Search

In survival studies, classical inferences for left-truncated data require quasi-independence, a property that the joint density of truncation time and failure time is factorizable into their marginal densities in the observable region. The quasi-independence hypothesis is testable; many authors have developed tests for left-truncated data with or without right-censoring. In this paper, we propose a class of test statistics for testing the quasi-independence that unifies the existing methods and generates new useful statistics such as conditional Spearman's rank correlation coefficient. Asymptotic normality of the proposed class of statistics is given. We show that a new set of tests can be powerful under certain alternatives by theoretical and empirical power comparison. [ABSTRACT FROM AUTHOR]

Purpose In low- and middle-income, HIV-endemic regions of sub-Saharan Africa, morbidity and mortality from the common epithelial cancers of the developed world are rising. Even among HIV-infected individuals, access to antiretroviral therapy has enhanced life expectancy, shifting the distribution of cancer diagnoses toward non-AIDS-defining malignancies, including breast cancer. Building on our prior research, we recently initiated the South African Breast Cancer and HIV Outcomes study. Methods We will recruit a cohort of 3,000 women newly diagnosed with breast cancer at hospitals in high (average, 20%) HIV prevalence areas, in Johannesburg, Durban, Pietermaritzburg, and Empangeni. At baseline, we will collect information on demographic, behavioral, clinical, and other factors related to access to health care. Every 3 months in year 1 and every 6 months thereafter, we will collect interview and chart data on treatment, symptoms, cancer progression, comorbidities, and other factors. Wewill compare survival rates of HIV-infected and uninfected women with newly diagnosed breast cancer and their likelihood of receiving suboptimal anticancer therapy. We will identify determinants of suboptimal therapy and context-specific modifiable factors that future interventions can target to improve outcomes. We will explore molecular mechanisms underlying potentially aggressive breast cancer in both HIV-infected and uninfected patients, as well as the roles of pathogens, states of immune activation, and inflammation in disease progression. Conclusion Our goals are to contribute to development of evidence-based guidelines for the management of breast cancer in HIV-positive women and to improve outcomes for all patients with breast cancer in resource-constrained settings. [ABSTRACT FROM AUTHOR]

Importance: Advantages of using efavirenz as part of treatment for children infected with human immunodeficiency virus (HIV) include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir-boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission.Objective: To evaluate whether nevirapine-exposed children achieving initial viral suppression with ritonavir-boosted lopinavir-based therapy can transition to efavirenz-based therapy without risk of viral failure.Design, Setting, and Participants: Randomized, open-label noninferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, from June 2010 to December 2013, enrolling 300 HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission who were aged 3 years or older and had plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir-based therapy; 298 were randomized and 292 (98%) were followed up to 48 weeks after randomization.Interventions: Participants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148).Main Outcomes and Measures: Risk difference between groups in (1) viral rebound (ie, ≥1 HIV RNA measurement of >50 copies/mL) and (2) viral failure (ie, confirmed HIV RNA >1000 copies/mL) with a noninferiority bound of -0.10. Immunologic and clinical responses were secondary end points.Results: The Kaplan-Meier probability of viral rebound by 48 weeks was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n = 4) in the efavirenz group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to ∞) and for viral failure was -0.007 (1-sided 95% CI, -0.036 to ∞). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group.Conclusions and Relevance: Among HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission and with initial viral suppression with ritonavir-boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these.Trial Registration: clinicaltrials.gov Identifier: NCT01146873. [ABSTRACT FROM AUTHOR]

Background: Lower levels of global DNA methylation in tissue and blood have been associated with increased cancer risk. Conversely, cross-sectional analyses of healthier lifestyle patterns have been associated with higher levels of global DNA methylation. Objective: In this trial, we explored the associations between changes in lifestyle modifications (diet, weight loss), metabolic markers, and global epigenetic biomarkers in white blood cells. Methods: Study participants were Hispanic, African American, and Afro-Caribbean overweight and sedentary female breast cancer survivors (n = 24) who participated in a larger randomized, crossover, pilot study of a 6-mo weight loss intervention and who had available blood specimens. Anthropometric measures, a food-frequency questionnaire, and peripheral blood were collected at baseline, 6 mo, and 12 mo. Plasma samples were analyzed for metabolic markers (insulin, glucose). We measured DNA methylation of long interspersed nucleotide element 1 (LINE-1) and satellite 2 by pyrosequencing and MethyLight, respectively, and global DNA methylation by the luminometric methylation assay (LUMA). Results: DNA methylation of LINE-1 was statistically significantly elevated at 6 mo [75.5% vs. 78.5% (P< 0.0001)] and 12 mo [75.5% vs. 77.7% (P< 0.0001)], compared to baseline. Over a 12-mo period, changes in percentage body fat and plasma glucose concentrations were positively associated with LINE-1 DNA methylation (β= 0.19, P = 0.001) and LUMA DNA methylation levels (β = 0.24, P = 0.02), respectively. Similarly, 12-mo changes in dietary measures such as vegetable (β = 0.009, P= 0.048), protein (β = 0.04, P= 0.001), and total caloric (β = 0.05, P = 0.01) intake were positively associated with changes in LUMA DNA methylation, as was intake of fruit positively associated with changes in LINE-1 DNA methylation (β = 0.004, P = 0.02). Conclusions: Our hypothesis-generating results suggest that lifestyle modifications may be associated with changes in global DNA methylation detectable at 6 and 12 mo. These biomarkers may be useful intermediate biomarkers to use in future intervention trials. [ABSTRACT FROM AUTHOR]

