Combination prevention: new hope for stopping the epidemic.

HIV research has identified approaches that can be combined to be more effective in transmission reduction than any 1 modality alone: delayed adolescent sexual debut, mutual monogamy or sexual partner reduction, correct and consistent condom use, pre-exposure prophylaxis with oral antiretroviral drugs or vaginal microbicides, voluntary medical male circumcision, antiretroviral therapy (ART) for prevention (including prevention of mother to child HIV transmission [PMTCT]), treatment of sexually transmitted infections, use of clean needles for all injections, blood screening prior to donation, a future HIV prime/boost vaccine, and the female condom. The extent to which evidence-based modalities can be combined to prevent substantial HIV transmission is largely unknown, but combination approaches that are truly implementable in field conditions are likely to be far more effective than single interventions alone. Analogous to PMTCT, "treatment as prevention" for adult-to-adult transmission reduction includes expanded HIV testing, linkage to care, antiretroviral coverage, retention in care, adherence to therapy, and management of key co-morbidities such as depression and substance use. With successful viral suppression, persons with HIV are far less infectious to others, as we see in the fields of sexually transmitted infection control and mycobacterial disease control (tuberculosis and leprosy). Combination approaches are complex, may involve high program costs, and require substantial global commitments. We present a rationale for such investments and cite an ongoing research agenda that seeks to determine how feasible and cost-effective a combination prevention approach would be in a variety of epidemic contexts, notably that in a sub-Saharan Africa

Stable incidence rates of tuberculosis (TB) among human immunodeficiency virus (HIV)-negative South African gold miners during a decade of epidemic HIV-associated TB.

During the last decade, annual tuberculosis (TB) case-notification rates increased 4-fold, to >4000 cases/100000 person-years, in the study workforce, among whom prevalence of human immunodeficiency virus (HIV) was 30% in 2000. Three separate cohort studies, totalling 6454 HIV-negative participants, were combined and analyzed for time trends. Observed incidence of TB varied between 962 (1991-1994) and 1589 (1999-2000) cases/100000 person-years (P=.17, test for trend). There was, however, a progressive increase in age, and, for each period, older age was associated with increased incidence rates of TB (P<.001). Having adjusted for age differences, there was no significant association between incidence of TB and calendar period (P=.81, test for trend). Relative to 1991-1994, multivariate-adjusted incidence-rate ratios were 0.94, for 1995-1997, 0.96, for 1998-1999, and 1.05, for 1999-2000. Preventing a secondary epidemic of TB among HIV-negative individuals may be achievable with conventional means, even in settings with a high burden of HIV-associated TB

The inheritance of resistance to bacterial leaf spot of lettuce caused by Xanthomonas campestris pv. vitians in three lettuce cultivars.

Lettuce yields can be reduced by the disease bacterial leaf spot (BLS) caused by the pathogen Xanthomonas campestris pv. vitians (Xcv) and host resistance is the most feasible method to reduce disease losses. The cultivars La Brillante, Pavane and Little Gem express an incompatible host-pathogen interaction as a hypersensitive response (HR) to California strains of Xcv resulting in resistance. Little was known about the inheritance of resistance; however, resistance to other lettuce pathogens is often determined by resistance gene candidates (RGCs) encoding nucleotide-binding leucine-rich repeat (NB-LRR) proteins. Therefore, we determined the inheritance of BLS resistance in the cultivars La Brillante, Little Gem and Pavane and mapped it relative to RGCs. The reaction to Xcv was analyzed in nine F1, F2 and recombinant inbred line populations of lettuce from HR×compatible or HR×HR crosses. The HR in La Brillante, Pavane and Little Gem is conditioned by single dominant genes, which are either allelic or closely linked genes. The resistance gene in La Brillante was designated Xanthomonas resistance 1 (Xar1) and mapped to lettuce linkage group 2. Xar1 is present in a genomic region that contains numerous NB-LRR encoding RGCs and functional pathogen resistance loci in the RGC2 family. The Xar1 gene confers a high level of BLS resistance in the greenhouse and field that can be introgressed into commercial lettuce cultivars to reduce BLS losses using molecular markers

Probing the Evolution of the Galaxy Interaction/Merger Rate Using Collisional Ring Galaxies

We present the results from our program to determine the evolution of the galaxy interaction/merger rate with redshift using the unique star-forming characteristics of collisional ring galaxies. We have identified 25 distant collisional ring galaxy candidates (CRGCs) in a total of 162 deep Hubble Space Telescope Wide Field/Planetary Camera-2 images obtained from the HST Archives. Based on measured and estimated redshifts, these 25 CRGCs all lie in the redshift interval of 0.1 < z < 1. Using the local collisional ring galaxy volume density and the new ``standard'' cosmology, we find that in order to account for the number of identified CRGCs in our surveyed fields, the galaxy interaction/merger rate, parameterized as (1 + z)^m, must increase steeply with redshift.We determine a minimum value of m = 5.2 $\pm$ 0.7, though m could be as high as 7 or 8. We can rule out a non-evolving (m = 0) and weakly evolving (m = 1-2) galaxy interaction/merger rate at greater than the 4 sigma level of confidence.Comment: Accepted in the Astrophysical Journal (11 pages, 4 figures). Higher resolution version of the figures is available at http://www.astro.cornell.edu/~vassilis/papers

Re-analysis of health and educational impacts of a school-based deworming programme in western Kenya: a pure replication.

