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Background: The U.S. Family Smoking Prevention and Tobacco Control Act of 2009 requires updating of the existing text-only health warning labels on tobacco packaging with nine new warning statements accompanied by pictorial images. Survey and experimental research in the U.S. and other countries supports the effectiveness of pictorial health warning labels compared with text-only warnings for informing smokers about the risks of smoking and encouraging cessation. Yet very little research has examined differences in reactions to warning labels by race/ethnicity, education or income despite evidence that population subgroups may differ in their ability to process health information. The purpose of the present study was to evaluate the potential impact of pictorial warning labels compared with text-only labels among U.S. adult smokers from diverse racial/ethnic and socioeconomic subgroups., Methods/findings: Participants were adult smokers recruited from two online research panels (n = 3,371) into a web-based experimental study to view either the new pictorial warnings or text-only warnings. Participants viewed the labels and reported their reactions. Adjusted regression models demonstrated significantly stronger reactions for the pictorial condition for each outcome salience (b = 0.62, p<.001); perceived impact (b = 0.44, p<.001); credibility (OR = 1.41, 95% CI = 1.22-1.62), and intention to quit (OR = 1.30, 95% CI = 1.10-1.53). No significant results were found for interactions between condition and race/ethnicity, education, or income. The only exception concerned the intention to quit outcome, where the condition-by-education interaction was nearly significant (p = 0.057)., Conclusions: Findings suggest that the greater impact of the pictorial warning label compared to the text-only warning is consistent across diverse racial/ethnic and socioeconomic populations. Given their great reach, pictorial health warning labels may be one of the few tobacco control policies that have the potential to reduce communication inequalities across groups. Policies that establish strong pictorial warning labels on tobacco packaging may be instrumental in reducing the toll of the tobacco epidemic, particularly within vulnerable communities.

Objective: To investigate the efficacy of etanercept in improving the symptoms and underlying inflammation in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS)., Methods: Fifteen patients with TRAPS were enrolled in a prospective, open-label, dose-escalation study. Patients recorded attacks, symptom severity, and use of ancillary medications in a daily diary. Blood samples were collected during each period and measured for levels of acute-phase reactants. Between 7 years and 9 years after the conclusion of the initial study, patients completed a followup survey and were evaluated to determine the long-term outcome of etanercept treatment., Results: Etanercept treatment significantly attenuated the total symptom score and reduced the frequency of symptoms. Etanercept also reduced levels of acute-phase reactants, particularly during asymptomatic periods. During a 10-year followup period, patients continued to receive etanercept for a median of 3.3 years, with a number of patients switching to anti-interleukin-1β receptor therapy or not receiving biologic agents, most frequently citing injection site reactions and lack of efficacy as reasons for discontinuation. However, patients continuing to receive etanercept had reduced symptoms at followup., Conclusion: Etanercept reduces symptoms and serum levels of inflammatory markers of TRAPS in a dose-dependent manner, but does not completely normalize symptoms or acute-phase reactant levels. Although long-term adherence to etanercept is poor, continuing to receive etanercept may provide continued symptomatic benefit., (Copyright © 2012 by the American College of Rheumatology.)

Background: Pluripotent stem cells represent one promising source for cellular cardiomyoplasty. In this study, we used cardiac magnetic resonance to examine the ability of highly enriched cardiomyocytes (CMs) derived from murine embryonic stem cells (ESC) to form grafts and improve contractile function of infarcted rat hearts., Methods and Results: Highly enriched ESC-CMs were obtained by inducing cardiac differentiation of ESCs stably expressing a cardiac-restricted puromycin resistance gene. At the time of transplantation, enriched ESC-CMs expressed cardiac-specific markers and markers of developing CMs, but only 6% of them were proliferating. A growth factor-containing vehicle solution or ESC-CMs (5 to 10 million) suspended in the same solution was injected into athymic rat hearts 1 week after myocardial infarction. Initial infarct size was measured by cardiac magnetic resonance 1 day after myocardial infarction. Compared with vehicle treatment, treatment with ESC-CMs improved global systolic function 1 and 2 months after injection and significantly increased contractile function in initially infarcted areas and border zones. Immunohistochemistry confirmed successful engraftment and the persistence of α-actinin-positive ESC-CMs that also expressed α-smooth muscle actin. Connexin-43-positive sites were observed between grafted ESC-CMs but only rarely between grafted and host CMs. No teratomas were observed in any of the animals., Conclusions: Highly enriched and early-stage ESC-CMs were safe, formed stable grafts, and mediated a long-term recovery of global and regional myocardial contractile function after infarction.