Objective: Large studies describing the profile of high-risk Human papillomavirus (hrHPV) genotypes among women in sub- Saharan Africa are lacking. Here we describe the prevalence and distribution of hrHPV genotypes among HIV-negative women in South Africa, with and without cervical intraepithelial neoplasia (CIN). Methods: We report data on 8,050 HIV-negative women, aged 17-65 years, recruited into three sequential studies undertaken in Cape Town, South Africa. Women had no history of previous cervical cancer screening. Cervical samples were tested for hrHPV DNA using the Hybrid Capture 2 (HC2) assay and all positive samples were genotyped using a PCR-based assay (Line Blot). Women underwent colposcopy and biopsy/endocervical curettage to determine CIN status. The prevalence and distribution of specific hrHPV genotypes were examined by age and CIN status. Results: Overall, 20.7% (95% CI, 19.9-21.6%) of women were hrHPV-positive by HC2, with women with CIN having the highest rates of positivity. Prevalence decreased with increasing age among women without CIN; but, a bimodal age curve was observed among women with CIN. HPV 16 and 35 were the most common hrHPV genotypes in all age and CIN groups. HPV 45 became more frequent among older women with CIN grade 2 or 3 (CIN2,3). Younger women (17-29 years) had more multiple hrHPV genotypes overall and in each cervical disease group than older women (40-65 years). Conclusion: HPV 16, 35, and 45 were the leading contributors to CIN 2,3. The current HPV vaccines could significantly reduce HPV-related cervical disease; however, next generation vaccines that include HPV 35 and 45 would further reduce cervical disease in this population. [ABSTRACT FROM AUTHOR]

Background: High levels of the carcinogenic organochlorine pesticides chlordane and dieldrin have been reported in the well water of homes in North Stamford. It is unclear if the contamination is associated with an increase in the cancer rate in North Stamford. Methods: We reviewed the demographics of the towns surrounding North Stamford and chose New Canaan, Wilton, Weston, and Darien as towns with sufficiently similar demographics that would permit comparison of cancer incidence with North Stamford. Data were obtained from the Connecticut Tumor Registry regarding the number of different cancers diagnosed per year from 1998 to 2007 in North Stamford and the four nearby towns. We compared the annual cancer incidence of these communities in total and by cancer types. Results: here was no statistically significant difference in the average annual cancer incidence from 1998 to 2007 between North Stamford and the four other communities. here was also no statistically significant difference seen in the incidence of the various cancer types. Conclusion: Chlordane and dieldrin contamination of the well water of homes in North Stamford may not be associated with a higher incidence of cancer. [ABSTRACT FROM AUTHOR]

Despite its superior efficacy, clozapine is helpful in only a subset of patients with schizophrenia unresponsive to other antipsychotics. This lack of complete success has prompted the frequent use of various clozapine combination strategies despite a paucity of evidence from randomized controlled trials supporting their efficacy. Pimozide, a diphenylbutylpiperidine, possesses pharmacological and clinical properties distinct from other typical antipsychotics. An open-label trial of pimozide adjunctive treatment to clozapine provided promising pilot data in support of a larger controlled trial. Therefore, we conducted a double-blind, placebo-controlled, parallel-designed 12-week trial of pimozide adjunctive treatment added to ongoing optimal clozapine treatment in 53 patients with schizophrenia and schizoaffective disorder partially or completely unresponsive to clozapine monotherapy. An average dose of 6.48 mg/day of pimozide was found to be no better than placebo in combination with clozapine at reducing Positive and Negative Syndrome Scale total, positive, negative, and general psychopathology scores. There is no suggestion from this rigorously conducted trial to suggest that pimozide is an effective augmenting agent if an optimal clozapine trial is ineffective. However, given the lack of evidence to guide clinicians and patients when clozapine does not work well, more controlled trials of innovative strategies are warranted. [ABSTRACT FROM AUTHOR]

Background. Nevirapine resistance after failed prophylaxis to prevent mother-to-child human immunodeficiency virus (HIV) transmission can compromise subsequent nevirapine-based highly active antiretroviral therapy (HAART). Methods. Nevirapine-exposed children who achieved virologic suppression with lopinavir/ritonavir-based induction HAART before switch to nevirapine-based HAART or who continued the lopinavir/ritonavir regimen were studied. Nevirapine-resistant HIV was quantified (⩾1% frequency) in plasma before therapy and archived in peripheral blood mononuclear cells after induction HAART with ultradeep pyrosequencing. The primary endpoint was virologic failure (confirmed viremia ⩾1000 copies/mL by 52 weeks) on nevirapine-based HAART, and Receiver operating characteristic analysis identified threshold levels of resistance associated with failure. Results. Nevirapine resistance mutations were detected in plasma at a median frequency of 25.6% in 41 (33%) of 124 children starting HAART at median 9 months of age. After a median nine months of induction HAART, nevirapine-resistant HIV remained archived in cells in 59 (61%) of 96 children (median 13.6% of cells). The threshold frequency of nevirapine resistance in plasma most predictive of virologic failure on nevirapine-based HAART was 25%. Children maintaining resistance before therapy at or above this threshold frequency had a 3.5 fold higher risk of failure (95% confidence interval, 1.1-10.8) than children without detectable plasma resistance. In contrast, virologic failure was not independently associated with age, resistance in plasma below 25% frequencies, or archived in cells. Conclusions. Virologic suppression with lopinavir/ritonavir-based HAART in nevirapine-exposed children raises the threshold level of resistance at which reuse of nevirapine-based therapy is compromised. Standard genotyping may allow identification of children likely to benefit from an induction-switch approach. [ABSTRACT FROM AUTHOR]

