A Weak Neutralizing Antibody Response to Hepatitis C Virus Envelope Glycoprotein Enhances Virus Infection

We have completed a phase 1 safety and immunogenicity trial with hepatitis C virus (HCV) envelope glycoproteins, E1 and E2, with MF59 adjuvant as a candidate vaccine. Neutralizing activity to HCV genotype 1a was detected in approximately 25% of the vaccinee sera. In this study, we evaluated vaccinee sera from poor responders as a potential source of antibody dependent enhancement (ADE) of HCV infection. Sera with poor neutralizing activity enhanced cell culture grown HCV genotype 1a or 2a, and surrogate VSV/HCV pseudotype infection titer, in a dilution dependent manner. Surrogate pseudotypes generated from individual HCV glycoproteins suggested that antibody to the E2 glycoprotein; but not the E1 glycoprotein, was the principle target for enhancing infection. Antibody specific to FcRII expressed on the hepatic cell surface or to the Fc portion of Ig blocked enhancement of HCV infection by vaccinee sera. Together, the results from in vitro studies suggested that enhancement of viral infectivity may occur in the absence of a strong antibody response to HCV envelope glycoproteins

A cohort study of in utero polychlorinated biphenyl (PCB) exposures in relation to secondary sex ratio

Abstract: Background: Polychlorinated biphenyls (PCBs) are ubiquitous industrial chemicals that persist in the environment and in human fatty tissue. PCBs are related to a class of compounds known as dioxins, specifically 2,3,7,8-TCDD (tetrachloro-dibenzodioxin), which has been implicated as a cause of altered sex ratio, especially in relation to paternal exposures. Methods: In the 1960's, serum specimens were collected from pregnant women participating in the Child Health and Development Study in the San Francisco Bay Area. The women were interviewed and their serum samples stored at -20°C. For this study, samples were thawed and a total of eleven PCBs were determined in 399 specimens. Secondary sex ratio, or sex ratio at birth, was evaluated as a function of maternal serum concentrations using log-binomial and logistic regression, controlling for hormonally active medications taken during pregnancy. Results: The relative risk of a male birth decreased by 33% comparing women at the 90th percentile of total PCBs with women at the 10th percentile (RR = 0.67; 95% CI, 0.48–0.94; p = 0.02), or by approximately 7% for each 1 μg/L increase in total PCB concentration. Although some congener-specific associations with sex ratio were only marginally statistically significant, all nine PCB congeners with < 30% of samples below the LOQ showed the same direction of association, an improbable finding under the null hypothesis. Conclusion: Maternal exposure to PCBs may be detrimental to the success of male sperm or to the survival of male embryos. Findings could be due to contaminants, metabolites or PCBs themselves

Financial incentives for return of service in underserved areas: a systematic review

<p>Abstract</p> <p>Background</p> <p>In many geographic regions, both in developing and in developed countries, the number of health workers is insufficient to achieve population health goals. Financial incentives for return of service are intended to alleviate health worker shortages: A (future) health worker enters into a contract to work for a number of years in an underserved area in exchange for a financial pay-off.</p> <p>Methods</p> <p>We carried out systematic literature searches of PubMed, the Excerpta Medica database, the Cumulative Index to Nursing and Allied Health Literature, and the National Health Services Economic Evaluation Database for studies evaluating outcomes of financial-incentive programs published up to February 2009. To identify articles for review, we combined three search themes (health workers or students, underserved areas, and financial incentives). In the initial search, we identified 10,495 unique articles, 10,302 of which were excluded based on their titles or abstracts. We conducted full-text reviews of the remaining 193 articles and of 26 additional articles identified in reference lists or by colleagues. Forty-three articles were included in the final review. We extracted from these articles information on the financial-incentive programs (name, location, period of operation, objectives, target groups, definition of underserved area, financial incentives and obligation) and information on the individual studies (authors, publication dates, types of study outcomes, study design, sample criteria and sample size, data sources, outcome measures and study findings, conclusions, and methodological limitations). We reviewed program results (descriptions of recruitment, retention, and participant satisfaction), program effects (effectiveness in influencing health workers to provide care, to remain, and to be satisfied with work and personal life in underserved areas), and program impacts (effectiveness in influencing health systems and health outcomes).</p> <p>Results</p> <p>Of the 43 reviewed studies 34 investigated financial-incentive programs in the US. The remaining studies evaluated programs in Japan (five studies), Canada (two), New Zealand (one) and South Africa (one). The programs started between 1930 and 1998. We identified five different types of programs (service-requiring scholarships, educational loans with service requirements, service-option educational loans, loan repayment programs, and direct financial incentives). Financial incentives to serve for one year in an underserved area ranged from year-2000 United States dollars 1,358 to 28,470. All reviewed studies were observational. The random-effects estimate of the pooled proportion of all eligible program participants who had either fulfilled their obligation or were fulfilling it at the time of the study was 71% (95% confidence interval 60–80%). Seven studies compared retention in the <it>same </it>(underserved) area between program participants and non-participants. Six studies found that participants were less likely than non-participants to remain in the same area (five studies reported the difference to be statistically significant, while one study did not report a significance level); one study did not find a significant difference in retention in the same area. Thirteen studies compared provision of care or retention in <it>any </it>underserved area between participants and non-participants. Eleven studies found that participants were more likely to (continue to) practice in any underserved area (nine studies reported the difference to be statistically significant, while two studies did not provide the results of a significance test); two studies found that program participants were significantly less likely than non-participants to remain in any underserved area. Seven studies investigated the satisfaction of participants with their work and personal lives in underserved areas.</p> <p>Conclusion</p> <p>Financial-incentive programs for return of service are one of the few health policy interventions intended to improve the distribution of human resources for health on which substantial evidence exists. However, the majority of studies are from the US, and only one study reports findings from a developing country, limiting generalizability. The existing studies show that financial-incentive programs have placed substantial numbers of health workers in underserved areas and that program participants are more likely than non-participants to work in underserved areas in the long run, even though they are less likely to remain at the site of original placement. As none of the existing studies can fully rule out that the observed differences between participants and non-participants are due to selection effects, the evidence to date does not allow the inference that the programs have caused increases in the supply of health workers to underserved areas.</p

