Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure.

Vδ2+ γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2+ T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2+ counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vδ2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vδ2+ T cell pro-inflammatory cytokine production. Higher Vδ2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vδ2+ T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria

Assessment of farmers knowledge and preferences for planting materials to fill-gaps in banana plantations in southwestern Uganda

Banana (Musa spp.) plantations in central Uganda used to be productive for 30-100 years. Due to prevalence of the banana weevil (Cosmopolites sordidus L.), life spans have fallen to only <5 years. This forces farmers to establish new plantations or replant existing ones, usually using infested materials. To determine farmers’ knowledge and sources of planting materials and the cleaning techniques used, a household survey was conducted in southwestern Uganda. Up to 99% of the farmers reported C. sordidus as their major pest, and at least 50% reported gap-filling mainly due to land and banana weevil pressure. Most farmers (>80%) obtained planting materials from home/neighbours’ gardens. Corm paring (recommended for cleaning) was minimal, with 87% of farmers just trimming a few roots from the suckers. Most (90%) farmers preferred maiden suckers for gap-filling, believing that they establish and mature faster, and withstand weevil damage compared with other planting materials. Based on farmers’ experience and the results of an on-station study at the National Agricultural Research Laboratories (NARL), Kawanda, we recommend the use of maiden suckers when replanting in already infested plantations or those at risk

The use of common bean (Phaseolus vulgaris ) traditional varieties and their mixtures with commercial varieties to manage bean fly (Ophiomyia spp .) infestations in Uganda

The bean fly (Ophiomyia spp.) is considered the most economically damaging field insect pest of common beans in Uganda. Despite the use of existing pest management approaches, reported damage has remained high. Forty-eight traditional and improved common bean varieties currently grown in farmers’ fields were evaluated for resistance against bean fly. Data on bean fly incidence, severity and root damage from bean stem maggot were collected. Generalized linear mixed model (GLMM) revealed significant resistance to bean fly in the Ugandan traditional varieties. A popular resistant traditional variety and a popular susceptible commercial variety were selected from the 48 varieties and evaluated in pure and mixed stands. The incidence of bean fly infestation on both varieties in mixtures with different arrangements (systematic random versus rows), and different proportions within each of the two arrangements, was measured and analysed using GLMMs. The proportion of resistant varieties in a mixture and the arrangement type significantly decreased bean fly damage compared to pure stands, with the highest decrease in damage registered in the systematic random mixture with at least 50 % of resistant variety. The highest reduction in root damage, obvious 21 days after planting, was found in systematic random mixtures with at least 50 % of the resistant variety. Small holder farmers in East Africa and elsewhere in the world have local preferences for growing bean varieties in genetic mixtures. These mixtures can be enhanced by the use of resistant varieties in the mixtures to reduce bean fly damage on susceptible popular varieties

Behind the scenes of the PRIME intervention: designing a complex intervention to improve malaria care at public health centres in Uganda.

In Uganda, health system challenges limit access to good quality healthcare and contribute to slow progress on malaria control. We developed a complex intervention (PRIME), which was designed to improve quality of care for malaria at public health centres. Responding to calls for increased transparency, we describe the PRIME intervention's design process, rationale, and final content and reflect on the choices and challenges encountered during the design of this complex intervention. To develop the intervention, we followed a multistep approach, including the following: 1) formative research to identify intervention target areas and objectives; 2) prioritization of intervention components; 3) review of relevant evidence; 4) development of intervention components; 5) piloting and refinement of workshop modules; and 6) consolidation of the PRIME intervention theories of change to articulate why and how the intervention was hypothesized to produce desired outcomes. We aimed to develop an intervention that was evidence-based, grounded in theory, and appropriate for the study context; could be evaluated within a randomized controlled trial; and had the potential to be scaled up sustainably. The process of developing the PRIME intervention package was lengthy and dynamic. The final intervention package consisted of four components: 1) training in fever case management and use of rapid diagnostic tests for malaria (mRDTs); 2) workshops in health centre management; 3) workshops in patient-centred services; and 4) provision of mRDTs and antimalarials when stocks ran low. The slow and iterative process of intervention design contrasted with the continually shifting study context. We highlight the considerations and choices made at each design stage, discussing elements we included and why, as well as those that were ultimately excluded. Reflection on and reporting of 'behind the scenes' accounts of intervention design may improve the design, assessment, and generalizability of complex interventions and their evaluations