Background: Uncertainties remain over whether prophylactic surgery or surveillance is the better management option for intraductal papillary mucinous neoplasm of the pancreas. The aim of this preliminary study was to determine if differences in anxiety and quality of life exist between patients who have surgery or undergo surveillance.Methods: Recruited patients were given the Hospital Anxiety and Depression Scale, a general survey that evaluates anxiety, and the Functional Assessment of Cancer Therapy-Pancreas, a disease-specific survey that assesses quality of life. Questionnaires were scored by standardized algorithms and compared using Student's t test or Wilcoxon rank-sum test.Results: Sixteen patients had surgery and 16 patients were undergoing surveillance. Mean age was 66.8 ± 19.9 years. Responses from both groups were remarkably similar. Surgery patients scored higher on the anxiety questionnaire than surveillance patients, although not statistically significant (p = 0.09). Surgery patients scored lower on the functional well-being domain of the quality-of-life instrument (p = 0.03), though there were no differences in overall quality of life.Conclusion: Prophylactic surgery does not reduce quality of life, and a protocol of surveillance does not appear to generate undue anxiety in this select patient group. Further investigation with more patients is required to validate these findings. [ABSTRACT FROM AUTHOR]

Background Screen-and-treat approaches to cervical cancer prevention are an attractive option for low-resource settings, but data on their long-term efficacy are lacking. We evaluated the efficacy of two screen-and-treat approaches through 36 months of follow-up in a randomized trial. Methods A total of 6637 unscreened South African women aged 35–65 years who were tested for the presence of high-risk human papillomavirus (HPV) DNA in cervical samples underwent visual inspection of the cervix using acetic acid staining and HIV serotesting. Of these, 6555 were randomly assigned to three study arms: 1) HPV-and-treat, in which all women with a positive HPV DNA test result underwent cryotherapy; 2) visual inspection-and-treat, in which all women with a positive visual inspection test result underwent cryotherapy; or 3) control, in which further evaluation or treatment was delayed for 6 months. All women underwent colposcopy with biopsy at 6 months. All women who were HPV DNA– or visual inspection–positive at enrollment, and a subset of all other women had extended follow-up to 36 months (n = 3639) with yearly colposcopy. The endpoint—cervical intraepithelial neoplasia grade 2 or worse (CIN2+)—was analyzed using actuarial life-table methods. All statistical tests were two-sided. Results After 36 months, there was a sustained statistically significant decrease in the cumulative detection of CIN2+ in the HPV-and-treat arm compared with the control arm (1.5% vs 5.6%, difference = 4.1%, 95% confidence interval [CI] = 2.8% to 5.3%, P < .001). The difference in the cumulative detection of CIN2+ in the visual inspection-and-treat arm compared with the control was less (3.8% vs 5.6%, difference = 1.8%, 95% CI = 0.4% to 3.2%, P = .002). Incident cases of CIN2+ (identified more than 12 months after enrollment) were less common in the HPV-and-treat arm (0.3%, 95% CI = 0.05% to 1.02%) than in the control (1.0%, 95% CI = 0.5% to 1.7%) or visual inspection-and-treat (1.3%, 95% CI = 0.8% to 2.1%) arms. Conclusions In this trial, a screen-and-treat approach using HPV DNA testing identified and treated prevalent cases of CIN2+ and appeared to reduce the number of incident cases of CIN2+ that developed more than 12 months after cryotherapy. [ABSTRACT FROM PUBLISHER]

The article discusses a study which investigated if nevirapine-exposed infants who achieved viral suppression with protease inhibitor (PI)-based therapy could maintain viral suppression when shifted to nevirapine. The study included children who received either PI- or nevirapine-based therapy between April 2005 and May 2009. After 52 weeks of randomization, the children were tested for HIV-1 RNA and plasma viremia. Study authors found less frequent plasma viremia in patients who were switched from PI-based therapy to nevirapine-based regimen. They concluded that HIV-infected children shifter to nevirapine-based treatment after achieving viral suppression with ritonavir-boosted lopinavir regimen have lower rates of viremia.

Background. Early weaning has been recommended to reduce postnatal human immunodeficiency virus (HIV) transmission. We evaluated the safety of stopping breast-feeding at different ages for mortality of uninfected children born to HIV-infected mothers. Methods. During a trial of early weaning, 958 HIV-infected mothers and their infants were recruited and followed up from birth to 24 months postpartum in Lusaka, Zambia. One-half of the cohort was randomized to wean abruptly at 4 months, and the other half of the cohort was randomized to continue breast-feeding. We examined associations between uninfected child mortality and actual breast-feeding duration and investigated possible confounding and effect modification. Results. The mortality rate among 749 uninfected children was 9.4% by 12 months of age and 13.6% by 24 months of age. Weaning during the interval encouraged by the protocol (4-5 months of age) was associated with a 2.03-fold increased risk of mortality (95% confidence interval [CI], 1.13-3.65), weaning at 6-11 months of age was associated with a 3.54-fold increase (95% CI, 1.68-7.46), and weaning at 12-18 months of age was associated with a 4.22-fold increase (95% CI, 1.59-11.24). Significant effect modification was detected, such that risks associated with weaning were stronger among infants born to mothers with higher CD4+ cell counts (>350 cells/μL). Conclusion. Shortening the normal duration of breast-feeding for uninfected children born to HIV-infected mothers living in low-resource settings is associated with significant increases in mortality extending into the second year of life. Intensive nutritional and counseling interventions reduce but do not eliminate this excess mortality. [ABSTRACT FROM AUTHOR]

