End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.

To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-patient-reported outcomes), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the end-organ considerations, measurement of cure, and low-resource settings panels as well as relevant findings and recommendations from the biomarkers panel.

End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain.

To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.

Meningococcal Conjugate and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccination Among HIV-infected Youth.

BACKGROUND: The meningococcal conjugate vaccine (MCV4) and the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) were first recommended for adolescents in the US in 2005. The goal of our study was to determine MCV4 and Tdap vaccines coverage among perinatally and behaviorally HIV-infected adolescents in 2006 and to compare coverage estimates in our study population to similarly aged healthy youth in 2006. METHODS: Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY) is a retrospective cohort study of HIV-infected youth in 22 HIV specialty clinics across the US. Among LEGACY participants ≥11 years of age in 2006, we conducted a cross-sectional analysis to determine MCV4, Tdap and MCV4/Tdap vaccine coverage. We compared vaccine coverage among our study population to coverage among similarly aged youth in the 2006 National Immunization Survey for Teens (NIS-Teen Survey). Multivariable mixed effects logistic regression modeling was used to examine associations between MCV4/Tdap vaccination and mode of HIV transmission. RESULTS: MCV4 and Tdap coverage rates among 326 eligible participants were 31.6% and 28.8%, respectively. Among adolescents 13-17 years of age, MCV4 and Tdap coverage was significantly higher among HIV-infected youth than among youth in the 2006 NIS-Teen Survey (P <0.01). In multivariable analysis, perinatally HIV-infected youth were significantly more likely to have received MCV4/Tdap vaccination compared with their behaviorally infected counterparts (adjusted odds ratio: 5.1; 95% confidence interval: 2.0, 12.7). HIV-infected youth with CD4 cell counts of 200-499 cells/µL were more likely to have had MCV4/Tdap vaccination compared with those with CD4 counts ≥500 cells/µL (adjusted odds ratio: 2.2; 95% confidence interval: 1.2, 4.3). Participants with plasma HIV RNA viral loads of >400 copies/mL were significantly less likely to have received MCV4/Tdap vaccination (P < 0.05). CONCLUSIONS: MCV4 and Tdap coverage among HIV-infected youth was suboptimal but higher than for healthy adolescents in the 2006 NIS-Teen Survey. Perinatal HIV infection was associated with increased likelihood of vaccination. Specific measures are needed to improve vaccine coverage among adolescents in the US.

Obesity and Pulmonary Function in African Americans.

BACKGROUND: Obesity prevalence in United States (US) adults exceeds 30% with highest prevalence being among blacks. Obesity is known to have significant effects on respiratory function and obese patients commonly report respiratory complaints requiring pulmonary function tests (PFTs). However, there is no large study showing the relationship between body mass index (BMI) and PFTs in healthy African Americans (AA). OBJECTIVE: To determine the effect of BMI on PFTs in AA patients who did not have evidence of underlying diseases of the respiratory system. METHODS: We reviewed PFTs of 339 individuals sent for lung function testing who had normal spirometry and lung diffusion capacity for carbon monoxide (DLCO) with wide range of BMI. RESULTS: Functional residual capacity (FRC) and expiratory reserve volume (ERV) decreased exponentially with increasing BMI, such that morbid obesity resulted in patients breathing near their residual volume (RV). However, the effects on the extremes of lung volumes, at total lung capacity (TLC) and residual volume (RV) were modest. There was a significant linear inverse relationship between BMI and DLCO, but the group means values remained within the normal ranges even for morbidly obese patients. CONCLUSIONS: We showed that BMI has significant effects on lung function in AA adults and the greatest effects were on FRC and ERV, which occurred at BMI values < 30 kg/m2. These physiological effects of weight gain should be considered when interpreting PFTs and their effects on respiratory symptoms even in the absence of disease and may also exaggerate existing lung diseases.

Correlates of HIV testing refusal among emergency department patients in the opt-out testing era.

Opt-out HIV screening is recommended by the CDC for patients in all healthcare settings. We examined correlates of HIV testing refusal among urban emergency department (ED) patients. Confidential free HIV screening was offered to 32,633 ED patients in an urban tertiary care facility in Washington, DC, during May 2007-December 2011. Demographic differences in testing refusals were examined using χ(2) tests and generalized linear models. HIV testing refusal rates were 47.7 % 95 % CI (46.7-48.7), 11.7 % (11.0-12.4), 10.7 % (10.0-11.4), 16.9 % (15.9-17.9) and 26.9 % (25.6-28.2) in 2007, 2008, 2009, 2010 and 2011 respectively. Persons 33-54 years of age [adjusted prevalence ratio (APR) 1.42, (1.36-1.48)] and those ≥ 55 years [APR 1.39 (1.31-1.47)], versus 33-54 years; and females versus males [APR 1.07 (1.02-1.11)] were more likely to refuse testing. Opt-out HIV testing is feasible and sustainable in urban ED settings. Efforts are needed to encourage testing among older patients and women.

