Development and utilization of a decision support tool for the optimization of fertilizer application in smallholder farms in Uganda

This paper presents the development and pilot of the Fertilizer Optimization Tool (FOT), a decision support tool for use by extension agents in  advising smallholder farmers in Uganda in applying optimum (rather than maximum) fertilizer by considering the farmers’ financial abilities. The FOT is made up of three components which includes, the optimizer tool, the nutrient substitution table, and a fertilizer calibration tool. The FOT was developed using field trial data collected on specific agro-ecological zones and mapped using global positioning systems in 13 Sub-Saharan Africa countries. The FOT provides site- and farmer-specific fertilizer recommendations, providing both economic and environmental benefits. Results are based on a survey of 241 households, 57 technical personnel and tracking of 33 FOT users over a 3-season period. Results show a progressive shift in farmers’ attitude towards the value of fertilizer. More FOT users (71%) disagreed with the statement that fertilizers destroy soils, compared with  non-FOT users (52%). Crop yields (tons/ha) were significantly higher for crops receiving fertilizers compared to those not. While it is generally accepted that using fertilizer improves crop response and achieves better yields, the value of FOT was reported in terms of rationalization of investment by farmers. The average seasonal investment was approx. $43, giving a return on investment of over 107%. Given the evidence  generated from Uganda, there is a need for considering out scaling the FOT technology to other countries in Africa, which are faced with the same challenges of low fertilizer use among smallholder farmers. Using the mobile FOT app provides a further cost-effective opportunity to out scale the approach to benefit more smallholder farmers in sub-Saharan Africa. Further development of the FOT is suggested, particularly in the wake of increased focus on multi-nutrient fertilizer blends, and the need to adjust for soil PH, moisture, and long-term impacts of nutrient substitution. Key words: decision support tool, fertilizer optimization tool, precision agriculture, site-specific fertilizer recommendation

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Isolate specificity and polygenic inheritance of resistance in barley to the heterologous rust pathogen Puccinia graminis f. sp. avenae

Barley is a near-nonhost to numerous heterologous (nonadapted) rust pathogens because a small proportion of genotypes are somewhat susceptible. We assessed 66 barley accessions and three mapping populations (Vada x SusPtrit, Cebada Capa x SusPtrit, and SusPtrit x Golden Promise) for response to three Swedish oat stem rust (Puccinia graminis f. sp. avenae) fungal isolates and determined that barley is a near-nonhost to P. graminis f. sp. avenae and that resistance was polygenically inherited. The parental genotypes Vada and Golden Promise were immune to all three isolates, whereas Cebada Capa was immune to two isolates and moderately resistant to the third. Phenotypic data from the Vada x SusPtrit mapping population and the barley accessions tested also demonstrated isolate-specific resistance. In particular, the SusPtrit parent and several other accessions allowed sporulation by isolate Ingeberga but were resistant to isolate Evertsholm. Nine chromosomal regions carried quantitative trait loci (QTL) (Rpgaq1 to Rpgaq9) of varying effect, most of which colocated to previously identified QTL for resistance to other heterologous rust pathogens. Rpgaq1 on chromosome 1H (Vada and Golden Promise) was effective toward all isolates tested. Microscopic examination indicated that resistance was prehaustorial in Vada whereas, in SusPtrit, both pre- and posthaustorial mechanisms play a role.</p