BACKGROUND: Helminth (worm) infections cause morbidity among poor communities worldwide. An influential study conducted in Kenya in 1998-99 reported that a school-based drug-and-educational intervention had benefits regarding worm infections and school attendance. Effects were seen among children treated with deworming drugs, untreated children in intervention schools and children in nearby non-intervention schools. Combining these effects, the intervention was reported to increase school attendance by 7.5% in treated children. Effects on other outcomes (worm infections, anaemia, nutritional status and examination performance) were also investigated. METHODS: In this pure replication, we used data provided by the original authors to re-analyse the study according to their methods. We compared these results against those presented in the original paper. RESULTS: Although most results were reproduced as originally reported, we identified discrepancies of several types between the original findings and re-analysis. For worm infections, re-analysis showed reductions similar to those originally reported. For anaemia prevalence, in contrast to the original findings, re-analysis found no evidence of benefit. For nutritional status, both original findings and re-analysis described modest evidence for a small improvement. For school attendance, re-analysis showed benefits similar to those originally found in intervention schools for both children who did and those who did not receive deworming drugs. However, after correction of coding errors, there was little evidence of an indirect effect on school attendance among children in schools close to intervention schools. Combining these effects gave a total increase in attendance of 3.9% among treated children, which was no longer statistically significant. As in the original results, re-analysis found no effect of the intervention on examination performance. CONCLUSIONS: Re-applying analytical approaches originally used, but correcting various errors, we found little evidence for some previously-reported indirect effects of a deworming intervention. Effects on worm infections, nutritional status, examination performance and school attendance on children in intervention schools were largely unchanged

Pregnancy and contraceptive use among women participating in an HIV prevention trial in Tanzania.

OBJECTIVES: Information on pregnancy rates and factors associated with pregnancy and contraceptive use is important for clinical trials in women in sub-Saharan Africa where withdrawal of investigational products may be required in the event of pregnancy with a consequent effect on sample size and trial power. METHODS: A prospective cohort analysis of pregnancy and contraceptive use was conducted in Tanzanian women enrolled in a randomised placebo-controlled trial of herpes simplex virus-suppressive therapy with acyclovir to measure the effect on HIV incidence in HIV-negative women and on genital and plasma HIV viral load in HIV-positive women. The cohort was followed every 3 months for 12-30 months. Women at each visit were categorised into users or non-users of contraception. Pregnancy rates and factors associated with pregnancy incidence and contraceptive use were measured. RESULTS: Overall 254 of 1305 enrolled women became pregnant at least once during follow-up (pregnancy rate: 12.0/100 person-years). Younger age, being unmarried, higher baseline parity and changes in contraceptive method during follow-up were independently associated with pregnancy. Having paid sex and being HIV positive were associated with lower risk of pregnancy. Uptake of contraception was associated with young age, being unmarried, occupation, parity and the number and type of sexual partners. CONCLUSIONS: Data on use of contraceptive methods and risk factors for pregnancy can help to guide decisions on trial eligibility and the need for additional counselling. Mandatory reliable contraceptive use in study participants may be required to reduce pregnancy rates in studies where pregnancy is contraindicated

Re-analysis of health and educational impacts of a school-based deworming programme in western Kenya: a statistical replication of a cluster quasi-randomized stepped-wedge trial.

INTRODUCTION: Helminth (worm) infections cause morbidity among poor communities worldwide. An influential study conducted in Kenya in 1998-99 reported that a school-based drug-and-educational intervention had benefits for worm infections and school attendance. METHODS: In this statistical replication, we re-analysed data from this cluster quasi-randomized stepped-wedge trial, specifying two co-primary outcomes: school attendance and examination performance. We estimated intention-to-treat effects using year-stratified cluster-summary analysis and observation-level random-effects regression, and combined both years with a random-effects model accounting for year. The participants were not blinded to allocation status, and other interventions were concurrently conducted in a sub-set of schools. A protocol guiding outcome data collection was not available. RESULTS: Quasi-randomization resulted in three similar groups of 25 schools. There was a substantial amount of missing data. In year-stratified cluster-summary analysis, there was no clear evidence for improvement in either school attendance or examination performance. In year-stratified regression models, there was some evidence of improvement in school attendance [adjusted odds ratios (aOR): year 1: 1.48, 95% confidence interval (CI) 0.88-2.52, P = 0.147; year 2: 1.23, 95% CI 1.01-1.51, P = 0.044], but not examination performance (adjusted differences: year 1: -0.135, 95% CI -0.323-0.054, P = 0.161; year 2: -0.017, 95% CI -0.201-0.166, P = 0.854). When both years were combined, there was strong evidence of an effect on attendance (aOR 1.82, 95% CI 1.74-1.91, P < 0.001), but not examination performance (adjusted difference -0.121, 95% CI -0.293-0.052, P = 0.169). CONCLUSIONS: The evidence supporting an improvement in school attendance differed by analysis method. This, and various other important limitations of the data, caution against over-interpretation of the results. We find that the study provides some evidence, but with high risk of bias, that a school-based drug-treatment and health-education intervention improved school attendance and no evidence of effect on examination performance

HIV Infection among Young People in Northwest Tanzania: The Role of Biological, Behavioural and Socio-Demographic Risk Factors.