Background: Approximately 800,000 children die each year due to pneumococcal disease and >90% of these deaths occur in developing countries where few children have access to life-saving serotype-based vaccines. Understanding the serotype epidemiology of invasive pneumococcal disease (IPD) among children is necessary for vaccine development and introduction policies. The aim of this study was to systematically estimate the global and regional distributions of serotypes causing IPD in children <5 years of age., Methods and Findings: We systematically reviewed studies with IPD serotype data among children <5 years of age from the published literature and unpublished data provided by researchers. Studies conducted prior to pneumococcal conjugate vaccine (PCV) introduction, from 1980 to 2007, with ≥12 months of surveillance, and reporting ≥20 serotyped isolates were included. Serotype-specific proportions were pooled in a random effects meta-analysis and combined with PD incidence and mortality estimates to infer global and regional serotype-specific PD burden. Of 1,292, studies reviewed, 169 were included comprising 60,090 isolates from 70 countries. Globally and regionally, six to 11 serotypes accounted for ≥70% of IPD. Seven serotypes (1, 5, 6A, 6B, 14, 19F, 23F) were the most common globally; and based on year 2000 incidence and mortality estimates these seven serotypes accounted for >300,000 deaths in Africa and 200,000 deaths in Asia. Serotypes included in both the 10- and 13-valent PCVs accounted for 10 million cases and 600,000 deaths worldwide., Conclusions: A limited number of serotypes cause most IPD worldwide. The serotypes included in existing PCV formulations account for 49%-88% of deaths in Africa and Asia where PD morbidity and mortality are the highest, but few children have access to these life-saving vaccines. Please see later in the article for the Editors' Summary.

Background: Secondary transmission remains a significant concern among HIV-infected youth. Little is known, however, about how partner-specific sexual risk behaviors for the secondary transmission of HIV may differ between the 2 largest subgroups of HIV-positive youth, women-who-have-sex-with-men (WSM) and men-who-have-sex-with-men (MSM), METHODS: During 2003-2004, a convenience sample of HIV-infected youth, 13 to 24 years of age, were recruited from 15 Adolescent Medicine Trials Network clinical sites. Approximately 10 to 15 youth were recruited at each site. Participants completed an ACASI survey including questions about sex partners in the past year. Cross-sectional data analyses, including bivariate and multivariable regressions, using generalized estimating equations, were conducted during 2008 to compare recent partner-specific sexual risk behaviors between WSM and MSM., Results: Of 409 participants, 91% (371) were included in this analysis, including 176 WSM and 195 MSM. Ninety-two percent (163 WSM, 177 MSM) provided information on characteristics of their sexual partners. There were significant differences between the 2 groups in recent partner-specific sexual risk behaviors including: lower rates of condom use at last sex among WSM (61% WSM vs. 78% MSM; P = 0.0011); a larger proportion of the sex partners of MSM reported as concurrent (56% MSM vs. 36% WSM; P = 0.0001); and greater use of hard drugs at last sex by MSM and/or their partner (18% MSM vs. 4% WSM; P = 0.0008). When measuring risk as a composite measure of sexual risk behaviors known to be associated with HIV transmission, both groups had high rates of risky behaviors, 74.7% among young MSM compared to 68.1% of WSM., Conclusions: These data suggest that recent partner-specific sexual risk behaviors for HIV transmission are high among young infected MSM and WSM. These findings suggest the need to offer interventions to reduce the secondary transmission of HIV to all HIV-positive youth in care. However, differences in risk behaviors between young MSM and WSM supports population-specific interventions.

The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects > or =18 to <25 years old receiving (> or =28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC(0-24)), maximum concentration of drug in serum (C(max)), concentration at 24 h postdose (C(24)), and total apparent oral clearance (CL/F) values were 35,971 ng x hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC(0-24), C(max), C(24), and CL/F values were 2,762 ng.hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P < or = 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir C(max) and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.