To estimate the lifetime distribution of right-censored length-biased data, we propose a pseudo-partial likelihood approach that allows us to derive two nonparametric estimators. With its closed-form estimators and explicit limiting variances, this approach retains the simplicity of conditional analysis, and has only a small efficiency loss compared with the unconditional analysis. Under some regularity conditions, we show that the two estimators are uniformly consistent and converge weakly to Gaussian processes. A simulation study demonstrates that the proposed estimators have satisfactory finite-sample performance. Application to an Alzheimer’s disease study is reported. [ABSTRACT FROM PUBLISHER]

By embedding the missing covariate data into a left-truncated and right-censored survival model, we propose a new class of weighted estimating functions for the Cox regression model with missing covariates. The resulting estimators, called the pseudo-partial likelihood estimators, are shown to be consistent and asymptotically normal. A simulation study demonstrates that, compared with the popular inverse-probability weighted estimators, the new estimators perform better when the observation probability is small and improve efficiency of estimating the missing covariate effects. Application to a practical example is reported. [ABSTRACT FROM PUBLISHER]

We obtain a pseudo-partial likelihood for proportional hazards models with biased-sampling data by embedding the biased-sampling data into left-truncated data. The log pseudo-partial likelihood of the biased-sampling data is the expectation of the log partial likelihood of the left-truncated data conditioned on the observed data. In addition, asymptotic properties of the estimator that maximize the pseudo-partial likelihood are derived. Applications to length-biased data, biased samples with right censoring and proportional hazards models with missing covariates are discussed. [ABSTRACT FROM PUBLISHER]

Background: We previously reported no benefit of early weaning for HIV-free survival of children born to HIV-infected mothers in intent-to-treat analyses. Since early weaning was poorly accepted, we conducted a secondary analysis to investigate whether beneficial effects may have been hidden. Methods: 958 HIV-infected women in Lusaka, Zambia, were randomized to abrupt weaning at 4 months (intervention) or to continued breastfeeding (control). Children were followed to 24 months with regular HIV PCR tests and examinations to determine HIV infection or death. Detailed behavioral data were collected on when all breastfeeding ended. Most participants were recruited before antiretroviral treatment (ART) became available. We compared outcomes among motherchild pairs who weaned earlier or later than intended by study design adjusting for potential confounders. Results: Of infants alive, uninfected and still breastfeeding at 4 months in the intervention group, 16.1% who weaned as instructed acquired HIV or died by 24 months compared to 16.0% who did not comply (p = 0.98). Children of women with less severe disease during pregnancy (not eligible for ART) had worse outcomes if their mothers weaned as instructed (RH = 2.60 95% CI: 1.06-6.36) compared to those who continued breastfeeding. Conversely, children of mothers with more severe disease (eligible for ART but did not receive it) who weaned early had better outcomes (p-value interaction = 0.002). In the control group, weaning before 15 months was associated with 3.94-fold (95% CI: 1.65-9.39) increase in HIV infection or death among infants of mothers with less severe disease. Conclusion: Incomplete adherence did not mask a benefit of early weaning. On the contrary, for women with less severe disease, early weaning was harmful and continued breastfeeding resulted in better outcomes. For women with more advanced disease, ART should be given during pregnancy for maternal health and to reduce transmission, including through breastfeeding. [ABSTRACT FROM AUTHOR]

Background Adjuvant radiotherapy following breast conservation surgery (BCS) is considered to be an indicator of quality of care for the majority of women with breast cancer, but many women do not receive adjuvant radiotherapy. We investigated the association of surgeon-related factors with receipt of adjuvant radio- therapy after BCS. Methods We used the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database to identify women aged 65 years or older with stage I/II breast cancer who were diagnosed between 1991 and 2002 and underwent BCS. We collected demographic and clinical data from SEER and treatment information from Medicare claims data. The American Medical Association Masterfile was used to obtain information on surgeons' characteristics, including sex, medical school location (United States or elsewhere), and type of degree (MD or Doctorate in Osteopathic Medicine [DO]). The associations of patient (age, race, rural vs urban residence, comorbidities, marital status), tumor (hormone receptor status, grade, stage), and surgeon-related factors with receipt of adjuvant radiotherapy were analyzed using Generalized Estimating Equations to control for clustering. All statistical tests were two-sided. Results Of 29 760 women in our sample, 22 207 (75%) received radiotherapy. Patients who received adjuvant radiotherapy were younger, had fewer comorbidities, and were more likely to be white, married, from an urban area, and diagnosed in a later year compared with those who did not. They were also more likely to have a surgeon who was female (79% vs 73%), had an MD degree (75% vs 68%), or was US trained (75% vs 70%). The multivariable analysis confirmed the association of radiotherapy with having a surgeon who was female (odds ratio [OR] = 1.13; 95% confidence interval [CI] = 1.06 to 1.27), had an MD degree (OR = 1.55; 95% CI = 1.24 to 1.91), was US trained (OR = 1.12; 95% CI = 1.01 to 1.25), or had more than 15 patients (OR = 1.18; 95% CI = 1.10 to 1.28). Conclusions Surgeon characteristics were associated with patients' receipt of adjuvant radiotherapy after BCS after controlling for patient and tumor characteristics, although the individual effect sizes were small for surgeon sex, location of training, and type of medical degree. More research is warranted to confirm the associations to determine whether they reflect surgeon behavior, patient response, or physician-patient interactions. [ABSTRACT FROM AUTHOR]