Antibody-mediated enhancement aggravates chikungunya virus infection and disease severity

The arthropod-transmitted chikungunya virus (CHIKV) causes a flu-like disease that is characterized by incapacitating arthralgia. The re-emergence of CHIKV and the continual risk of new epidemics have reignited research in CHIKV pathogenesis. Virus-specific antibodies have been shown to control virus clearance, but antibodies present at sub-neutralizing concentrations can also augment virus infection that exacerbates disease severity. To explore this occurrence, CHIKV infection was investigated in the presence of CHIKV-specific antibodies in both primary human cells and a murine macrophage cell line, RAW264.7. Enhanced attachment of CHIKV to the primary human monocytes and B cells was observed while increased viral replication was detected in RAW264.7 cells. Blocking of specific Fc receptors (FcγRs) led to the abrogation of these observations. Furthermore, experimental infection in adult mice showed that animals had higher viral RNA loads and endured more severe joint inflammation in the presence of sub-neutralizing concentrations of CHIKV-specific antibodies. In addition, CHIKV infection in 11 days old mice under enhancing condition resulted in higher muscles viral RNA load detected and death. These observations provide the first evidence of antibody-mediated enhancement in CHIKV infection and pathogenesis and could also be relevant for other important arboviruses such as Zika virus

Neurodevelopmental toxicity of prenatal polychlorinated biphenyls (PCBs) by chemical structure and activity: a birth cohort study

Abstract Background Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxins. Although there is growing evidence to support an association between PCBs and deficits of neurodevelopment, the specific mechanisms are not well understood. The potentially different roles of specific PCB groups defined by chemical structures or hormonal activities e.g., dioxin-like, non-dioxin like, or anti-estrogenic PCBs, remain unclear. Our objective was to examine the association between prenatal exposure to defined subsets of PCBs and neurodevelopment in a cohort of infants in eastern Slovakia enrolled at birth in 2002-2004. Methods Maternal and cord serum samples were collected at delivery, and analyzed for PCBs using high-resolution gas chromatography. The Bayley Scales of Infant Development -II (BSID) were administered at 16 months of age to over 750 children who also had prenatal PCB measurements. Results Based on final multivariate-adjusted linear regression model, maternal mono-ortho-substituted PCBs were significantly associated with lower scores on both the psychomotor (PDI) and mental development indices (MDI). Also a significant association between cord mono-ortho-substituted PCBs and reduced PDI was observed, but the association with MDI was marginal (p = 0.05). Anti-estrogenic and di-ortho-substituted PCBs did not show any statistically significant association with cognitive scores, but a suggestive association between di-ortho-substituted PCBs measured in cord serum and poorer PDI was observed. Conclusion Children with higher prenatal mono-ortho-substituted PCB exposures performed more poorly on the Bayley Scales. Evidence from this and other studies suggests that prenatal dioxin-like PCB exposure, including mono-ortho congeners, may interfere with brain development in utero. Non-dioxin-like di-ortho-substituted PCBs require further investigation

The importance of examining movements within the US health care system: sequential logit modeling

Background: Utilization of specialty care may not be a discrete, isolated behavior but rather, a behavior of sequential movements within the health care system. Although patients may often visit their primary care physician and receive a referral before utilizing specialty care, prior studies have underestimated the importance of accounting for these sequential movements. Methods: The sample included 6,772 adults aged 18 years and older who participated in the 2001 Survey on Disparities in Quality of Care, sponsored by the Commonwealth Fund. A sequential logit model was used to account for movement in all stages of utilization: use of any health services (i.e., first stage), having a perceived need for specialty care (i.e., second stage), and utilization of specialty care (i.e., third stage). In the sequential logit model, all stages are nested within the previous stage. Results: Gender, race/ethnicity, education and poor health had significant explanatory effects with regard to use of any health services and having a perceived need for specialty care, however racial/ethnic, gender, and educational disparities were not present in utilization of specialty care. After controlling for use of any health services and having a perceived need for specialty care, inability to pay for specialty care via income (AOR = 1.334, CI = 1.10 to 1.62) or health insurance (unstable insurance: AOR = 0.26, CI = 0.14 to 0.48; no insurance: AOR = 0.12, CI = 0.07 to 0.20) were significant barriers to utilization of specialty care. Conclusions: Use of a sequential logit model to examine utilization of specialty care resulted in a detailed representation of utilization behaviors and patient characteristics that impact these behaviors at all stages within the health care system. After controlling for sequential movements within the health care system, the biggest barrier to utilizing specialty care is the inability to pay, while racial, gender, and educational disparities diminish to non-significance. Findings from this study represent how Americans use the health care system and more precisely reveals the disparities and inequalities in the U.S. health care system

Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior

Antibody-dependent enhancement of plaque formation on cell lines of macrophage origin - a sensitive assay for antiviral antibody.

An assay for antiviral antibody based on antibody-dependent plaque enhancement (ADPE) in the macrophage cell line P388D1 is described which is as sensitive as, or more sensitive than a radioimmune assay. The method is applicable to a range of Togaviridae and Bunyaviridae although not to Picornaviridae and Herpesviridae. The variables affecting the assay are investigated.link_to_subscribed_fulltex