Despite the considerable resources that have been dedicated to HIV prevention interventions and services over the past decade, HIV incidence among young people in the United States remains alarmingly high. One reason is that the majority of prevention efforts continue to focus solely on modifying individual behavior, even though public health research strongly suggests that changes to a community's structural elements, such as their programs, practices, and laws or policies, may result in more effective and sustainable outcomes. Connect to Protect is a multi-city community mobilization intervention that focuses on altering or creating community structural elements in ways that will ultimately reduce youth HIV incidence and prevalence. The project, which spans 6 years, is sponsored by the Adolescent Medicine Trials Network for HIV/AIDS Interventions at multiple urban clinical research sites. This paper provides an overview of the study's three phases and describes key factors in setting a firm foundation for the initiation and execution of this type of undertaking. Connect to Protect's community mobilization approach to achieving structural change represents a relatively new and broad direction in HIV prevention research. To optimize opportunities for its success, time and resources must be initially placed into laying the groundwork. This includes activities such as building a strong overarching study infrastructure to ensure protocol tasks can be met across sites; tapping into local site and community expertise and knowledge; forming collaborative relationships between sites and community organizations and members; and fostering community input on and support for changes at a structural level. Failing to take steps such as these may lead to insurmountable implementation problems for an intervention of this kind.

Background: Hyperphosphatemia underlies development of hyperparathyroidism, osteodystrophy, extraosseous calcification, and is associated with increased mortality in hemodialysis patients., Methods: To determine whether calcium acetate or sevelamer hydrochloride best achieves recently recommended treatment goals of phosphorus

Unlabelled: The purpose of this investigation was to evaluate the use of a commercially available lactose-free fatty-meal food supplement, as an alternative to sincalide cholescintigraphy, to develop a standard methodology, and to determine normal gallbladder ejection fractions (GBEFs) for this supplement., Methods: Twenty healthy volunteers all had negative medical histories for hepatobiliary and gallbladder disease, had no personal or family history of hepatobiliary disease, and were not taking any medication known to affect gallbladder emptying. All were prescreened with a complete blood cell count, comprehensive metabolic profile, gallbladder and liver ultrasonography, and conventional cholescintigraphy. Three of the 20 subjects were eliminated from the final analysis because of an abnormality in one of the above studies., Results: After gallbladder filling on conventional cholescintigraphy, the subjects ingested the supplement and an additional 60-min study was acquired. GBEFs were calculated and ranged from 33% to 95% (mean +/- SD, 62.6% +/- 21.3%). Statistical analysis determined the lower range of normal to be 32.6%. Maximal gallbladder emptying occurred between 55 and 60 min., Conclusion: A standard methodology and normal GBEFs (> or =33%) were established for supplement-stimulated cholescintigraphy.

The validity of self-report of drug use has been found to vary widely. Moreover, previous research has focused on samples of adults. In 1996-1998, human immunodeficiency virus (HIV)-infected adolescents and high-risk, noninfected adolescents (n = 182) were recruited at 16 locations in 13 US cities into the Reaching for Excellence in Adolescent Care and Health (REACH) project, to the authors' knowledge, the first national study of disease progression among HIV-positive adolescents who were infected through sexual behavior or injection drug use. Self-report of marijuana use was assessed through audio computer-assisted self-administered interviewing (ACASI). Urines were tested for marijuana at a certified laboratory by using the enzyme-multiplied immunoassay technique. Conditional kappas for 2-, 5-, and 7-day self-reports were 0.57, 0.71, and 0.69, respectively. Maximum sensitivity was obtained from a combination of ACASI and urine drug testing. Contrary to previous studies, the data suggest that if a single evaluative instrument is to be used for prevalence, ACASI is more sensitive than urine drug testing for marijuana overall, but particularly for HIV-infected adolescents.

The safety and immunogenicity of 5 acellular pertussis vaccines (ACVs) were compared in a multicenter, randomized, double-blind trial. A total of 481 healthy adults were given a single intramuscular booster dose of ACV or placebo. Three different dose levels were tested for 4 ACVs: full strength (the dose level proposed for infant immunization), one-third strength, and one-tenth strength. For 1 multicomponent vaccine, only the pertussis toxoid dose level varied. Minor injection site reactions were common and similar in frequency among vaccinated groups. Late-onset injection site reactions were seen in all ACV groups. Dose-related increases in mean antibody titers against vaccine antigens were seen after immunization with all ACVs. Antibody responses against antigens not known to be present in the vaccines were detected after immunization with 4/5 ACVs. Antibody levels fell significantly during the year after immunization. These data support evaluation of ACVs for broader use among adolescents and adults.