Immediate hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines: reports to VAERS.

BACKGROUND: Hypersensitivity disorders following vaccinations are a cause for concern. OBJECTIVE: To determine the type and rate by age, gender, and vaccine received for reported hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines. DESIGN: A systematic review of reports to the Vaccine Adverse Event Reporting System (VAERS) following monovalent 2009 pandemic influenza A (H1N1) vaccines. SETTING/PATIENTS: US Civilian reports following vaccine received from October 1, 2009 through May 31, 2010. MEASUREMENTS: Age, gender, vaccines received, diagnoses, clinical signs, and treatment were reviewed by nurses and physicians with expertise in vaccine adverse events. A panel of experts, including seven allergists reviewed complex illnesses and those with conflicting evidence for classification of the event. RESULTS: Of 1984 reports, 1286 were consistent with immediate hypersensitivity disorders and 698 were attributed to anxiety reactions, syncope, or other illnesses. The female-to-male ratio was ≥4:1 for persons 20-to-59 years of age, but approximately equal for children under 10. One hundred eleven reports met Brighton Collaboration criteria for anaphylaxis; only one-half received epinephrine for initial therapy. The overall rate of reported hypersensitivity reactions was 10.7 per million vaccine doses distributed, with a 2-fold higher rate for live vaccine. LIMITATIONS: Underreporting, especially of mild events, would result in an underestimate of the true rate of immediate hypersensitivity reactions. Selective reporting of events in adult females could have resulted in higher rates than reported for males. CONCLUSIONS: Adult females may be at higher risk of hypersensitivity reactions after influenza vaccination than men. Although the risk of hypersensitivity reactions following 2009 pandemic influenza A (H1N1) vaccines was low, all clinics administering vaccines should be familiar with treatment guidelines for these adverse events, including the use of intramuscular epinephrine early in the course of serious hypersensitivity reactions.

The effect of depression symptoms and social support on black-white differences in health-related quality of life in early pregnancy: the health status in pregnancy (HIP) study.

BACKGROUND: Lower physical and social functioning in pregnancy has been linked to an increased risk of preterm delivery and low birth weight infants, butt few studies have examined racial differences in pregnant women's perception of their functioning. Even fewer studies have elucidated the demographic and clinical factors contributing to racial differences in functioning. Our objective was to determine whether there are racial differences in health-related quality of life (HRQoL) in early pregnancy; and if so, to identify the contributions of socio-demographic characteristics, depression symptoms, social support and clinical factors to these differences. METHODS: Cross-sectional study of 175 women in early pregnancy attending prenatal clinics in urban setting. In multivariate analysis, we assessed the independent relation of black race (compared to white) to HRQoL scores from the eight domains of the Medical Outcomes (SF-36) SURVEY: Physical Functioning, Role-Physical, Bodily Pain, Vitality, General Health, Social Functioning, Role-Emotional, and Mental Health. We compared socio-demographic and clinical factors and depression symptoms between black and white women and assessed the relative importance of these factors in explaining racial differences in physical and social functioning. RESULTS: Black women comprised 59% of the sample; white women comprised 41%. Before adjustment, black women had scores that were 14 points lower in Physical Function and Bodily Pain, 8 points lower in General Health, 4 points lower in Vitality and 7 points lower in Social Functioning. After adjustment for depression symptoms, social support and clinical factors, black women still had HRQoL scores that were 4 to 10 points lower than white women, but the differences were no longer statistically significant. Level of social support and payment source accounted for most of the variation in Physical Functioning, Bodily Pain and General Health. Social support accounted for most of the differences in Vitality and Social Functioning. CONCLUSIONS: Payment source and social support accounted for much of the racial differences in physical and social function scores. Efforts to reduce racial differences might focus on improving social support networks and Socio-economic barriers.

Cervical pap screening cytological abnormalities among HIV-infected adolescents in the LEGACY cohort.

OBJECTIVES: To determine the prevalence of cervical Pap screening (CPAP-S), identify factors associated with CPAP-S, and explore risk factors for abnormal cervical cytology in female adolescents with perinatally and behaviorally acquired HIV infection. DESIGN: Cross-sectional. SETTING: LEGACY is a national observational cohort chart review study of 1478 HIV-infected persons (

Correlates of sexual activity and sexually transmitted infections among human immunodeficiency virus-infected youth in the LEGACY cohort, United States, 2006.

