The effect of current Schistosoma mansoni infection on the immunogenicity of a candidate TB vaccine, MVA85A, in BCG-vaccinated adolescents: An open-label trial.

INTRODUCTION: Helminth infection may affect vaccine immunogenicity and efficacy. Adolescents, a target population for tuberculosis booster vaccines, often have a high helminth burden. We investigated effects of Schistosoma mansoni (Sm) on the immunogenicity and safety of MVA85A, a model candidate tuberculosis vaccine, in BCG-vaccinated Ugandan adolescents. METHODS: In this phase II open label trial we enrolled 36 healthy, previously BCG-vaccinated adolescents, 18 with no helminth infection detected, 18 with Sm only. The primary outcome was immunogenicity measured by Ag85A-specific interferon gamma ELISpot assay. Tuberculosis and schistosome-specific responses were also assessed by whole-blood stimulation and multiplex cytokine assay, and by antibody ELISAs. RESULTS: Ag85A-specific cellular responses increased significantly following immunisation but with no differences between the two groups. Sm infection was associated with higher pre-immunisation Ag85A-specific IgG4 but with no change in antibody levels following immunisation. There were no serious adverse events. Most reactogenicity events were of mild or moderate severity and resolved quickly. CONCLUSIONS: The significant Ag85A-specific T cell responses and lack of difference between Sm-infected and uninfected participants is encouraging for tuberculosis vaccine development. The implications of pre-existing Ag85A-specific IgG4 antibodies for protective immunity against tuberculosis among those infected with Sm are not known. MVA85A was safe in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02178748

BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial.

BACKGROUND: Trials done in infants with low birthweight in west Africa suggest that BCG vaccination reduces all-cause mortality in the neonatal period, probably because of heterologous protection against non-tuberculous infections. This study investigated whether BCG alters all-cause infectious disease morbidity in healthy infants in a different high-mortality setting, and explored whether the changes are mediated via trained innate immunity. METHODS: This was an investigator-blind, randomised, controlled trial done at one hospital in Entebbe, Uganda. Infants who were born unwell (ie, those who were not well enough to be discharged directly home from the labour ward because they required medical intervention), with major congenital malformations, to mothers with HIV, into families with known or suspected tuberculosis, or for whom cord blood samples could not be taken, were excluded from the study. Any other infant well enough to be discharged directly from the labour ward was eligible for inclusion, with no limitation on gestational age or birthweight. Participants were recruited at birth and randomly assigned (1:1) to receive standard dose BCG 1331 (BCG-Danish) on the day of birth or at age 6 weeks (computer-generated randomisation, block sizes of 24, stratified by sex). Investigators and clinicians were masked to group assignment; parents were not masked. Participants were clinically followed up to age 10 weeks and contributed blood samples to one of three immunological substudies. The primary clinical outcome was physician-diagnosed non-tuberculous infectious disease incidence. Primary immunological outcomes were histone trimethylation at the promoter region of TNF, IL6, and IL1B; ex-vivo production of TNF, IL-6, IL-1β, IL-10, and IFNγ after heterologous stimulation; and transferrin saturation and hepcidin levels. All outcomes were analysed in the modified intention-to-treat population of all randomly assigned participants except those whose for whom consent was withdrawn. This trial is registered with the International Standard Randomised Controlled Trial Number registry (#59683017). FINDINGS: Between Sept 25, 2014, and July 31, 2015, 560 participants were enrolled and randomly assigned to receive BCG at birth (n=280) or age 6 weeks (n=280). 12 participants assigned to receive BCG at birth and 11 participants assigned to receive BCG at age 6 weeks were withdrawn from the study by their parents shortly after randomisation and were not included in analyses. During the first 6 weeks of life before the infants in the delayed vaccination group received BCG vaccination, physician-diagnosed non-tuberculous infectious disease incidence was lower in infants in the BCG at birth group than in the delayed group (98 presentations in the BCG at birth group vs 129 in the delayed BCG group; hazard ratio [HR] 0·71 [95% CI 0·53-0·95], p=0·023). After BCG in the delayed group (ie, during the age 6-10 weeks follow-up), there was no significant difference in non-tuberculous infectious disease incidence between the groups (88 presentations vs 76 presentations; HR 1·10 [0·87-1·40], p=0·62). BCG at birth inhibited the increase in histone trimethylation at the TNF promoter in peripheral blood mononuclear cells occurring in the first 6 weeks of life. H3K4me3 geometric mean fold-increases were 3·1 times lower at the TNF promoter (p=0·018), 2·5 times lower at the IL6 promoter (p=0·20), and 3·1 times lower at the IL1B promoter (p=0·082) and H3K9me3 geometric mean fold-increases were 8·9 times lower at the TNF promoter (p=0·0046), 1·2 times lower at the IL6 promoter (p=0·75), and 4·6 times lower at the IL1B promoter (p=0·068), in BCG-vaccinated (BCG at birth group) versus BCG-naive (delayed BCG group) infants. No clear effect of BCG on ex-vivo production of TNF, IL-6, IL-1β, IL-10, and IFNγ after heterologous stimulation, or transferrin saturation and hepcidin concentration, was detected (geometric mean ratios between 0·68 and 1·68; p≥0·038 for all comparisons). INTERPRETATION: BCG vaccination protects against non-tuberculous infectious disease during the neonatal period, in addition to having tuberculosis-specific effects. Prioritisation of BCG on the first day of life in high-mortality settings might have significant public-health benefits through reductions in all-cause infectious morbidity and mortality. FUNDING: Wellcome Trust. TRANSLATIONS: For the Luganda and Swahili translations of the abstract see Supplementary Materials section

