AIDS Clinical Trials Group protocol 076, a randomized, double-masked, placebo-controlled trial that demonstrated that a zidovudine regimen could prevent perinatal HIV-1 transmission. We estimated the zidovudine treatment effect using the relative reduction in transmission risk among women randomized to treatment with zidovudine compared with women randomized to receive placebo. Univariate and multivariate statistical analyses were used to assess whether the treatment effect differed in magnitude according to potential antepartum or intrapartum risk factors. RESULTS: In the univariate analysis, the zidovudine treatment effect was found to differ significantly in magnitude according to quartile of maternal weight at the time of study entry (interaction test, P = .03); among women in the heaviest-weight quartile (weight more than 82 kg), there was a 26% relative reduction in transmission risk, compared with a 79% relative reduction among the other three quartiles (interaction test, P = .05). In the zidovudine treatment group, women who transmitted HIV-1 were significantly more likely than nontransmitters to have had antepartum procedures or conditions associated with increased risk of fetal exposure to maternal blood or cervicovaginal secretions (43% compared with 19%, P = .04). In the multivariate analysis, adjustment for the plasma HIV-1 RNA level and CD4+ cell percentage did not eliminate the differential treatment effect according to these factors. CONCLUSION: High maternal weight and conditions associated with fetal exposure to maternal blood or cervicovaginal secretions may diminish the efficacy of zidovudine chemoprophylaxis.

The contribution of assay variation and biological variation to the total variability of plasma HIV-1 RNA measurements. The Women Infant Transmission Study Clinics. Virology Quality Assurance Program.

OBJECTIVES: To assess the specific contributions of assay variation and biological variation to the total variation of plasma HIV-1 RNA measured by the Roche Monitor assay and the extent to which batch assays reduced both assay variability and total variability compared with real-time determinations. DESIGN: A retrospective analysis of data obtained from three trials conducted by the Adult and Pediatric AIDS Clinical Trials Groups (ATCG), the Women and Infants Transmission Study (WITS) and the NIAID-sponsored Virology Quality Assurance Program. METHODS: Within-subject variation was assessed from stored, serially collected plasma samples from 663 subjects enrolled in the ACTG and WITS studies. Interassay and intra-assay variation were estimated from two of the clinical trials and 22 laboratories that participated in a quality assurance program and were used to estimate the effect of real-time testing on total variation. RESULTS: The total variation (standard deviation) from a random effects model was 0.26 log10 RNA copies/ml. The estimated interassay variation was 0.08 log10 and intra-assay variation was 0.12 log10 RNA copies/ml. Biological variation accounted for 56-80% of total variation. The effect of real-time testing compared with batch testing was minimal. CONCLUSION: Our estimates of total within-subject HIV-1 RNA variation support the current recommendation to obtain at least two specimens, preferably obtained less than 2 weeks apart, for viral RNA measurement before starting therapy. The major contribution of biological variation to the total variation supports the use of real-time HIV-1 RNA assays, provided that consistent specimen collection procedures are followed and acceptable assay proficiency is maintained.

A comparison of the bioavailabilities of oral and intravenous ethanol in healthy male volunteers.

OBJECTIVES: Ethanol (EtOH), the antidote for methanol and ethylene glycol, is administered by the oral (PO) and intravenous (IV) routes. Serum concentrations (SCs) of 100 mg/dL or more are targeted for clinical effect. This study was completed to validate the assumption that there are minimal differences in SC achieved between these two routes. METHODS: Twenty healthy male volunteers were randomized to receive either PO or IV EtOH. Subjects abstained from EtOH for 48 hours before each phase. After a seven-day washout period, the subjects crossed over to the other group. Inclusion criteria were no history of medical problems, age between 21 and 40 years, and actual body weight within 10% of ideal weight. Baseline EtOH SCs were obtained before participation in each phase. Two hours after a standard breakfast, the subjects received 700 mg/kg of PO or IV EtOH. PO EtOH was administered as a 20% solution in juice over 10 minutes. IV EtOH, controlled by an infusion pump, was administered as a 10% solution over 30 minutes. Blood was drawn for EtOH SCs at 45, 75, 105, 135, 165, 225, 285, and 345 minutes after start of the dose. RESULTS: All initial EtOH SCs were 0. EtOH SCs were higher after IV administration. Mean peak SC was 103.6 mg/dL after IV administration and 71.3 mg/dL after PO administration (p<0.0001). Mean time to peak was 46.5 minutes after IV administration and 103.5 minutes after PO administration (p<0.0001). Total area under the curve was 17,440 min-mg/dL after IV administration and 13,875 min-mg/dL after PO administration (p<0.003). The order of treatments did not affect results (p>0.1). CONCLUSION: Significant differences exist between the SCs of EtOH as well as the times to peak SC after PO and IV administrations.

