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BackgroundIMPAACT 2014 study is a phase I/II, multicenter, open-label, nonrandomized study of doravirine (DOR) co-formulated with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) as fixed-dose combination (DOR FDC) in adolescents with HIV-1. We report the efficacy, safety, and tolerability of DOR FDC through 96 weeks.MethodsParticipants were adolescents aged 12 to

Abstract Toxins of toxin-antitoxin systems use diverse mechanisms to inhibit bacterial growth. In this study, we characterize the translation inhibitor toxin MenT3 of Mycobacterium tuberculosis, the bacterium responsible for tuberculosis in humans. We show that MenT3 is a robust cytidine specific tRNA nucleotidyltransferase in vitro, capable of modifying the aminoacyl acceptor ends of most tRNA but with a marked preference for tRNASer, to which long stretches of cytidines are added. Furthermore, transcriptomic-wide analysis of MenT3 targets in M. tuberculosis identifies tRNASer as the sole target of MenT3 and reveals significant detoxification attempts by the essential CCA-adding enzyme PcnA in response to MenT3. Finally, under physiological conditions, only in the presence the native menAT3 operon, an active pool of endogenous MenT3 targeting tRNASer in M. tuberculosis is detected, likely reflecting the importance of MenT3 during infection.

Abstract We describe the geographical variation in tree species composition across Amazonian forests and show how environmental conditions are associated with species turnover. Our analyses are based on 2023 forest inventory plots (1 ha) that provide abundance data for a total of 5188 tree species. Within-plot species composition reflected both local environmental conditions (especially soil nutrients and hydrology) and geographical regions. A broader-scale view of species turnover was obtained by interpolating the relative tree species abundances over Amazonia into 47,441 0.1-degree grid cells. Two main dimensions of spatial change in tree species composition were identified. The first was a gradient between western Amazonia at the Andean forelands (with young geology and relatively nutrient-rich soils) and central–eastern Amazonia associated with the Guiana and Brazilian Shields (with more ancient geology and poor soils). The second gradient was between the wet forests of the northwest and the drier forests in southern Amazonia. Isolines linking cells of similar composition crossed major Amazonian rivers, suggesting that tree species distributions are not limited by rivers. Even though some areas of relatively sharp species turnover were identified, mostly the tree species composition changed gradually over large extents, which does not support delimiting clear discrete biogeographic regions within Amazonia.

Abstract Nucleotidyltransferases (NTases) control diverse physiological processes, including RNA modification, DNA replication and repair, and antibiotic resistance. The Mycobacterium tuberculosis NTase toxin family, MenT, modifies tRNAs to block translation. MenT toxin activity can be stringently regulated by diverse MenA antitoxins. There has been no unifying mechanism linking antitoxicity across MenT homologues. Here we demonstrate through structural, biochemical, biophysical and computational studies that despite lacking kinase motifs, antitoxin MenA1 induces auto-phosphorylation of MenT1 by repositioning the MenT1 phosphoacceptor T39 active site residue towards bound nucleotide. Finally, we expand this predictive model to explain how unrelated antitoxin MenA3 is similarly able to induce auto-phosphorylation of cognate toxin MenT3. Our study reveals a conserved mechanism for the control of tuberculosis toxins, and demonstrates how active site auto-phosphorylation can regulate the activity of widespread NTases.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Biofilm-related biomaterial infections are notoriously challenging to treat and can lead to chronic infection and persisting inflammation. To date, a large body of research can be reviewed for coatings which potentially prevent bacterial infection while promoting implant integration. Yet only a very small number has been translated from bench to bedside. This study provides an in-depth analysis of the stability, antibacterial mechanism, and biocompatibility of medical grade polycaprolactone (mPCL), coated with human serum albumin (HSA), the most abundant protein in blood plasma, and tannic acid (TA), a natural polyphenol with antibacterial properties. Molecular docking studies demonstrated that HSA and TA interact mainly through hydrogen-bonding, ionic and hydrophobic interactions, leading to smooth and regular assemblies. In vitro bacteria adhesion testing showed that coated scaffolds maintained their antimicrobial properties over 3 days by significantly reducing S. aureus colonization and biofilm formation. Notably, amplitude modulation-frequency modulation (AMFM) based viscoelasticity mapping and transmission electron microscopy (TEM) data suggested that HSA/TA-coatings cause morphological and mechanical changes on the outer cell membrane of S. aureus leading to membrane disruption and cell death while proving non-toxic to human primary cells. These results support this antibiotic-free approach as an effective and biocompatible strategy to prevent biofilm-related biomaterial infections.