BACKGROUND: To determine the prevalence and correlates of sexual activity and sexually transmitted infections (STIs) among human immunodeficiency virus (HIV)-infected youth. METHODS: The Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY) is an observational medical record study of perinatally and behaviorally HIV-infected (PHIV and BHIV) youth followed at 22 US HIV clinics. PHIV youth were HIV infected at birth or by breast-feeding. BHIV youth were HIV infected sexually or by injection drug use. We determined the prevalence of sexual activity during 2006 and examined correlates of sexual activity among 13- to 24-year-old PHIV youth using multivariable generalized linear models. Among sexually active persons, we determined the association between mode of HIV acquisition and non-HIV STI diagnosis using multivariable generalized linear models. RESULTS: In all, 34% (195/571) of PHIV and 89% (162/181) of BHIV youth were sexually active. Eighty percent (155/195) of sexually active PHIV youth reported ever using condoms. Ninety-three percent discussed sex with a health care provider. Increasing age (adjusted prevalence ratio [APR]: 1.17 per year of age, 95% confidence interval [CI] = 1.12-1.23), having a boyfriend/girlfriend (APR: 2.74, 95% CI = 1.75-4.29), and injection drug use (APR: 1.38, 95% CI = 1.06-1.79) correlated with sexual activity after adjusting for socio-demographic and HIV-related clinical variables. Among sexually active youth, after adjusting for relevant confounders, PHIV youth were less likely than BHIV youth to have been diagnosed with an STI in 2006 (APR: 0.25, 95% CI = 0.13-0.46). CONCLUSIONS: Sexual activity among HIV-infected adolescents is common. Factors associated with sexual activity in this study should be taken into account in developing behavioral risk reduction interventions targeting PHIV youth.

Monitoring adverse events following yellow fever vaccination using an integrated telephone and Internet-based system.

TeleWatch is an automated telephone/Internet-based system that collects medical product adverse event reports in real-time through an algorithm driven by the patient. 1341 patients, who received yellow fever vaccine and were recruited through 15 travel clinics, contacted the system within 48h of vaccination and 765 (57%) made follow-up contacts. Participation rates were higher among females and persons older than 60 years of age. TeleWatch can be expanded for use in large campaigns involving influenza or other vaccines.

Longitudinal study of depressive symptoms and health-related quality of life during pregnancy and after delivery: the Health Status in Pregnancy (HIP) study.

OBJECTIVE: Depressive symptoms are known to affect functioning in early pregnancy. We estimated the effect of a change in depressive symptoms status on health-related quality of life (HRQoL) throughout pregnancy and after delivery. METHODS: Longitudinal study of 200 women. The independent variable was depressive symptoms, defined as a Center for Epidemiologic Studies Depression (CES-D) score of > or =16. The dependent variable was HRQoL from 8 domains of the Medical Outcomes Study (SF-36) Short Form. Women were categorized based on the change in CES-D score: (1) never depressed, (2) became well, (3) became depressed and (4) always depressed. A random effects model was used to (1) estimate the effect of a change in depressive symptomatology from the first to the second trimester on HRQOL in the second trimester and (2) estimate the change in depressive symptomatology from the second to the third trimester on HRQoL in the third trimester and after delivery, adjusting for covariates. Intra-individual correlations were accounted for using generalized estimating equations (GEE). RESULTS: The proportion of women with depressive symptoms was 15%, 14%, and 30% in the first, second and third trimesters, respectively, and 9% after delivery. Women who became depressed had scores in the social domains that were 10-23 points and 19-31 points lower in the second and third trimesters, respectively, compared to women with no depressive symptoms. Women who became well had scores that were 3-31 points lower, compared to women with no depressive symptoms. CONCLUSIONS: Alterations in depressive symptomatology have a substantial effect on functioning during pregnancy and after delivery.

An algorithm for treatment of patients with hypersensitivity reactions after vaccines.

Concerns about possible allergic reactions to immunizations are raised frequently by both patients/parents and primary care providers. Estimates of true allergic, or immediate hypersensitivity, reactions to routine vaccines range from 1 per 50000 doses for diphtheria-tetanus-pertussis to approximately 1 per 500000 to 1000000 doses for most other vaccines. In a large study from New Zealand, data were collected during a 5-year period on 15 marketed vaccines and revealed an estimated rate of 1 immediate hypersensitivity reaction per 450000 doses of vaccine administered. Another large study, conducted within the Vaccine Safety Datalink, described a range of reaction rates to >7.5 million doses. Depending on the study design and the time after the immunization event, reaction rates varied from 0.65 cases per million doses to 1.53 cases per million doses when additional allergy codes were included. For some vaccines, particularly when allergens such as gelatin are part of the formulation (eg, Japanese encephalitis), higher rates of serious allergic reactions may occur. Although these per-dose estimates suggest that true hypersensitivity reactions are quite rare, the large number of doses that are administered, especially for the commonly used vaccines, makes this a relatively common clinical problem. In this review, we present background information on vaccine hypersensitivity, followed by a detailed algorithm that provides a rational and organized approach for the evaluation and treatment of patients with suspected hypersensitivity. We then include 3 cases of suspected allergic reactions to vaccines that have been referred to the Clinical Immunization Safety Assessment network to demonstrate the practical application of the algorithm.