A genome-wide association and replication study of blood pressure in Ugandan early adolescents.

BACKGROUND: Genetic association studies of blood pressure (BP) have mostly been conducted in non-African populations. Using the Entebbe Mother and Baby Study (EMaBS), we aimed to identify genetic variants associated with BP among Ugandan adolescents. METHODS: Systolic and diastolic BP were measured among 10- and 11-year olds. Whole-genome genotype data were generated using Illumina omni 2.5M arrays and untyped variants were imputed. Genome-wide association study (GWAS) was conducted using linear mixed model regression to account for population structure. Linear regression analysis was used to assess whether variants previously associated with BP (p < 5.0 × 10-8 ) in published BP GWASs were replicated in our study. RESULTS: Of the 14 million variants analyzed among 815 adolescents, none reached genome-wide significance (p < 5.0×10-8 ) for association with systolic or diastolic BP. The most strongly associated variants were rs181430167 (p = 6.8 × 10-7 ) for systolic BP and rs12991132 (p = 4.0 × 10-7 ) for diastolic BP. Thirty-three (17 single nucleotide polymorphisms (SNPs) for systolic BP, 15 SNPs for diastolic BP and one SNP for both) of 330 variants previously identified as associated with BP were replicated in this study, but none remained significant after accounting for multiple testing. CONCLUSION: Variants showing suggestive associations are worthy of future investigation. Replication results suggest that variants influencing adolescent BP may overlap somewhat with those already established in previous studies, largely based on adults in Western settings

Models of and approaches to the station management of six African community radio broadcasters

This article is a political economy critique that contributes to current scholarship on community radio and development by examining the question of the management of six networks from Mali, Mozambique and Uganda. This discussion argues that understanding the models and functions of management committees will go a long way towards contributing to conversations on how community radios could achieve social, institutional, financial and ideological sustainability. The article also examines how management committees approach their work in the age of new Information Communication Technologies (especially mobile phones, computers and the Internet), and whether there is a gender digital divide within such committees. At the centre of the current discussion, therefore, is an attempt to understand the flow and contestation of power within community radio management committees

Comparative accuracy of sonography, mammography and the BI-RADS characterization of breast masses among adult women at Mulago Hospital, Uganda