Abstract Bacteria have evolved a broad range of systems that provide defence against their viral predators, bacteriophages. Bacteriophage Exclusion (BREX) systems recognise and methylate 6 bp non-palindromic motifs within the host genome, and prevent replication of non-methylated phage DNA that encodes these same motifs. How BREX recognises cognate motifs has not been fully understood. In this study we characterise BREX from pathogenic Salmonella and present X-ray crystallographic structures of the conserved BREX protein, PglX. The PglX N-terminal domain encodes the methyltransferase, whereas the C-terminal domain is for motif recognition. We also present the structure of PglX bound to the phage-derived DNA mimic, Ocr, an inhibitor of BREX activity. Our analyses propose modes for DNA-binding by PglX and indicate that both methyltransferase activity and defence require larger BREX complexes. Through rational engineering of PglX we broaden both the range of phages targeted, and the host motif sequences that are methylated by BREX. Our data demonstrate that PglX is used to recognise specific DNA sequences for BREX activity, contributing to motif recognition for both phage defence and host methylation.

Abstract Introduction Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG), and lamivudine (3TC) have been approved in the US for adults and children with HIV weighing ≥ 6 kg. This analysis assessed the ability of previously developed ABC, DTG, and 3TC pediatric population pharmacokinetic (PopPK) models using multiple formulations to describe and predict PK data in young children using dispersible tablet (DT) and tablet formulations of ABC/DTG/3TC FDC in the IMPAACT 2019 study. Methods IMPAACT 2019 was a Phase I/II study assessing the PK, safety, tolerability, and efficacy of ABC/DTG/3TC FDC in children with HIV-1. Intensive and sparse PK samples were collected over 48 weeks. Existing drug-specific pediatric PopPK models for ABC (2-compartment), DTG (1-compartment), and 3TC (1-compartment) were applied to the IMPAACT 2019 drug concentration data without re-estimation (external validation) of PopPK parameters. Drug exposures were then simulated across World Health Organization weight bands for children weighing ≥ 6 to

Abstract The ocean’s methane emission to the atmosphere is dominated by continental shelves where cold seeps are globally common features. Seeps emit methane into the hydrosphere, but temporal variations and controls of seep activity and the efficiency of the microbial methane filter in the water column are scarce. Here we address these knowledge gaps by measuring whole water column methane inventories and methanotrophic activity at a temporal resolution of 2 hours at a North Sea cold seep (Doggerbank) in summer and autumn. We found that bottom water methane inventories were 68% (summer) and 11% (autumn) higher during low tide compared to high tide coinciding with increased methanotrophic activity. The activity of methanotrophs was reduced during autumn when the water column was fully mixed and matched by higher methane emissions to the atmosphere. Our results show that tides are underappreciated controls on seepage and methanotrophic activity and methane sea–atmosphere fluxes.

Abstract Background Older adults receiving home care have a higher risk of visiting the emergency department (ED) than community-dwelling older adults not receiving home care. This may result from a higher incidence of comorbidities and reduced functional autonomy in home care recipients. Since people receive different types of home care because of their different comorbidities and autonomy profiles, it is possible that distinguishing between the form of home care can help identify subpopulations with different risks for ED visits and help develop targeted interventions. This study aimed to compare the risk of visiting the ED in older adults receiving different forms of home care with those living at home without receiving home care in a national cohort in one year. Methods A retrospective cohort study using claims data collected in 2019 on the Dutch population aged ≥ 65 years (N = 3,314,440) was conducted. Participants were classified as follows: no claimed home care (NO), household help (HH), personal care (PC), HH + PC, and nursing home care at home (NHH). The primary outcome was the number of individuals that visited the ED. Secondary outcomes were the number of individuals whose home care changed, who were institutionalized, or who died. Exploratory logistic regression was applied. Results There were 2,758,093 adults in the NO group, 131,260 in the HH group, 154,462 in the PC group, 96,526 in the HH + PC group, and 34,612 in the NHH group. More ED visits were observed in the home care groups than in the NO group, and this risk increased to more than two-fold for the PC groups. There was a significant change to a more intensive form of home care, institutionalization, or death in all groups. Conclusions Distinguishing between the form of home care older adults receive identifies subpopulations with different risks for ED visits compared with community-dwelling older adults not receiving home care on a population level. Home care transitions are frequent and mostly involve more intensive care or death. Although older adults not receiving home care have a lower risk of ED visits, they contribute most to the absolute volume of ED visits.