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene (BaP), are air pollutants released by the World Trade Center (WTC) fires and urban combustion sources. BaP-DNA adducts provide a measure of PAH-specific genetic damage, which has been associated with increased risk of adverse birth outcomes and cancer. We previously reported that levels of BaP-DNA adducts in maternal and umbilical cord blood obtained at delivery were elevated among subjects who had resided within 1 mile of the WTC site during the month after 9/11; and that elevated blood adducts in combination with in utero exposure to environmental tobacco smoke (ETS) were significantly associated with decreased fetal growth. OBJECTIVE: Our aim was to assess possible effects of prenatal exposure to WTC pollutants on child development. METHODS: After 11 September 2001, we enrolled a cohort of nonsmoking pregnant women who delivered at three lower Manhattan hospitals. We have followed a subset of children through their third birthdays and measured cognitive and motor development using the Bayley-II Scales of Child Development (BSID-II). RESULTS: In multivariate analyses, we found a significant interaction between cord blood adducts and in utero exposure to ETS on mental development index score at 3 years of age (p = 0.02, n = 98) whereas neither adducts nor ETS alone was a significant predictor of (BSID-II) cognitive development. CONCLUSION: Although limited by small numbers, these results suggest that exposure to elevated levels of PAHs in conjunction with prenatal ETS exposure may have contributed to a modest reduction in cognitive development among cohort children. [ABSTRACT FROM AUTHOR]

Background Recently, increasing numbers of women receiving adjuvant chemotherapy for breast cancer have also received granulocyte colony-stimulating factors (G-CSFs) or granulocyte-macrophage colony-stimulating factors (GM-CSFs). Although these growth factors support chemotherapy, their long-term safety has not been evaluated. We studied the association between G-CSF use and incidence of leukemia in a population- based sample of breast cancer patients. Methods Among women aged 65 years or older in the Surveillance, Epidemiology, and End Results-Medicare database who were diagnosed with stages I-Ill breast cancer from January 1, 1991, to December 31, 1999, we identified those who received G-CSF or GM-CSF concurrently with chemotherapy. We used Cox proportional hazards models to estimate hazard ratios for the association of treatment with G-CSF or GM-CSF and subsequent (through December 31, 2003) diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). All statistical tests were two-sided. Results Of 5510 women treated with chemotherapy, 906 (16%) received G-CSF or GM-CSF therapy, and 64 (1.16%) were subsequently diagnosed with either MDS or AML before a cancer recurrence. Use of G-CSF and GM-CSF was associated with more recent diagnosis, younger age, urban residence, fewer comorbidities, receipt of radiation therapy, positive lymph nodes, and cyclophosphamide treatment. Of the 906 patients who were treated with G-CSF, 16 (1.77%) developed AML or MDS; of the 4604 patients not treated with G-CSF, 48(1.04%) developed AML or MDS. The hazard rate ratio for AML or MDS among those treated with G-CSF or GM-CSF compared with those who were not was 2.14 (95% confidence interval [CI] = 1.12 to 4.08). AML or MDS developed within 48 months of breast cancer diagnosis in 1.8% of patients who received G-CSF or GM-CSF but only in 0.7% of patients who did not (hazard ratio = 2.59, 95% CI = 1.30 to 5.15). Conclusions The use of G-CSF was associated with a doubling in the risk of subsequent AML or MDS among the population that we studied, although the absolute risk remained low. Even if this association is confirmed, the benefits of G-CSF may still outweigh the risks. Meanwhile, however, G-CSF use should not be assumed to be risk free. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitously distributed human mutagens and carcinogens. However, lack of adequate air monitoring data has limited understanding of the effects of airborne PAHs on fetal growth. To address this gap in knowledge, we examined the association between prenatal exposure to airborne PAHs and birth weight, birth length, and birth head circumference, respectively, in Krakow, Poland, and New York City (NYC). METHODS: The parallel prospective cohort studies enrolled nonsmoking, healthy, and nonoccupationally exposed women and their newborns. Personal air monitoring of pregnant women was conducted over 48 hr. To control for maternal environmental tobacco smoke (ETS) exposure, we excluded those with umbilical cord plasma cotinine concentrations > 25 ng/mL. Mean cord plasma cotinine concentrations in both ethnic groups were ≤ 0.5 ng/mL. RESULTS: Prenatal PAH exposure was 10-fold higher in Krakow than in NYC. Prenatal PAH exposure was associated with significantly reduced birth weight in both Krakow Caucasians (p < 0.01) and in NYC African Americans (p < 0.01), controlling for known and potential confounders, but not in NYC Dominicans. Within the lower exposure range common to the two cities (1.80–36.47 ng/m³), the effect per unit PAH exposure on birth weight was 6-fold greater for NYC African Americans than for Krakow Caucasians (p = 0.01). CONCLUSIONS: These results confirm the adverse reproductive effect of relatively low PAH concentrations in two populations and suggest increased susceptibility of NYC African Americans. Fetal growth impairment has been linked to child developmental and health problems. Thus, substantial health benefits would result from global reduction of PAH emissions. [ABSTRACT FROM AUTHOR]