Three antibody reagents that neutralize primary human immunodeficiency virus type 1 (HIV-1) isolates were tested for magnitude and breadth of neutralization when used alone or in double or triple combinations. Hyperimmune anti-HIV immunoglobulin (HIVIG) is derived from the plasma of HIV-1-infected donors, and monoclonal antibodies (MAbs) 2F5 and 2G12 bind to distinct regions of the HIV-1 envelope glycoprotein. The antibodies were initially tested against a panel of 15 clade B HIV-1 isolates, using a single concentration that is achievable in vivo (HIVIG, 2,500 microg/ml; MAbs, 25 microg/ml). Individual antibody reagents neutralized many of the viruses tested, but antibody potency varied substantially among the viruses. The virus neutralization produced by double combinations of HIVIG plus 2F5 or 2G12, the two MAbs together, or the triple combination of HIVIG, 2F5, and 2G12 was generally equal to or greater than that predicted by the effect of individual antibodies. Overall, the triple combination displayed the greatest magnitude and breadth of neutralization. Synergistic neutralization was evaluated by analyzing data from dose-response curves of each individual antibody reagent compared to the triple combination and was demonstrated against each of four viruses tested. Therefore, combinations of polyclonal and monoclonal anti-HIV antibodies can produce additive or synergistic neutralization of primary HIV-1 isolates. Passive immunotherapy for treatment or prophylaxis of HIV-1 should consider mixtures of potent neutralizing antibody reagents to expand the magnitude and breadth of virus neutralization.

Unlabelled: Iodine-123-labeled IPT (N-(3-iodopropen-2-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane) is an analog of cocaine that selectively binds the presynaptic dopamine transporter. This study sought to characterize changes in the striatal uptake of IPT with normal aging., Methods: The sample included 18 healthy human volunteers. Their ages ranged from 19 to 67 yr. Dynamic SPECT scans of the brain were acquired with about 185 MBq (5 mCi) of IPT on a triple-headed camera. The images were reconstructed with a three-dimensional restorative filter and corrected for attenuation. The mean concentration of radioactivity [microCi/ml] was measured in the head of the caudate and body of the putamen. The remainder of the supratentorial brain was used as a reference., Results: The specific uptake of IPT was higher in the caudate than in the putamen of each subject. It decreased significantly with age in both regions. The mean specific uptake in seven volunteers who were less than 30 yr old was 17.6 +/- 4.9 in the caudate and 13.3 +/- 4.0 in the putamen, compared to only 11.97 +/- 3.30 and 7.8 +/- 2.68, respectively, in the six middle-aged subjects (t = 2.53 and 2.90, df = 11, p = 0.027 and 0.014). However, there were no significant differences between the six middle-aged subjects and the five volunteers who were older than 60 yr, whose respective means were 9.0 +/- 1.6 and 6.2 +/- 0.7 (t = 1.83 and 1.28, df = 9, p = 0.10 and 0.23). The results were supported by regression analysis, which indicated that changes with age were not optimally described as a linear function when compared to several nonlinear alternatives. The fit improved when the models accounted for relatively rapid rates of decline during young adulthood, followed by less rapid decline throughout middle age., Conclusion: The results are consistent with the findings from previous studies that have shown that the specific uptake values for radiopharmaceuticals that bind the dopamine transporter decline with advancing age. However, results of this study suggest that the effects of aging may be nonlinear and regionally distinct.

To examine the possible influence of obstetric factors, substance use during pregnancy, and other maternal factors on the relationship between a low maternal CD4+ level and vertical transmission of human immunodeficiency virus type 1 (HIV-1), data were analyzed from the Mothers and Infants Cohort Study, a prospective cohort followed for up to 4 years between 1986 and 1992 in Brooklyn and the Bronx, New York. The overall transmission rate for the cohort was 25.1% (95% confidence interval (CI) = 19.0-31.3). Prenatal CD4+ lymphocyte measurements were available for 162 HIV-seropositive mothers of infants with known infection outcomes. Among mothers who smoked cigarettes after the first trimester, those whose mean prenatal CD4+ level was < 20% had more than a threefold increased risk of transmitting their infection to their infants [relative risk (RR) = 3.30; 95% CI = 1.46-7.44; p = 0.004]. Among mothers who developed premature rupture of membranes, those with a low CD4+ level had a similarly increased risk of vertical transmission (RR = 4.33; 95% CI = 1.78-10.5; p = 0.003). These relative risks were much higher than those for mothers who did not smoke after the first trimester (RR = 1.14; 95% CI = 0.48-2.70; p = 0.76) or have premature rupture of membranes (RR = 1.29; 95% CI = 0.61-2.74; p = 0.50), indicating that these factors modified the effect of CD4+ level on transmission. Among all mothers without regard to CD4+ level, those who experienced preterm premature rupture of membranes were also at greater risk of transmission (RR = 2.24; 95% CI = 1.07-4.69; p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

