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

How Can We Realize Sustainable Development Goals in Rocky Desertified Regions by Enhancing Crop Yield with Reduction of Environmental Risks?

To meet the sustainable development goals in rocky desertified regions like Guizhou Province in China, we should maximize the crop yield with minimal environmental costs. In this study, we first calculated the yield gap for 6 main crop species in Guizhou Province and evaluated the quantitative relationships between crop yield and influencing variables utilizing ensembled artificial neural networks. We also tested the influence of adjusting the quantity of local fertilization and irrigation on crop production in Guizhou Province. Results showed that the total yield of the selected crops had, on average, reached over 72.5% of the theoretical maximum yield. Increasing irrigation tended to be more consistently effective at increasing crop yield than additional fertilization. Conversely, appropriate reduction of fertilization may even benefit crop yield in some regions, simultaneously resulting in significantly higher fertilization efficiency with lower residuals in the environment. The total positive impact of continuous intensification of irrigation and fertilization on most crop species was limited. Therefore, local stakeholders are advised to consider other agricultural management measures to improve crop yield in this region

Spatial and Temporal Variation, Simulation and Prediction of Land Use in Ecological Conservation Area of Western Beijing

Exploring land use change is crucial to planning land space scientifically in a region. Taking the ecological conservation area (ECA) in western Beijing as the study area, we employ ArcGIS 10.2, landscape pattern index and multiple mathematical statistics to explore the temporal and spatial variation of land use from 2000 to 2020. Patch-generating Land Use Simulation (PLUS), Future Land Use Simulation (FLUS) and Markov models were used to simulate and predict the current land use in 2020. The models were evaluated for accuracy, and the more accurate PLUS model was selected and used to simulate and predict the potential land use in the study area in 2030 under two management scenarios. The main findings of this research are: (1) From 2000 to 2020, the construction land increased constantly, and the area of cultivated land and grassland decreased significantly. (2) For predicting the spatial distribution of land use in the study area, the PLUS model was more accurate than the FLUS model. (3) The land-use prediction of the study area in 2030 shows that the area of grassland, forest and water is approximately equal to their corresponding value in 2020, but the construction land increased constantly by occupying the surrounding cultivated land. According to this research, the continuous decrease of cultivated land in favor of increasing construction land will cause losses to the ecological service function of the ECA, which is not beneficial to the sustainable development of the region. Relevant departments should take corresponding measures to reduce this practice and promote sustainable development, particularly in the southern and western areas of the ECA where there is less construction land

Periodic Relations between Terrestrial Vegetation and Climate Factors across the Globe

In this paper, cross-spectrum analysis was used to verify the agreement of periodicity between the global LAI (leaf area index) and climate factors. The results demonstrated that the LAI of deciduous forests and permanent wetlands have high agreement with temperature, rainfall and radiation over annual cycles. A low agreement between the LAI and seasonal climate variables was observed for some of the temperate and tropical vegetation types including shrublands and evergreen broadleaf forests, possibly due to the diversity of vegetation and human activities. Across all vegetation types, the LAI demonstrated a large time lag following variation in radiation (&gt;1 month), whereas relatively short lag periods were observed between the LAI and annual temperature (around 2 weeks)/rainfall patterns (less than 10 days), suggesting that the impact of radiation on global vegetation growth is relatively slow, which is in accord with the results of previous studies. This work can provide a benchmark of the phenological drivers in global vegetation, from the perspective of periodicity, as well as helping to parameterize and refine the DGVMs (Dynamic Global Vegetation Models) for different vegetation types

Planted forest is catching up with natural forest in China in terms of carbon density and carbon storage

Over the last several decades, China has taken multiple measures for afforestation and natural forest protection, including setting the goal of carbon neutrality by the middle of 21th century. In order to support the practice of relevant policies from the scientific perspective, it is essential to precisely estimate the carbon storage of arbor forest, as it plays an important role in the carbon cycle of ecosystems. In this study, we first used the latest four phases of national forest inventory data to investigate the variation of carbon storage for both natural and planted arbor forest in China during the covered period (1999-2018). Then we used machine leaning methods to simulate the carbon density based on various kinds of environmental factors and analyzed the contribution of each influencing factor. Our results demonstrate that the total carbon storage for arbor forest in China kept increasing over the last two decades, but this increment was mainly brought about by the continuous expansion of forest land. The gap of carbon sequestration between natural forest and planted forest showed a significant trend of reduction. Additionally, tree age was identified as the dominant factor for influencing the spatiotemporal variation of carbon density among all the independent variables while the impact of climatic factor was limited. Therefore, the future improvement of carbon sequestration of arbor forest in should mainly rely on additional projects of afforestation, reforestation, green space conservation and reduction of emissions in China. Conclusions of this study have important implications for policy makers and other stakeholders to evaluate the previous achievement of environmental projects and can also help to set future plans and finally realize the goals of carbon neutrality