Productivity of mixtures and evolutionary populations of wheat, barley, beans and rice

Mixtures of different varieties of barley (Hordeum vulgare), wheat (Triticum ssp.) are grown by farmers in Ethiopia, Iran, Jordan, as a means of diversifying production and/or coping with difficult or uncertain growing conditions. Similarly, mixtures of different varieties of beans (Phaseolus vulgaris) were grown by farmers in Bhutan, Nepal and Uganda, with mixtures of Rice (Oryza sativa) were also grown by Bhutan and Nepal farmers. The mixture of all crops in all countries were grown for three consecutive years under IFAD – EPB project. Varietal diversity can improve farmers’ productivity, capabilities to manage pests and diseases and allows farmers to select suitable cultivars in response to varied or uncertain climatic conditions. Moreover, varietal diversification can improve the nutritional security of smallholder farmers

Virological outcomes and genotypic resistance on dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

Background ODYSSEY showed superior efficacy for dolutegravir-based antiretroviral therapy (ART) versus standard of care (SOC) in children living with HIV starting first-line or second-line ART aged 4 weeks or older. Here, we aim to compare virological outcomes and resistance in the dolutegravir group versus SOC for first-line and second-line ART up to 96 weeks. Methods ODYSSEY was an open-label, multicentre, randomised, non-inferiority trial done in 29 centres in seven countries (Germany, Spain, South Africa, Thailand, the UK, Uganda, and Zimbabwe). ODYSSEY recruited children living with HIV aged at least 28 days and younger than 18 years, weighing at least 3 kg, starting first-line ART (ODYSSEY A), or switching to second-line therapy after treatment failure (ODYSSEY B). Children were randomly assigned (1:1) to dolutegravir plus two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs; dolutegravir group) versus the SOC group (non-nucleoside reverse transcriptase inhibitor [NNRTI], boosted protease inhibitor, or non-dolutegravir integrase strand-transfer inhibitor, plus two NRTIs). Two randomised cohorts were combined in this exploratory analysis: children weighing at least 14 kg were enrolled between Sept 20, 2016, and June 22, 2018, and children weighing less than 14 kg were enrolled between July 5, 2018, and Aug 26, 2019. Virological failure was defined as an inadequate virological response at week 24 with an ART switch or confirmed HIV-1 RNA viral load of at least 400 copies per mL after week 36. Virological suppression was defined as two consecutive viral loads of less than 400 copies per mL and was compared between groups, including an ART switch and death as competing risks. Children with virological failure were tested for post-failure genotypic resistance, with baseline results used to identify emergent resistance. Development of emergent resistance was a secondary trial outcome and all other outcomes are exploratory. ODYSSEY was registered with ClinicalTrials.gov (NCT02259127), EUDRACT (2014–002632–14), and ISRCTN (ISRCTN91737921). Findings In ODYSSEY at enrolment, 381 participants started first-line ART (ODYSSEY A: 189 in the dolutegravir group and 192 in the SOC group) and 407 participants started second-line ART (ODYSSEY B: 202 in the dolutegravir group and 205 in the SOC group). 72 participants in ODYSSEY A and 13 participants in ODYSSEY B weighed less than 14 kg. 401 (51%) of 788 participants were female and 387 (49%) were male. Virological suppression occurred significantly earlier in the dolutegravir group (adjusted [cause-specific] hazard ratio [HR] 1·57 [95% CI 1·35 to 1·83]; p<0·0001). Overall, 51 (13%) participants had virological failure by 96 weeks in the dolutegravir group versus 86 (22%) in the SOC group (including 18 [10%] vs 43 [22%] in ODYSSEY A and in 33 [16%] vs 43 [21%] in ODYSSEY B; adjusted HR 0·56 [0·40 to 0·79]; p=0·0011). Among ODYSSEY B participants starting dolutegravir, virological failure was higher in children starting zidovudine (HR 2·22 [1·01 to 4·88]; p=0·048) and similar in those starting tenofovir disoproxil fumarate (1·19 [0·50 to 2·83]; p=0·70) compared with abacavir. Time to virological suppression was marginally faster in participants receiving second-line dolutegravir and abacavir with high-level abacavir resistance at baseline compared with those with no, low-level, intermediate-level resistance (cause-specific HR 1·70 [1·01 to 2·85]; p=0·046); and failure rates by week 96 were similar (HR 0·90 [0·23 to 3·61]; p=0·88). An estimated 1% (95% CI 0 to 2) of participants in the dolutegravir group versus 20% (14 to 26) in the SOC group in ODYSSEY A had emergent resistance to at least one drug-class within their first-line regimen (risk difference –20% [–25 to –14]; p<0·0001); 4% (1 to 6) versus 5% (2 to 8) had resistance to drug within their initial second-line regimen (risk difference –1% [–5 to 3]; p=0·60). 3% (0 to 5) of participants in the dolutegravir group had emergent integrase strand-transfer inhibitors resistance compared with 3% (1 to 6) of participants in the SOC group who had emergent resistance to the anchor drug (risk difference 0% [–4 to 3]; p=0·78). Interpretation Dolutegravir led to faster virological suppression and lower risk of virological failure than NNRTIs and boosted protease inhibitor-based SOC. Participants starting second-line dolutegravir-based ART with an abacavir or tenofovir backbone were at lower risk of virological failure than those starting zidovudine. During first-line therapy, dolutegravir protected against emergent resistance; starting second-line therapy, the risk of emergent resistance to nucleoside reverse transcriptase inhibitor backbone, and anchor drugs, was similar among participants starting dolutegravir within their second-line regimen and those starting mainly boosted protease inhibitor-based SOC. Funding Penta Foundation, ViiV Healthcare, and UK Medical Research Council