Near-surface wind speed exerts profound impacts on many environmental issues, while the long-term (≥60 years) trend and multidecadal variability in the wind speed and its underlying causes in global high-elevation and mountainous areas (e.g., Tibetan Plateau) remain largely unknown. Here, by examining homogenized wind speed data from 104 meteorological stations over the Tibetan Plateau for 1961–2020 and ERA5 reanalysis datasets, we investigated the variability and long-term trend in the near-surface wind speed and revealed the role played by the westerly and Asian monsoon. The results show that the homogenized annual wind speed displays a decreasing trend (−0.091 m s−1 per decade, p

Abstract Camera trapping has revolutionized wildlife ecology and conservation by providing automated data acquisition, leading to the accumulation of massive amounts of camera trap data worldwide. Although management and processing of camera trap‐derived Big Data are becoming increasingly solvable with the help of scalable cyber‐infrastructures, harmonization and exchange of the data remain limited, hindering its full potential. There is currently no widely accepted standard for exchanging camera trap data. The only existing proposal, “Camera Trap Metadata Standard” (CTMS), has several technical shortcomings and limited adoption. We present a new data exchange format, the Camera Trap Data Package (Camtrap DP), designed to allow users to easily exchange, harmonize and archive camera trap data at local to global scales. Camtrap DP structures camera trap data in a simple yet flexible data model consisting of three tables (Deployments, Media and Observations) that supports a wide range of camera deployment designs, classification techniques (e.g., human and AI, media‐based and event‐based) and analytical use cases, from compiling species occurrence data through distribution, occupancy and activity modeling to density estimation. The format further achieves interoperability by building upon existing standards, Frictionless Data Package in particular, which is supported by a suite of open software tools to read and validate data. Camtrap DP is the consensus of a long, in‐depth, consultation and outreach process with standard and software developers, the main existing camera trap data management platforms, major players in the field of camera trapping and the Global Biodiversity Information Facility (GBIF). Under the umbrella of the Biodiversity Information Standards (TDWG), Camtrap DP has been developed openly, collaboratively and with version control from the start. We encourage camera trapping users and developers to join the discussion and contribute to the further development and adoption of this standard.

Abstract Background Despite Spirochetales being a ubiquitous and medically important order of bacteria infecting both humans and animals, there is extremely limited information regarding their bacteriophages. Of the genus Treponema, there is just a single reported characterised prophage. Results We applied a bioinformatic approach on 24 previously published Treponema genomes to identify and characterise putative treponemal prophages. Thirteen of the genomes did not contain any detectable prophage regions. The remaining eleven contained 38 prophage sequences, with between one and eight putative prophages in each bacterial genome. The prophage regions ranged from 12.4 to 75.1 kb, with between 27 and 171 protein coding sequences. Phylogenetic analysis revealed that 24 of the prophages formed three distinct sequence clusters, identifying putative myoviral and siphoviral morphology. ViPTree analysis demonstrated that the identified sequences were novel when compared to known double stranded DNA bacteriophage genomes. Conclusions In this study, we have started to address the knowledge gap on treponeme bacteriophages by characterising 38 prophage sequences in 24 treponeme genomes. Using bioinformatic approaches, we have been able to identify and compare the prophage-like elements with respect to other bacteriophages, their gene content, and their potential to be a functional and inducible bacteriophage, which in turn can help focus our attention on specific prophages to investigate further.

BackgroundDrugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1.MethodsIn this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation. Women were enrolled at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Participants were randomly assigned (1:1:1) to one of three oral regimens: dolutegravir, emtricitabine, and tenofovir alafenamide; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate. Up to 14 days of antepartum ART before enrolment was permitted. Women with known multiple gestation, fetal anomalies, acute significant illness, transaminases more than 2·5 times the upper limit of normal, or estimated creatinine clearance of less than 60 mL/min were excluded. Primary safety analyses were pairwise comparisons between ART regimens of the proportion of maternal and infant adverse events of grade 3 or higher up to 50 weeks post partum. Secondary efficacy analyses at 50 weeks post partum included a comparison of the proportion of women with plasma HIV-1 RNA of less than 200 copies per mL in the combined dolutegravir-containing groups versus the efavirenz-containing group. Analyses were done in the intention-to-treat population, which included all randomly assigned participants with available data. This trial was registered with ClinicalTrials.gov, NCT03048422.FindingsBetween Jan 19, 2018, and Feb 8, 2019, we randomly assigned 643 pregnant women to the dolutegravir, emtricitabine, and tenofovir alafenamide group (n=217), the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (n=215), and the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (n=211). At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), median CD4 count was 466 cells per μL (308-624), and median HIV-1 RNA was 903 copies per mL (152-5183). 607 (94%) women and 566 (92%) of 617 liveborn infants completed the study. Up to the week 50 post-partum visit, the estimated probability of experiencing an adverse event of grade 3 or higher was 25% in the dolutegravir, emtricitabine, and tenofovir alafenamide group; 31% in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group; and 28% in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (no significant difference between groups). Among infants, the estimated probability of experiencing at least one adverse event of grade 3 or higher by postnatal week 50 was 28% overall, with small and non-statistically significant differences between groups. By postnatal week 50, 14 infants whose mothers were in the efavirenz-containing group (7%) died, compared with six in the combined dolutegravir groups (1%). 573 (89%) women had HIV-1 RNA data available at 50 weeks post partum: 366 (96%) in the dolutegravir-containing groups and 186 (96%) in the efavirenz-containing group had HIV-1 RNA less than 200 copies per mL, with no significant difference between groups.InterpretationSafety and efficacy data during pregnancy and up to 50 weeks post partum support the current recommendation of dolutegravir-based ART (particularly in combination with emtricitabine and tenofovir alafenamide) rather than efavirenz, emtricitabine, and tenofovir disoproxil fumarate, when started in pregnancy.FundingNational Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

The COVID-19 pandemic resulted in an unanticipated, near-universal shift from in-person to virtual instruction in the spring of 2020. During the 2020-21 school year, schools began to reopen, and families were faced with decisions regarding the instructional mode for their children. We leverage administrative, survey, and virtual-learning data to examine the determinants of family learning-mode choice and associations between virtual education, student engagement, and academic achievement. Family preference for virtual (versus face-to-face) instruction was highly associated with subsequent school-level infection rates and appeared relatively uniform within schools. We find that students assigned to a higher proportion of instructional days in virtual mode experienced higher rates of attendance but negative achievement growth compared to students who were assigned a higher proportion of instructional days in face-to-face mode. Insights from this study can be used to better understand family preferences as well as to target and refine virtual learning in a post-COVID-19 society.

The value of no-take marine protected areas (MPAs) in providing fisheries-independent information to evaluate the status of adjacent fish stocks is increasingly being recognised. However, to ensure robust assessments of fisheries using this approach, MPAs need to be representative of the wider fished area and sampling should include multiple MPA and fished locations spanning the area of interest. The spiny lobster Jasus edwardsii fishery in Aotearoa New Zealand’s Hauraki Gulf has been in decline since the late 1990s, but latest stock estimates suggest a dramatic recovery following catch reductions in 2018. We compared J. edwardsii populations on shallow reefs (

Despite progress in providing antiretroviral therapy to pregnant women living with HIV, a substantial number of vertical transmissions continue to occur. Novel approaches leveraging modern potent, safe, and well-tolerated antiretroviral drugs are urgently needed.

Abstract Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Growers rely on broad-spectrum agrochemicals to manage one of the most economically important fruit tree diseases, huanglongbing (HLB, citrus greening disease), presumptively caused by the gram-negative bacterium ‘Candidatus Liberibacter asiaticus’ (CLas). Although genetic resistance would be an attractive alternative to chemical management, this option is not yet available for HLB. Here, we tested whether a single chain variable fragment (scFv) antibody targeting the predicted CLas outer membrane transporter NodT can inhibit CLas growth or HLB disease development when expressed in ‘Duncan’ grapefruit (Citrus × paradisi). CLas NodT is similar to TolC and could be involved in Type I secretion and virulence. The scFv antibody was expressed in grapefruit trees as a C-terminal translational fusion to the Flowering Locus T protein of Poncirus trifoliata (FT-scFv) to promote expression in the phloem. Wild-type and FT-scFv-expressing transgenic lines were challenged with CLas using three inoculation approaches: psyllid-mediated inoculation, vegetative graft inoculation, and natural exposure in grove-like conditions. With the first two approaches, HLB symptom expression and CLas bacterial titers in FT-scFv grapefruit lines were not significantly different from wild-type controls. In the grove trial, one FT-scFv line exhibited a slight, but significant, reduction in canopy chlorosis compared to wild-type controls. Wild-type and FT-scFv lines were similar in all other metrics. We conclude that the expression of anti-NodT FT-scFv antibody in grapefruit did not decrease HLB susceptibility. Although our approach was unsuccessful, we hope that documenting our results will be useful for those seeking to develop HLB-resistant citrus germplasm in the future. [Figure: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.