Our prospective cohort study of nonsmoking African-American and Dominican mothers and children in New York City is evaluating the role of prenatal exposure to urban pollutants, including polycyclic aromatic hydrocarbons (PAHs), environmental tobacco smoke (ETS), and pesticides, in the pathogenesis of neurobehavioral disorders. We used the Bayley Scales of Infant Development to evaluate the effects on child mental and psychomotor development of prenatal exposure to airborne PAHs monitored during pregnancy by personal air sampling. Behavioral development was assessed by the Child Behavior Checklist. We adjusted for potential confounders including sociodemographic factors and prenatal exposure to ETS and chlorpyrifos. Prenatal exposure to PAHs was not associated with psychomotor development index or behavioral problems. However, high prenatal exposure to PAHs (upper quartile) was associated with lower mental development index at age 3 [β = -5.69; 95% confidence interval (CI), -9.05 to -2.33; p < 0.01]. The odds of cognitive developmental delay were also significantly greater for children with high prenatal exposure (odds ratio = 2.89; 95% CI, 1.33 to 6.25; p = 0.01). General estimated equation analysis showed a significant age × PAH effect on mental development (p = 0.01), confirming the age-specific regression findings. Further adjustment for lead did not alter the relationships. There were no differences in effect sizes by ethnicity. The results require confirmation but suggest that environmental PAHs at levels recently encountered in New York City air may adversely affect children's cognitive development at 3 years of age, with implications for school performance. [ABSTRACT FROM AUTHOR]

In outcome studies of cases filed within a study window, the sample may be skewed if many cases are still pending when the window closes and not included in the study. We refer to cases that are completed within the window as “observed” and those still pending as “censored.” We propose two methods for reducing possible bias: a “self-consistent” estimator that imputes values to the censored cases and an “inverse probability weighting” estimator that assigns weights to the observed cases. In the body of the article we describe these methods for the nonmathematical reader and in the Appendix give a more mathematical treatment. We then apply the self-consistent estimator first to simulated data and then to the landmark study of reversals in death penalty cases by Professor James S. Liebman and his colleagues. In these examples the two methods are equivalent. Liebman et al. simply excluded censored cases and reported a reversal rate of 68%. Application of our methods to the Liebman data reduces the reversal rate to 62.2% (95% c.i. 60.1%, 64.4%). In general, our method largely removes the bias that affects sample estimates when censored cases are just ignored. [ABSTRACT FROM AUTHOR]

Background. Rates of perinatal human immunodeficiency virus (HIV) transmission are higher among HIV infected mothers with more advanced disease, but effects of maternal disease on HIV-uninfected offspring are unclear. We investigated the hypothesis that the severity of HIV disease and immune dysfunction among mothers is associated with increased morbidity and mortality among their uninfected infants. Methods. In a birth cohort of 20 HIV-uninfected infants born to HIV-infected mothers in Lusaka, Zambia, e investigated associations between markers of more advanced maternal HIV disease and child mortality, hospital admissions, and infant weight through 4 months of age. Results. Mortality in the cohort of uninfected infants was 4.6% (95% confidence interval [CI], 2.8-6.3) through 4 months of age. Infants of mothers with CD4+ T cell counts of <350 cells/mL were more likely to die (hazard ratio [HR], 2.87; 95% CI, 1.03-8.03) and were more likely to be hospitalized (HR, 2.28; 95% CI, 1.17- 4.45), after adjusting for other factors, including maternal death and low birth weight. The most common cause of infant death and hospitalization was pneumonia and/or sepsis. A maternal viral load of 1100,000 copies/mL was associated with significantly lower child weight through 4 months of age. Conclusion. Children born to HIV-infected mothers with advanced disease who escaped perinatal or early breastfeeding-related HIV infection are nonetheless at high risk of mortality and morbidity during the first few months of life. HIV-related immunosuppression appears to have adverse consequences for the health of infants, in addition to risks of vertical transmission. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) are toxic pollutants released by the World Trade Center (WTC) fires and various urban combustion sources. Benzo[a]pyrene (BaP) is a representative member of the class of PAHs. PAH-DNA adducts, or BaP-DNA adducts as their proxy, provide a measure of chemical-specific genetic damage that has been associated with increased risk of adverse birth outcomes and cancer. To learn whether PAHs from the WTC disaster increased levels of genetic damage in pregnant women and their newborns, we analyzed BaP-DNA adducts in maternal (n = 170) and umbilical cord blood (n = 203) obtained at delivery from nonsmoking women who were pregnant on 11 September 2001 and were enrolled at delivery at three downtown Manhattan hospitals. The mean adduct levels in cord and maternal blood were highest among newborns and mothers who resided within 1 mi of the WTC site during the month after 11 September, intermediate among those who worked but did not live within this area, and lowest in those who neither worked nor lived within 1 mi (reference group). Among newborns of mothers living within 1 mi of the WTC site during this period, levels of cord blood adducts were inversely correlated with linear distance from the WTC site (p = 0.02). To learn whether PAHs from the WTC disaster may have affected birth outcomes, we analyzed the relationship between these outcomes and DNA adducts in umbilical cord blood, excluding preterm births to reduce variability. There were no independent fetal growth effects of either PAH-DNA adducts or environmental tobacco smoke (ETS), but adducts in combination with in utero exposure to ETS were associated with decreased fetal growth. Specifically, a doubling of adducts among ETS-exposed subjects corresponded to an estimated average 276-g (8%) reduction in birth weight (p = 0.03) and a 1.3-cm (3%) reduction in head circumference (p = 0.04). The findings suggest that exposure to elevated levels of PAHs, indicated by PAH-DNA adducts in cord blood, may have contributed to reduced fetal growth in women exposed to the WTC event. [ABSTRACT FROM AUTHOR]