Urban and rural prevalence of diabetes and pre- diabetes and risk factors associated with diabetes in Tanzania and Uganda

CITATION: Chiwanga, F. S., et al. 2016. Urban and rural prevalence of diabetes and pre- diabetes and risk factors associated with diabetes in Tanzania and Uganda. Global Health Action, 9(1):31440, doi:10.3402/gha.v9.31440.The original publication is available at http://www.tandfonline.comENGLISH SUMMARY : Background: The increase in prevalence of diabetes and pre-diabetes in sub-Saharan Africa underlines the importance of understanding its magnitude and causes in different population groups. We analyzed data from the Africa/Harvard Partnership for Cohort Research and Training (PaCT) studies to determine the prevalence of diabetes and pre-diabetes and risk factors associated with diabetes. Methodology: Participants were randomly selected from peri-urban (n 297) and rural (n 200) communities in Uganda, and teachers were recruited from schools (n 229) in urban Tanzania. We used a standardized questionnaire to collect socio-demographic and self-reported disease status including diabetes status. Blood glucose was also measured after participants fasted for 8 h. We used standard protocols for anthropometric and blood pressure measurement. Results: The overall prevalence of diabetes was 10.1% and was highest in rural Ugandan residents (16.1%) compared to teachers in Tanzania (8.3%) and peri-urban Ugandan residents (7.6%). The prevalence of pre-diabetes was 13.8%. The prevalence of self-reported diabetes was low across all sites, where 68% of participants with diabetes were not captured by self-report. In ultivariable logistic regression analysis, family history (OR 2.5, 95% CI: 1.1, 5.6) and hypertension (OR 2.3, 95% CI: 1.1, 5.2) were significantly associated with diabetes. Conclusions: The prevalence of diabetes and pre-diabetes in Uganda and Tanzania is high, differs markedly between population groups, and remains undiagnosed in an alarmingly high proportion of individuals. These findings highlight the need for large-scale, prospective studies to accurately quantify the burden and identify effective intervention and treatment strategies across diverse African populations.http://www.tandfonline.com/doi/full/10.3402/gha.v9.31440Publisher's versio

Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial

BACKGROUND: Cross-resistance after first-line antiretroviral treatment (ART) failure is expected to impair activity of nucleoside-reverse-transcriptase-inhibitors (NRTIs) in second-line therapy, but evidence for effect on virological outcomes is limited. METHODS: We performed an observational analysis of a randomised-controlled trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 HIV-infected adults/adolescents failing first-line ART (WHO criteria, virological confirmation) were randomised to a boosted protease-inhibitor (PI; standardised to lopinavir/ritonavir) with either 2/3 NRTIs (clinician-selected, without resistance testing; PI/NRTI); raltegravir (PI/RAL); or as monotherapy (PI-mono; discontinued after week 96). Predicted activity of prescribed second-line NRTIs was determined by genotypic resistance testing on stored baseline samples in PI/NRTI. Viral load was measured on stored samples in all patients obtained every 12-16 weeks. FINDINGS: Baseline genotypes were available in 391 (92%) in PI/NRTI. For the 230 (59%) taking no predicted-active NRTIs, there was a high rate of VL suppression (89%(176/198) <400 copies per mL at week-144), superior to PI/RAL (81%(312/383) at week 144; P=0.02) and PI-mono (61%(233/280) at week-96; P<0.0001). VL suppression was no better with 1 predicted-active NRTI (85%(95/112), P=0.3 vs no active NRTIs) and appeared worse with 2-3 predicted active NRTIs (77%(20/26), P=0.08 vs no active NRTIs). Over all follow-up, greater predicted NRTI activity was associated with worse VL suppression (global p=0.0004). INTERPRETATION: Genotypic resistance testing may not accurately predict NRTI activity in PI-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs

HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa.

OBJECTIVE: To determine drug resistance mutation (DRM) patterns in a large cohort of patients failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy regimens in programs without routine viral load (VL) monitoring and to examine intersubtype differences in DRMs. DESIGN: Sequences from 787 adults/adolescents who failed an NNRTI-based first-line regimen in 13 clinics in Uganda, Kenya, Zimbabwe, and Malawi were analyzed. Multivariable logistic regression was used to determine the association between specific DRMs and Stanford intermediate-/high-level resistance and factors including REGA subtype, first-line antiretroviral therapy drugs, CD4, and VL at failure. RESULTS: The median first-line treatment duration was 4 years (interquartile range 30-43 months); 42% of participants had VL ≥100,000 copies/mL and 63% participants had CD4 <100 cells/mm. Viral subtype distribution was A1 (40%; Uganda and Kenya), C (31%; Zimbabwe and Malawi), and D (25%; Uganda and Kenya), and recombinant/unclassified (5%). In general, DRMs were more common in subtype-C than in subtype-A and/or subtype-D (nucleoside reverse transcriptase inhibitor mutations K65R and Q151M; NNRTI mutations E138A, V106M, Y181C, K101E, and H221Y). The presence of tenofovir resistance was similar between subtypes [P (adjusted) = 0.32], but resistance to zidovudine, abacavir, etravirine, or rilpivirine was more common in subtype-C than in subtype-D/subtype-A [P (adjusted) < 0.02]. CONCLUSIONS: Non-B subtypes differ in DRMs at first-line failure, which impacts on residual nucleoside reverse transcriptase inhibitor and NNRTI susceptibility. In particular, higher rates of etravirine and rilpivirine resistance in subtype-C may limit their potential utility in salvage regimens