# Background Breast cancer is common among Ugandan women and mortality rate is significantly high. Uganda, like many low-income countries, has no national regular mammography screening programme, a gold standard in breast cancer imaging. Breast ultrasound and Breast Imaging Reporting and Data System (BI-RADS) classification is thus being promoted as a supplemental evaluation tool for breast masses. However, studies on the comparative accuracy of breast sonography, mammography and BI-RADS from low-income settings are limited. This study aimed to determine the accuracy of breast ultrasound, mammography and BI-RADS classification against histology in the evaluation of breast masses among adult women. # Methods This was a cross-sectional study conducted at Mulago National Referral Hospital involving women with breast masses. The women underwent breast ultrasound, mammography and needle biopsy for histological analysis. The breast lesions were also evaluated against the BI-RADS characterization criteria. # Results Overall, 212 breast masses were evaluated and included in the analysis. Of these, 50% (106) were benign and 50% (106) were malignant. The sensitivity for ultrasound and mammography separately was 68.5% and 72.5% respectively. The sensitivity for ultrasound and mammography combined was 85%. BI-RADS 5 category had the highest sensitivity at 59.9% while the highest specificity was noted among BI-RADS 3 and 5 at 100%. The highest accuracy was noted in the BI-RADS 5 category at 79.9%. # Conclusions Findings from this study demonstrate that combining ultrasound and mammography could have a higher sensitivity and diagnostic accuracy than when these imaging modalities are used independently. In addition, the BI-RADS reporting classification has an optimum positive predictive value and should be promoted to standardize breast imaging reporting

Lessons from the first clinical trial of a non-licensed vaccine among Ugandan adolescents: a phase II field trial of the tuberculosis candidate vaccine, MVA85A

Background: A more effective vaccine for tuberculosis (TB) is a global public health priority. Vaccines under development will always need evaluation in endemic settings, most of which have limited resources. Adolescents are an important target population for a new TB vaccine and for other vaccines which are relevant at school-age. However, in most endemic settings there is limited experience of trials of investigational products among adolescents, and adolescents are not routinely vaccinated. Methods: We used Modified vaccinia Ankara-expressing Ag85A (MVA85A), a well-tolerated candidate vaccine for tuberculosis, to assess the effect of Schistosoma mansoni infection on vaccine immunogenicity among Ugandan adolescents in primary school. We describe here the challenges and lessons learned in designing and implementing this first clinical trial among Ugandan adolescents using a non-licensed vaccine. Results: The school based immunization study was feasible and adhered to Good Clinical Practice principles. Engagement with the community and all stakeholders was critical for successful implementation of the trial. Creative and adaptable strategies were used to address protocol-specific, operational and logistical challenges. This study provided lessons and solutions that can be applied to other trials among adolescents in similar settings elsewhere, and to school-based immunization programs. Conclusion: Sufficient time and resources should be planned for community preparation and sensitization to ensure buy in and acceptance of a project of this kind. This trial shows that challenges to implementing early field trials in Africa are not insurmountable and that necessary well-planned high-quality ethical trials are feasible and should be encouraged. Trial Registration: ClinicalTrials.gov NCT02178748 03/06/2014</p

Climate journalism in a changing media ecosystem: Assessing the production of climate change‐related news around the world

Climate journalism gathers, evaluates, selects, and presents information about climate change, its characteristics, causes, and impacts, as well as ways to mitigate it, and distributes them via technical media to general and specialist audiences. It is an important source of information about climate change for many people. Currently, however, the media ecosystem surrounding climate journalism is changing, with economic conditions becoming more strenuous, more communicators joining the debate, and social media changing the affordances of communication. This advanced review synthesizes scholarship on the status quo and the changes taking place in climate journalism in the Global North and the Global South. While it demonstrates that the scholarship has distinct gaps and biases, it does distill several robust findings. First, it shows that the organizational embedding of climate journalism is changing, with specialist reporters becoming scarce and working under more strenuous conditions and with the emergence of online-born news media and niche sites specializing in climate journalism. It also suggests that few specialist climate journalists exist in the Global South. Second, it demonstrates that the range of roles available to climate journalists has diversified, with a shift from “gatekeeping” to “curating” roles. Third, it indicates that climate journalists’ relationships with their sources have changed. Elite sources have been, and still are, important, but their composition has shifted from scientists to a broader range of stakeholders. Correspondingly, there seems to be a strong and rising influence of stakeholder PR on climate journalism