The interpretation of diagnostic tests.

Laboratory diagnostic tests are central in the practice of modern medicine. Common uses include screening a specific population for evidence of disease and confirming or ruling out a tentative diagnosis in an individual patient. The interpretation of a diagnostic test result depends on both the ability of the test to distinguish diseased from nondiseased subjects and the particular characteristics of the patient and setting in which the test is being used. This article reviews statistical methodology for assessing laboratory diagnostic test accuracy and interpreting individual test results, with an emphasis on diagnostic tests that yield a continuous measurement. The article begins with a summary of basic concepts and terminology, then briefly discusses study design and reviews methods for assessing the accuracy of a single diagnostic test, comparing the accuracy of two or more diagnostic tests and interpreting individual test results.

Ovarian cancer: comparison of observer performance for four methods of interpreting CT scans.

PURPOSE: To assess the effects of four interpretative methods on observers' mean sensitivity and specificity by using computed tomography (CT) of ovarian carcinoma as a model. MATERIALS AND METHODS: CT scans in 98 patients with ovarian carcinoma and 49 women who were disease free were retrospectively reviewed by four experienced blinded radiologists to compare single-observer reading, single-observer reading with an anatomic checklist, paired-observer reading (simultaneous double reading), and replicated reading (combination of two independent readings). Confidence level scoring was used to identify three possible disease forms in each patient: extranodal tumor, lymphadenopathy, and ascites. Patient conditions were then categorized as abnormal or normal. RESULTS: There were no significant improvements in sensitivity or specificity for classification of patient conditions as abnormal or normal when comparing single-observer interpretation with single-observer interpretation with a checklist or paired-observer interpretation. Although there was no significant improvement in the mean sensitivity (93% vs 94%) by using the replicated reading method, there was a statistically significant improvement in mean specificity (85% vs 79%) for the replicated readings compared with single-observer interpretations (P < .05). CONCLUSION: Diagnostic aids such as checklists and paired simultaneous readings did not lead to an improved mean observer performance for experienced readers. However, an increase in the mean specificity occurred with replicated readings.

The effects of zidovudine in the subset of infants infected with human immunodeficiency virus type-1 (Pediatric AIDS Clinical Trials Group Protocol 076).

OBJECTIVE: To describe the effect of zidovudine on human immunodeficiency virus type 1 (HIV-1) and on the course of disease in infants who became infected while they and their mothers received zidovudine preventive therapy or placebo in Pediatric AIDS Clinical Trials Group Protocol 076. STUDY DESIGN: Observational substudy of a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: We compared the progression of disease, timing of HIV-1 transmission, and the plasma HIV-1 RNA level in infected infants of mother-infant pairs who were randomly assigned to receive zidovudine (n = 14) or placebo (n = 43). The development of genotypic zidovudine resistance was assessed among infected infants in the zidovudine treatment group. RESULTS: In this limited study, zidovudine therapy during pregnancy and labor and in the neonatal period for 6 weeks failed to have a major effect on rapid progression of disease, timing of transmission, and viral replication in HIV-infected infants. When the zidovudine treatment regimen failed to prevent maternal-infant transmission of HIV-1, resistance to zidovudine did not develop during study treatment. CONCLUSIONS: Our study supports the safety of zidovudine use in pregnancy and in the newborn period but demonstrates the continued need for more potent antiretroviral treatment of the infected infant.

Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine.