Weight loss programs for urban-based, postpartum African-American women: perceived barriers and preferred components.

OBJECTIVES: There are currently 1.85 million reproductive-aged women in the United States with diabetes or glucose intolerance. While it is known that postpartum weight retention can lead to obesity and diabetes, particularly among African-American women, little is known about African-American women's preferences for postpartum weight loss programs. Our objective was to explore urban-based African-American women's attitudes toward weight gain, perceived barriers to postpartum weight loss, and preferences for weight intervention strategies. METHODS: Focus groups of pregnant African-American women (n = 22) were conducted by a race-concordant moderator. Open-ended questions were posed to stimulate discussions which were audio taped and transcribed verbatim. Transcriptions were independently reviewed by two investigators who extracted quotations and coded each statement to identify major themes. RESULTS: The median age of participants was 26 years. Median pre-pregnancy or first trimester body-mass index was 31 kg/m(2). Fifty-seven percent of the women were multiparous and 68% were Medicaid recipients. We identified 16 themes with the majority of participant comments focused on: (1) effect of postpartum depression on motivation to lose weight; (2) strong desire to lose weight; (3) knowledge of adverse effects of obesity; (4) costs of weight loss programs; (5) negative impact of media coverage of successful celebrity postpartum weight loss; (6) limitations of childcare on ability to exercise; and (7) family-centered lifestyle behaviors that promote unhealthy eating. CONCLUSIONS: Weight loss interventions for African-American women with postpartum obesity should address psychological effects of childbearing, affordability, and perceptions of body image. Interventions should incorporate family-centered approaches and weight loss maintenance strategies.

Depressive symptoms and health-related quality of life in early pregnancy.

OBJECTIVE: Depressive symptoms can be associated with lower health-related quality of life in late pregnancy. Few studies have quantified the effect of depressive symptoms in early pregnancy or among a racially and economically diverse group. Our goal was to estimate the independent association of depressive symptoms with health-related quality of life among a diverse group of women in early pregnancy. METHODS: We conducted a cross-sectional study of 175 pregnant women receiving prenatal care in a community and university-based setting. We related the presence of depressive symptoms, defined as a Center for Epidemiologic Studies Depression Scale score of 16 or more to health-related quality of life scores from the 8 Medical Outcomes Study Short Form domains: Physical Functioning, Role-Physical, Bodily Pain, Vitality, General Health, Social Functioning, Role-Emotional, and Mental Health. Quantile regression was used to measure the independent association of depressive symptoms with each of the 8 domains. RESULTS: The study sample was 49% African American, 38% white, and 11% Asian. Mean (+/- standard deviation) gestational age was 14 +/- 6 weeks. The prevalence of depressive symptoms was 15%. Women with depressive symptoms had significantly lower health-related quality of life scores in all domains except Physical Functioning. After adjustment for sociodemographic, clinical, and social support factors, depressive symptoms were associated with health-related quality of life scores that were 30 points lower in Role-Physical, 19 points lower in Bodily Pain, 10 points lower in General Health, and 56 points lower in Role-Emotional. CONCLUSION: Women in early pregnancy with depressive symptoms have poor health-related quality of life. Early identification and management of depressive symptoms in pregnant women may improve their sense of well-being. LEVEL OF EVIDENCE: II-2.

HIV-1 infection as a risk factor for incomplete childhood immunization in Zambia.

Immunizations are of particular importance for human immunodeficiency virus type 1(HIV-1)-infected children as they are at increased risk of severe disease and death from several vaccine-preventable diseases. Outside the United States, however, research on the impact of the HIV-1 epidemic on childhood immunization coverage is sparse. We conducted a nested case-control study in hospitalized children with measles to assess whether HIV-1 infection was a risk factor for incomplete immunization with diphtheria-tetanus-pertussis vaccine (DTP) and oral polio vaccine (OPV). Of 473 children, whose immunization status was determined from the immunization record or maternal recall, 23% were incompletely immunized and 19% were HIV-1 infected. After adjusting for age, sex, and measles vaccination status, HIV-1 infection was significantly associated with incomplete immunization with DTP and OPV (adjusted OR 1.9; 95% CI 1.1, 3.3). In a subset of children for whom information on maternal education was available, less than 7 years of school education was a risk factor for incomplete immunization (adjusted OR 3.7; 95% CI 1.8. 7.5). Children from homes with more than three children were twice as likely to be incompletely immunized as those from homes with one to three children. Our findings suggest that HIV-1-infected children are at increased risk of vaccine-preventable diseases not only because of impaired immune responses but because of lower rates of vaccine coverage.