Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial

BACKGROUND Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). METHODS SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. FINDINGS Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm$^{3}$ (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm$^{3}$ (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m$^{2}$ (95% CI: 0.3, 1.0; p < 0.001)]. INTERPRETATION In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. FUNDING Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir

A Model for the Ultrastructure of Bone Based on Electron Microscopy of Ion-Milled Sections

The relationship between the mineral component of bone and associated collagen has been a matter of continued dispute. We use transmission electron microscopy (TEM) of cryogenically ion milled sections of fully-mineralized cortical bone to study the spatial and topological relationship between mineral and collagen. We observe that hydroxyapatite (HA) occurs largely as elongated plate-like structures which are external to and oriented parallel to the collagen fibrils. Dark field images suggest that the structures (“mineral structures”) are polycrystalline. They are approximately 5 nm thick, 70 nm wide and several hundred nm long. Using energy-dispersive X-ray analysis we show that approximately 70% of the HA occurs as mineral structures external to the fibrils. The remainder is found constrained to the gap zones. Comparative studies of other species suggest that this structural motif is ubiquitous in all vertebrates

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

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

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