BACKGROUND: Young people are at high risk of HIV and developing appropriate prevention programmes requires an understanding of the risk factors for HIV in this age group. We investigated factors associated with HIV among participants aged 15-30 years in a 2007-8 cross-sectional survey nested within a community-randomised trial of the MEMA kwa Vijana intervention in 20 rural communities in northwest Tanzania. METHODS: We analysed data for 7259(53%) males and 6476(47%) females. Using a proximate-determinant conceptual framework and conditional logistic regression, we obtained sex-specific Odds Ratios (ORs) for the association of HIV infection with socio-demographic, knowledge, behavioural and biological factors. RESULTS: HSV-2 infection was strongly associated with HIV infection (females: adjOR 4.4, 95%CI 3.2-6.1; males: adjOR 4.2, 95%CI 2.8-6.2). Several socio-demographic factors (such as age, marital status and mobility), behavioural factors (condom use, number and type of sexual partnerships) and biological factors (blood transfusion, lifetime pregnancies, genital ulcers, Neisseria gonorrhoeae) were also associated with HIV infection. Among females, lifetime sexual partners (linear trend, p<0.001), ≥2 partners in the past year (adjOR 2.0, 95%CI 1.4-2.8), ≥2 new partners in the past year (adjOR 1.9 95%CI 1.2, 3.3) and concurrent partners in the past year (adjOR 1.6 95%CI 1.1, 2.4) were all associated with HIV infection. CONCLUSIONS: Efforts must be intensified to find effective interventions to reduce HSV-2. Effective behavioural interventions focusing on reducing the number of sexual partnerships and risk behaviour within partnerships are also needed. An increase in risky sexual behaviour may occur following marriage dissolution or when a young woman travels outside of her community and interventions addressing the needs of these subgroups of vulnerable women may be important. TRIAL REGISTRATION: ClinicalTrial.gov NCT00248469

Women’s adaptation to STEM domains promotes resilience and a lesser reliance on heuristic thinking

Experiences that compel people to challenge social stereotypes can promote enhanced cognitive flexibility on a range of judgmental domains. Women in STEM (science, technology, engineering, and math) fields are chronically exposed to such experiences and may therefore also demonstrate these benefits. Two studies examined the differential effects of counterstereotypical experiences on women from STEM and non-STEM fields. Results showed that imagining or recollecting these experiences led women from STEM fields to exhibit a lesser reliance on heuristic thinking compared to women from non-STEM fields, and this difference was mediated by self-perceived resilience to the negative impact of gender stereotyping. Implications for psychologists’ and educators’ understanding of the relationship between counterstereotypical experiences and heuristic thinking are discussed

Microbicides development programme: engaging the community in the standard of care debate in a vaginal microbicide trial in Mwanza, Tanzania.

BACKGROUND: HIV prevention research in resource-limited countries is associated with a variety of ethical dilemmas. Key amongst these is the question of what constitutes an appropriate standard of health care (SoC) for participants in HIV prevention trials. This paper describes a community-focused approach to develop a locally-appropriate SoC in the context of a phase III vaginal microbicide trial in Mwanza City, northwest Tanzania. METHODS: A mobile community-based sexual and reproductive health service for women working as informal food vendors or in traditional and modern bars, restaurants, hotels and guesthouses has been established in 10 city wards. Wards were divided into geographical clusters and community representatives elected at cluster and ward level. A city-level Community Advisory Committee (CAC) with representatives from each ward has been established. Workshops and community meetings at ward and city-level have explored project-related concerns using tools adapted from participatory learning and action techniques e.g. chapati diagrams, pair-wise ranking. Secondary stakeholders representing local public-sector and non-governmental health and social care providers have formed a trial Stakeholders' Advisory Group (SAG), which includes two CAC representatives. RESULTS: Key recommendations from participatory community workshops, CAC and SAG meetings conducted in the first year of the trial relate to the quality and range of clinic services provided at study clinics as well as broader standard of care issues. Recommendations have included streamlining clinic services to reduce waiting times, expanding services to include the children and spouses of participants and providing care for common local conditions such as malaria. Participants, community representatives and stakeholders felt there was an ethical obligation to ensure effective access to antiretroviral drugs and to provide supportive community-based care for women identified as HIV positive during the trial. This obligation includes ensuring sustainable, post-trial access to these services. Post-trial access to an effective vaginal microbicide was also felt to be a moral imperative. CONCLUSION: Participatory methodologies enabled effective partnerships between researchers, participant representatives and community stakeholders to be developed and facilitated local dialogue and consensus on what constitutes a locally-appropriate standard of care in the context of a vaginal microbicide trial in this setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN64716212