Abstract Lee and Wolfe (Biometrics vol. 54pp. 11761178, 1998) proposed the two-stage sampling design for testing the assumption of independent censoring, which involves further follow-up of a subset of lost-to-follow-up censored subjects. They also proposed an adjusted estimator for the survivor function for a proportional hazards model under the dependent censoring model. In this paper, a new estimator for the survivor function is proposed for the semi-Markov model under the dependent censorship on the basis of the two-stage sampling data. The consistency and the asymptotic distribution of the proposed estimator are derived. The estimation procedure is illustrated with an example of lung cancer clinical trial and simulation results are reported of the mean squared errors of estimators under a proportional hazards and two different nonproportional hazards models. [ABSTRACT FROM AUTHOR]

A major challenge to developing therapeutic interventions for cognitive loss and dementia in aging individuals with Down syndrome (DS) is the selection of appropriate outcome measures. This report describes the adaptation of the Brief Praxis Test (a nonverbal cognitive test) as a primary outcome measure, as well as the selection of secondary outcome measures for a multicenter clinical trial of vitamin E in aging individuals with DS. Instruments were chosen to assess cognition, behavior, and clinical global function based on previous work in DS and in Alzheimer's disease. Measures of cognition included verbal and nonverbal memory, vocabulary, and orientation. An informant-based measure of behavior and function was adapted from several existing rating scales, and the Clinical Global Impression was adapted for use with this group. This report also describes initial experiences using these measures with the participants who were enrolled in the clinical trial. As in other populations of persons with dementia, verbal learning, memory, and delayed recall proved to be highly associated with the presence of dementia in our study participants. With the exception of visual memory and orientation measures (which proved too difficult to use with portions of this cohort), the tests employed proved useful in the assessment of individuals across a range of premorbid levels of intellectual disability. The authors conclude that the measures chosen for the assessment of behavior and functional ability and the use of the Clinical Global Impression appear to be appropriate for this population and comparable to instruments that have captured pharmacological benefits in other disease groups. [ABSTRACT FROM AUTHOR]

Inner-city, minority populations are high-risk groups for adverse birth outcomes and also are more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene (BaP), and other polycyclic aromatic hydrocarbons (PAHs) found in urban air. In a sample of nonsmoking African-American and Dominican women, we evaluated the effects on birth outcomes of prenatal exposure to ETS, using questionnaire data and plasma cotinine as a biomarker of exposure, and environmental PAHs using BaP-DNA adducts as a molecular dosimeter. We previously reported that among African Americans, high prenatal exposure to PAHs estimated by prenatal personal air monitoring was associated with lower birth weight (p = 0.003) and smaller head circumference (p = 0.01) after adjusting for potential confounders. In the present analysis, self-reported ETS was associated with decreased head circumference (p = 0.06). BaP-DNA adducts were not correlated with ETS or dietary PAHs. There was no main effect of BaP-DNA adducts on birth outcomes. However, there was a significant interaction between the two pollutants such that the combined exposure to high ETS and high adducts had a significant multiplicative effect on birth weight (p = 0.0g) and head circumference (p = 0.01) after adjusting for ethnicity, sex of newborns, maternal body mass index, dietary PAHs, and gestational age. This study provides evidence that combined exposure to environmental pollutants at levels currently encountered in New York City adversely affects fetal development. [ABSTRACT FROM AUTHOR]

Discusses the effects of transplacental exposure to environmental pollutants on birth outcomes in a multiethnic population. Association of high prenatal exposure to aromatic hydrocarbons (PAH) with lower birth rate; Explanation of the failure to find significant effect of PAH in the Hispanic subsamples.

Examines the intraindividual variability in aflatoxin B[sub 1]-albumin adducts on healthy adults in Taiwan. Effects of hepatitis B and C virus infection; Association of intraindividual variability in adduct levels to age of subjects and time intervals; Influence of endogenous factors.

Objectives. This study investigated the effect of parental bereavement on cancer incidence and survival. Methods. A cohort of 6284 Jewish Israelis who lost an adult son in the Yom Kippur War or in an accident between 1970 and 1977 was followed for 20 years. We compared the incidence of cancer in this cohort with that among nonbereaved members of the population by logistic regression analysis. The survival of bereaved parents with cancer was compared with that of matched controls with cancer. Results. Increased incidence was found for lymphatic and hematopoietic malignancies among the parents of accident victims (odds ratio [OR] = 2.01; 95% confidence interval [CI] = 1.30, 3.11) and among war-bereaved parents (OR = 1.47; 95% CI = 1.13, 1.92), as well as for melanomas (OR = 4.62 [95% CI = 1.93, 11.06] and 1.71 [95% CI = 1.06, 2.76], respectively). Accident-bereaved parents also had an increased risk of respiratory cancer (OR = 1.50; 95% CI = 1.07, 2.11). The survival study showed that the risk of death was increased by bereavement if the cancer had been diagnosed before the loss, but not after. Conclusions. This study showed an effect of stress on the incidence of malignancies for selected sites and accelerated demise among parents bereaved following a diagnosis of cancer, but not among those bereaved before such a diagnosis. (Am J Public Health. 2000;90:1601-1607) [ABSTRACT FROM AUTHOR]

Objectives. This study examined the relationship between directly observed therapy and treatment completion rates in the years before and after infusion of federal funding for tuberculosis (TB) control in 1993. Methods. An ecological study of estimated directly observed therapy rates and 12-month treatment completion rates from 1990 through 1994 was undertaken for TB control programs in all 25 cities and counties across the nation with 100 or more incident TB cases in any year from 1990 to 1993. Three cohorts were formed; high treatment completion, intermediate completion, and low completion. Results. In 1990, the median 12-month treatment completion rate was 80% for the entire study population, with a median estimated directly observed therapy rate of 16.8%. By 1994, those rates had increased to 87% and 49.4%, respectively, and increases were shown in all 3 cohorts. Conclusions. Directly observed therapy has had a marked impact on treatment completion rates in jurisdictions with historically low rates. But TB treatment completion rates of more than 90% can be attained with directly observed therapy rates far lower than those proposed by advocates of universal supervised therapy. [ABSTRACT FROM AUTHOR]