Zidovudine (ZDV) therapy during pregnancy and to the neonate reduced perinatal HIV transmission by nearly 70% in Pediatric AIDS Clinical Trials Group (PACTG) protocol 076. ZDV has been reported as positive in several in vitro carcinogenicity screening tests. We evaluated the short-term risk for tumors in 727 children with known ZDV exposure enrolled into the PACTG 076/219 and the Women and Infants Transmission Study (WITS). ZDV exposure in utero (antepartum) occurred in 97% and 99% of infants in PACTG 076/219 or WITS, respectively. Mean follow-up was 38.3 months with 366.9 person years follow-up for PACTG 076/219 and 14.5 months with 743.7 person years follow-up for WITS. No tumors of any nature were observed; relative risk was 0 (95% confidence interval [CI], 0-17.6). These data are reassuring regarding the short-term lack of tumors for ZDV-exposed infants observed to date. Longitudinal, standardized follow-up for infants with in utero antiretroviral exposure is necessary to assess long-term carcinogenicity.

Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams.

CONTEXT: With the success of zidovudine chemoprophylaxis for prevention of perinatal transmission of the human immunodeficiency virus (HIV), an increasing number of HIV-exposed but uninfected children will have in utero exposure to zidovudine and other antiretroviral drugs. OBJECTIVE: To evaluate the long-term effects of in utero exposure to zidovudine vs placebo among a randomized cohort of uninfected children. DESIGN: Prospective cohort study based on data collected during Pediatric AIDS Clinical Trials Group Protocol 076, a perinatal zidovudine HIV prevention trial, and Protocol 219, a long-term observational protocol. SETTING: Pediatric research clinics in the United States. PATIENTS: Two hundred thirty-four uninfected children born to 230 HIV-infected women enrolled in Protocol 076 and followed up through February 28, 1997, in Protocol 219 (122 in the zidovudine group and 112 in the placebo group). MAIN OUTCOME MEASURES: Physical growth measurements, immunologic parameters, cognitive/developmental function, occurrence of neoplasms, and mortality data assessed every 6 months for children younger than 24 months and yearly thereafter or as clinically indicated. Baseline echocardiogram and funduscopic evaluations were collected before 36 months of age. RESULTS: Median age of children at time of last follow-up visit was 4.2 years (range, 3.2-5.6 years). There were no significant differences between children exposed to zidovudine and those who received placebo in terms of sequential data on lymphocyte subsets; weight, height, and head circumference z scores; and cognitive/developmental function. No deaths or malignancies occurred. Two children (both exposed to zidovudine) are being followed up for abnormal, unexplained ophthalmic findings. One child exposed to zidovudine had a mild cardiomyopathy on echocardiogram at the age of 48 months; the child is clinically asymptomatic. CONCLUSIONS: No adverse effects were observed in HIV-uninfected children with in utero and neonatal exposure to zidovudine followed up for as long as 5.6 years. Continued prospective evaluations of children born to HIV-infected women who are exposed to antiretroviral or immunotherapeutic agents are critical to assess the long-term safety of interventions that prevent perinatal HIV transmission.

Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 Study.

OBJECTIVE: To determine the safety of the zidovudine (ZDV) regimen utilized in the Pediatric AIDS Clinical Trial Group (ACTG) 076 study. DESIGN: ACTG 076 was a randomized, double-blind, placebo-controlled trial which demonstrated that a ZDV regimen could prevent mother-to-child HIV-1 transmission. Infants were followed through 18 months of age and women were followed through 6 months postpartum. METHODS: Maternal complications, pregnancy outcomes, growth and development of the uninfected infants, and HIV-1 disease progression in the women were monitored prospectively. RESULTS: Maternal therapy was well tolerated. There was no serious pattern of adverse pregnancy outcomes associated with ZDV use. Amongst the ZDV-exposed infants, the only recognized toxicity was anemia within the first 6 weeks of life; the risk for anemia was not associated with premature delivery, duration of maternal treatment, degree of maternal immunosuppression, or maternal anemia. ZDV treatment was not associated with an increased incidence of newborn structural abnormalities. At 18 months of age, uninfected infants did not differ in growth parameters or immune function. No childhood neoplasias were reported in either group. In the women, at 6 months postpartum, there were no differences in clinical, immunologic, or virologic disease progression. CONCLUSION: There were no identified problems that would alter current recommendations for the routine use of ZDV for the prevention of mother-child HIV-1 transmission.

Estimating the accuracy of screening mammography: a meta-analysis.