112 Tunisian patients with rapidly progressing breast cancer (RPBC) were entered into a clinical trial evaluating combination chemotherapy as a primary form of treatment before surgery or radiotherapy. Three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) were administered at monthly intervals; patients were then randomized to surgery or radiotherapy to control the primary tumour, and 12 more cycles of CMF followed local/regional therapy. RPBC was sensitive to CMF; after only 3 cycles, 11% of evaluable patients showed complete remission and 78% had at least 25% diminution in tumour size. The disease-free interval (DFI) was substantially greater in this series than in a previously reported series treated by surgery and/or radiotherapy alone. No difference in DFI was found between patients randomized to receive surgery and those randomized to receive radiotherapy. Postmenopausal patients responded to CMF as well as premenopausal patients. Combination chemotherapy appears to play an important role in the control of RPBC, an aggressive malignancy often resembling inflammatory breast cancer.

Prerandomization renal biopsy specimens were examined in 102 patients upon entry into prospective therapeutic trials of lupus nephritis in an attempt to identify early predictors of renal failure outcome. All 11 renal failures occurred among the 72 individuals with diffuse proliferative or membranoproliferative glomerulonephritis (DPGN/MPGN); thus, these patients were at modestly, but significantly, increased risk of endstage renal disease compared to those with focal proliferative, membranous, or mesangial glomerulonephritis. Considering the low incidence of endstage renal disease among patients with DPGN/MPGN, we sought to refine the prognostic information obtained from renal morphology by semiquantitative scoring of individual histologic features and by derivation of composite histologic scores specified by Activity (AI) and Chronicity (CI) Indices. Among the 72 patients with DPGN/MPGN, the composite AI was more strongly predictive of renal failure than were the individual active histologic features; cellular crescents and extensive fibrinoid necrosis yielded positive associations, while endocapillary proliferation, leucocytic exudation, and hyaline thrombi in glomeruli and interstitial inflammation by themselves did not emerge as useful prognostic indicators. However, chronicity items (glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis) considered individually, as well as in the composite CI, were highly predictive of renal failure outcome. Particularly striking was the prognostic value of tubular atrophy; all 11 renal failures were among the 43 patients with tubular atrophy on prerandomization renal biopsy. While no single pathologic variable improved outcome predictions among those with tubular atrophy, examination for interactions among variables revealed that glomerular sclerosis and cellular crescents had a synergistic effect which augmented the prognostic information derived from analysis of tubular atrophy alone.(ABSTRACT TRUNCATED AT 250 WORDS)

In comparing two survival distributions, a Mantel-Haenszel statistic can be computed after each death as a non-linear two-sample rank statistic. The distributions of both the maximum and terminal statistics in such a sequence are studied numerically, in the absence of censoring, and appropriate critical values are determined. The maximum statistic is applied to simultaneous inference, and both the maximum and terminal statistics are used as the basis for early stopping procedures (especially in the pseudo-sequential context). Procedures based on the two statistics are compared for power and for early decision properties such as stopping index and (for exponential distributions) stopping time.

Suppose that a heterogeneous group of individuals is followed over time and that each individual can be in state 0 or state 1 at each time point. The sequence of states is assumed to follow a binary Markov chain. In this paper we model the transition probabilities for the 0 to 0 and 1 to 0 transitions by two logistic regressions, thus showing how the covariates relate to changes in state. With p covariates, there are 2(p + 1) parameters including intercepts, which we estimate by maximum likelihood. We show how to use transition probability estimates to test hypotheses about the probability of occupying state 0 at time i (i = 2, ..., T) and the equilibrium probability of state 0. These probabilities depend on the covariates. A recursive algorithm is suggested to estimate regression coefficients when some responses are missing. Extensions of the basic model which allow time-dependent covariates and nonstationary or second-order Markov chains are presented. An example shows the model applied to a study of the psychological impact of breast cancer in which women did or did not manifest distress at four time points in the year following surgery.