Tree-ring δ18O identifies similarity in timing but differences in depth of soil water uptake by trees in mesic and arid climates

Water availability and uptake by trees will be important to predict tree growth, especially in regions with increasingly drying climate. Tree-ring δ18O (δ18OTR) can be influenced by moisture, so it may be a useful tool for tracking soil moisture content (SMC) variation with respect to the depth from which water is taken up and the timing of water uptake. Here we analyzed the relationship between δ18OTR of conifers and monthly SMC at different depths (0–10 and 0–100 cm) at three dry and three humid sites in China. We found that SMC outperformed local precipitation amount in terms of strength of correlations with δ18OTR in most months during the growing season. At the dry sites, δ18OTR was significantly correlated with topsoil SMC (0–10 cm) but more weakly related to SMC at 0–100 cm during the main growing season (June-July-August), implying that the trees were primarily utilizing shallow water. Whereas humid sites had similar correlations at both depths, suggesting that these trees utilized water over depth. At both sites, the highest correlation between δ18OTR and SMC occurred in months with the strongest monsoonal precipitation (June for the humid sites and July/August for the dry sites), which may indicate rapid cycling of precipitation into surface soils and then into tree roots. These findings are supported by the root distribution at the dry and humid sites, but are contrary to Walter's tree-grass two-layer model that stressed the uptake of deep soil water by trees in dry regions. In summary, our study suggests similar soil water-use seasonality but different water uptake depths of trees under dry and humid climates. This implies that δ18OTR could be a reliable proxy for SMC variation, which may provide important evidence for understanding tree water-use adaptation to changing climate.National Natural Science Foundation of China24 month embargo; available online 2 August 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Geomorphically mediated carbon dynamics of floodplain soils and Implications for net effect of carbon erosion

The fate of organic carbon deposited in floodplain sediments is an important control on the magnitude and direction of the carbon flux from anthropogenically accelerated erosion and channelization of the riverine network. Globally, rates of deposition and the mean residence time (MRT) of carbon within different geomorphic settings remains poorly constrained. We sampled the soil profile to 0.8 m depth from two geomorphic zones: active channel belt (ACB) and lowland floodplain, under long-term pasture adjacent to the river Culm in SW England, UK. We evaluated sedimentation rates and carbon storage using fallout radionuclide 137Cs, particle size and total carbon analyses. Variation in decomposition was assessed via empirical and numerical techniques, using soil aggregate size and density fractionation combined with natural abundance C analysis. Carbon decomposition was simulated using the RothC model and catchment implications were explored using a floodplain evolution model. Sedimentation and carbon accumulation rates were 5-6 times greater in the ACB than the floodplain. Carbon decomposition rates also varied with geomorphic setting. Soil carbon in floodplain cores had more rapid decomposition rates indicated by greater 13C-enrichment and subsoils dominated by mineral-associated soil organic carbon. The carbon in ACB cores was less processed and 13C-depleted by comparison, with more light fraction and macroaggregate-carbon throughout the cores. Decomposition rates in the ACB were estimated to be 4-fold less than the floodplain, as indicated by the RothC model. Including the ACB in floodplain carbon MRT calculations in the floodplain evolution model increased overall MRT by 10%. The major differences in the balance of sedimentation and decomposition rates between active and inactive floodplains suggest that the relative extent of these contrasting floodplain zones is critical to the overall carbon balance of floodplains. Restoration projects could enhance soil carbon storage by maximising active floodplain areas by increasing river channel complexit

Borrowing information across patient subgroups in clinical trials, with application to a paediatric trial.

BACKGROUND Clinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis. METHODS We used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with relative weights allocated to subgroups in the Bayesian analysis. The impact on the planned analysis was then determined. RESULTS The methods were applied to an ongoing non-inferiority trial designed to compare antiretroviral therapy regimens in 707 children living with HIV and weighing ≥ 14 kg, with an additional group of 85 younger children weighing < 14 kg in whom the treatment effect will be estimated separately. Expert clinical opinion was elicited and demonstrated that substantial borrowing is supported. Clinical experts chose on average to allocate a relative weight of 78% (reduced from 90% based on sample size) to data from children weighing ≥ 14 kg in a Bayesian analysis of the children weighing < 14 kg. The total effective sample size in the Bayesian analysis was 386 children, providing 84% predictive power to exclude a difference of more than 10% between arms, whereas the 85 younger children weighing < 14 kg provided only 20% power in a standalone frequentist analysis. CONCLUSIONS Borrowing information from a larger subgroup or subgroups can facilitate estimation of treatment effects in small subgroups within a clinical trial, leading to improved power and precision. Informative prior distributions for interaction parameters are required to inform the degree of borrowing and can be informed by expert opinion. We demonstrated accessible methods for obtaining opinions