OBJECTIVE: To estimate the accuracy of mammographic screening. DESIGN: A meta-analysis of published literature. DATA SOURCES: Published English-language randomized controlled trials, case-control studies, and demonstration projects involving screening mammography were identified using recent review articles. We found additional references using MEDLINE searches combining the MeSH terms "mammography," "screening," and/or study authors and locations. STUDY SELECTION: We included all studies that provided information to calculate the true-positive rate (TPR) and the false-positive rate (FPR) for breast cancer screening. DATA EXTRACTION: Reported data were reviewed independently by the authors; calculations were compared and discrepancies resolved. We calculated the sensitivity as the number of breast cancers detected during the first round of screening (true positives) divided by the sum of the true positives and the false negatives (defined as cancer discovered within 1 year of screening). False-positives were determined by biopsy. DATA SYNTHESIS: TPR and FPR values from each study were plotted in receiver operating characteristic (ROC) space. Tests of homogeneity were performed to assess the validity of using summary ROC curves or a single point to summarize the data. The reported TPR and FPR of mammography ranged from 83% to 95% and 0.9% to 6.5%, respectively. The sensitivity of mammography is higher in women over the age of 50 years. CONCLUSIONS: The accuracy of mammography should be recognized and included in discussions about policies for screening for breast cancer. This meta-analysis, by quantifying the expected TPR/FPR, should assist program planners, physicians, and women to understand better the cost and clinical implications of such screening programs.

Maternal viral genotypic zidovudine resistance and infrequent failure of zidovudine therapy to prevent perinatal transmission of human immunodeficiency virus type 1 in pediatric AIDS Clinical Trials Group Protocol 076.

Maternal samples were assessed from 96 women enrolled in Pediatric AIDS Clinical Trials Group protocol 076 to determine the prevalence of human immunodeficiency virus type 1 (HIV-1) genotypic zidovudine resistance at entry, if zidovudine resistance developed on study, and the role of zidovudine resistance in vertical transmission of HIV-1 despite zidovudine therapy. Low and high levels of genotypic resistance were assessed by differential hybridization, oligoligation, or direct sequencing of plasma HIV-1 RNA for codons K70R and T215Y/F. None of the women had high-level genotypic resistance to zidovudine at study entry or delivery. For low-level zidovudine resistance, the 95% confidence intervals were 0.3%-6.8% for baseline prevalence and 0.3%-14% for delivery incidence. Low-level zidovudine resistance, adjusted for plasma viral RNA level at delivery, was not strongly associated with an increase in vertical transmission risk (odds ratio, 4.8; 95% confidence interval, 0.2-131; P = .35).

Absolute copy number and relative change in determinations of human immunodeficiency virus type 1 RNA in plasma: effect of an external standard on kit comparisons.

Use of a common set of human immunodeficiency virus type 1 (HIV-1) RNA standards eliminated differences among absolute HIV-1 RNA copy number estimates made with three commercially available assays. The relative changes in the viral RNA levels determined by the commercial assays were similar and were unaffected by the use of a common set of standards.

Smooth non-parametric receiver operating characteristic (ROC) curves for continuous diagnostic tests.

Receiver operating characteristic (ROC) curves have seen increasing use to assess the accuracy of diagnostic tests that yield continuous test results. We can calculate a fully non-parametric ROC curve from the empirical false positive rate (FPR) and true positive rate (TPR) at each possible decision threshold, but it may be quite jagged. We can obtain a smooth ROC curve by directly fitting a parameteric model, for example, binormal or bilogistic, to the actual test results, but substantial lack-of-fit may result if the distributional assumptions are not valid. A recently proposed alternative algorithm 'LABROC4' is insensitive to such departures, but is not fully flexible in that the form of the resulting ROC curve is restricted to be binormal. We propose a smooth non-parametric ROC curve derived from kernel density estimates of the two test result distributions. We obtain pointwise standard errors for the estimated TPR at each FPR and use them to construct pointwise confidence intervals for the ROC curve, using a logit transformation. We also obtain standard errors for the estimated TPR and FPR at given thresholds and use them to construct confidence rectangles in (FPR, TPR)-space that correspond to a specific threshold. We adapt existing methods for the unsmoothed non-parametric ROC curve to obtain the area under the ROC curve and its standard error; we also give partial areas and corresponding standard errors. We have created a FORTRAN algorithm 'ROC-&-ROL', available upon request. We compare ROC curves and areas obtained by applying our methods and its competitors to two data sets, one of which is fit well by parametric methods and LABROC4, the other of which is not.