The article presents a study which examines a strategy to prevent homelessness among individuals with severe mental illness, by providing a bridge between institutional and community care. This randomized clinical trial tested an approach to prevent homelessness among mentally ill individuals. Although it is widely believed that mentally disabled persons merit care and accommodation in the community, we frequently fail in providing it. In the United States, men and women with chronic mental illness such as schizophrenia have a 25& to 50% risk of becoming homeless, which is about 10 to 20 times the risk of homelessness for the general population. This study demonstrates that it is possible to intervene to prevent homelessness among individuals with severe mental illness. The view that these patients suffer homelessness and other deprivations because they cannot be reached may be unwarranted. Furthermore, the intervention that proved effective in this study was neither costly nor complex.

Objective. The effects of vitamin A supplementation on morbidity of children born to human immunodeficiency virus (HIV)-infected women were evaluated in a population where vitamin A deficiency is not endemic. Methods. A randomized, placebo-controlled trial of vitamin A supplementation was carried out in 118 offspring of HIV-infected women in Durban, South Africa. Those assigned to receive a supplement were given 50000 IU of vitamin A at 1 and 3 months of age; 100000 IU at 6 and 9 months; and 200 000 IU at 12 and 15 months. Morbidity in the past month was then recalled at each follow-up visit. Analysis was based on 806 child-months. Results. Among all children, the supplemented group had lower overall morbidity than the placebo group (OR = 0.69; 95% confidence interval [CI] = 0.48, 0.99). Among the 85 children of known HIV status (28 infected, 57 uninfected), morbidity associated with diarrhea was significantly reduced in the supplemented infected children (OR = 0.51; 95% CI = 0.27,0.99), whereas no effect of supplementation on diarrheal morbidity was noted among the uninfected children. Conclusion. In a population not generally vitamin A deficient, vitamin A supplementation for children of HIV-infected women appeared to be beneficial, reducing morbidity. The benefit was observed particularly for diarrhea among HIV- infected children. [ABSTRACT FROM AUTHOR]

Objectives. Circumstances of delivery among children with acquired immunodeficiency syndrome (AIDS) were investigated to assess whether they were consistent with predictions that intrapartum factors affect the risk of maternal-infant human immunodeficiency virus (HIV) transmissions. Methods. Pediatric AIDS patients (maternal-infant transmission; n = 632) reported to the New York City Health Department through 1991 were compared with a series of infants born to predominantly uninfected women. For each case patient, five control subjects were selected and matched from birth certificate files. Hypothesized case-control comparisons for mode of delivery and preselected complications were tested. Results. Compared with control subjects, case patients were less likely to have been delivered by cesarean section without complications (odds ration [OR] = 0.77; 95% confidence interval [CI] = 0.59, 1.01) and more likely to have been delivered with complications, whether delivery was by cesarean section (OR = 1.54; 95% CI = 0.98, 2.43) or vaginal (OR = 1.66; 95% CI = 1.15, 2.39). Conclusions. Assuming that HIV- infected and uninfected women have comparable circumstances of delivery conditional on sociomedical characteristics, these results suggest that intrapartum events may be associated with maternal-infant HIV transmission. [ABSTRACT FROM AUTHOR]

Focuses on a study which analyzed the survival of patients with treatment-related acute nonlymphocytic leukemia. Materials and methods; Results; Conclusion.

A correction to the article "Elevated Serum Gastrin Is Associated With a History of Advanced Neoplasia in Barrett's Esophagus" that was published in the previous issues of the journal is presented.

To evaluate the role of oxidative stress and aflatoxin exposure on risk of hepatocellular carcinoma (HCC), a case–control study nested within a large community-based cohort was conducted in Taiwan. Baseline urine samples, collected from a total of 74 incident HCC cases and 290 matched controls, were used to determine by enzyme-linked immunosorbent assays the level of urinary 15-F2t-isoprostane (15-F2t-IsoP), a biomarker of lipid peroxidation. These samples had been previously analyzed for urinary aflatoxin B1 (AFB1) metabolites and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG). Pearson partial correlation coefficient analysis showed that urinary AFB1 metabolites and 8-oxodG were significantly associated with the level of urinary 15-F2t-IsoP. After adjustment for potential confounding factors in a conditional logistic regression model, urinary 15-F2t-IsoP was significantly associated with risk of HCC [above versus below the mean odds ratio (OR) = 2.53, 95% confidence interval (CI) = 1.30–4.93]. Moreover, when compared with subjects in the lowest tertile of 15-F2t-IsoP, there was a trend of increasing risk of HCC (Ptrend = 0.0008), with adjusted ORs (95% CIs) of 3.87 (1.32–11.38) and 6.27 (2.17–18.13) for the second and third tertile, respectively. In addition, the combination of urinary 15-F2t-IsoP above the mean and chronic hepatitis B virus (HBV) infection resulted in an OR of 19.01 (95% CI = 6.67–54.17) compared with those with low urinary 15-F2t-IsoP and without HBV infection. These results suggest that elevated levels of urinary 15-F2t-IsoP may be related to increasing level of aflatoxin exposure and are associated with an increased risk of HCC. [ABSTRACT FROM AUTHOR]