Evaluation of Risk for Late Language Emergence after In Utero Antiretroviral Drug Exposure in HIV-exposed Uninfected Infants

This is not the published version.BACKGROUND Combination antiretroviral (cARV) regimens are recommended for pregnant women with HIV to prevent perinatal HIV transmission. Safety is a concern for infants who were HIV-exposed but uninfected (HEU), particularly for neurodevelopmental problems, such as language delays. METHODS We studied late language emergence (LLE) in HEU children enrolled in a US-based prospective cohort study. LLE was defined as a caregiver-reported score ≤ 10th percentile in any of 4 domains of the MacArthur-Bates Communicative Development Inventory for one-year-olds and as ≥1 standard deviation below age-specific norms for the Ages and Stages Questionnaire for two-year-olds. Logistic regression models were used to evaluate associations of in utero cARV exposure with LLE, adjusting for infant, maternal, and environmental characteristics. RESULTS 1,129 language assessments were conducted among 792 one- and two-year-olds (50% male, 62% black, and 37% Hispanic). Overall, 86% had in utero exposure to cARV and 83% to protease inhibitors. LLE was identified in 26% of one-year-olds and 23% of two-year-olds, with higher rates among boys. In adjusted models, LLE was not associated with maternal cARV or ARV drug classes in either age group. Among cARV-exposed one-year-olds, increased odds of LLE was observed for those exposed to atazanavir (aOR=1.83, 95% CI=1.10-3.04), particularly after the first trimester (aOR=3.56, p=0.001), compared to atazanavir-unexposed infants. No associations of individual ARV drugs with LLE were observed among two-year-olds. CONCLUSIONS In utero cARV exposure showed little association with LLE, except for a higher risk of language delay observed in one-year-old infants with atazanavir exposure

Language Impairment in Children Perinatally Infected with HIV Compared to Children Who Were HIV-Exposed and Uninfected

OBJECTIVE: To investigate risk for language impairment in children perinatally infected or exposed to HIV. METHOD: We evaluated the prevalence of language impairment (LI) in 7–16 year old children with perinatal HIV infection (HIV+) compared to children HIV-exposed and uninfected (HEU), using a comprehensive standardized language test (CELF-4). LI was classified as primary LI (Pri-LI) (monolingual English exposure and no cognitive or hearing impairment), concurrent LI (Con-LI) (cognitive or hearing impairment), or no LI. Associations of demographic, caregiver, HIV disease and antiretroviral treatment (ART) factors with LI category were evaluated using univariate and multivariable logistic regression models. RESULTS: Of 468 children with language assessments, 184 (39%) had LI. No difference was observed by HIV infection status for overall LI or for Pri-LI or Con-LI; mean (SD) CELF-4 scores were 88.5 (18.4) for HIV+ vs 87.5 (17.9) for HEU. After adjustment, Black children had higher odds of Pri-LI vs no LI (aOR=2.43, p=0.03). Children who were Black, Hispanic, had a caregiver with low education or low IQ, or a non-biological parent as caregiver had higher odds of Con-LI vs no LI. Among HIV+ children, viral load >400 copies/ml (aOR=3.04, p<0.001), CDC Class C (aOR=2.19, p=0.02) and ART initiation <6 months of age (aOR=2.12, p=0.02) were associated with higher odds of Con-LI vs. no LI. CONCLUSIONS: Children perinatally exposed to HIV are at high risk for LI, but such risk was not increased for youth with HIV. Risk factors differed for Pri-LI and Con-LI

Language Impairment in Children Perinatally Infected with HIV Compared to Children Who Were HIV-Exposed and Uninfected

Objective - To investigate risk for language impairment in children perinatally infected or exposed to HIV. Methods - We evaluated the prevalence of language impairment (LI) in 7–16 year old children with perinatal HIV infection (HIV+) compared to children HIV-exposed and uninfected (HEU), using a comprehensive standardized language test (CELF-4). LI was classified as primary LI (Pri-LI) (monolingual English exposure and no cognitive or hearing impairment), concurrent LI (Con-LI) (cognitive or hearing impairment), or no LI. Associations of demographic, caregiver, HIV disease and antiretroviral treatment (ART) factors with LI category were evaluated using univariate and multivariable logistic regression models. Results - Of 468 children with language assessments, 184 (39%) had LI. No difference was observed by HIV infection status for overall LI or for Pri-LI or Con-LI; mean (SD) CELF-4 scores were 88.5 (18.4) for HIV+ vs 87.5 (17.9) for HEU. After adjustment, Black children had higher odds of Pri-LI vs no LI (aOR=2.43, p=0.03). Children who were Black, Hispanic, had a caregiver with low education or low IQ, or a non-biological parent as caregiver had higher odds of Con-LI vs no LI. Among HIV+ children, viral load \u3e400 copies/ml (aOR=3.04, pp=0.02) and ART initiation (aOR=2.12, p=0.02) were associated with higher odds of Con-LI vs. no LI. Conclusions - Children perinatally exposed to HIV are at high risk for LI, but such risk was not increased for youth with HIV. Risk factors differed for Pri-LI and Con-LI

Preventing HIV Among Young People: Research Priorities for the Future

To review the current state of knowledge on the prevention of sexual transmission of HIV in adolescents and to highlight existing gaps and priority areas for future research

Clades of huge phages from across Earth's ecosystems.

Bacteriophages typically have small genomes1 and depend on their bacterial hosts for replication2. Here we sequenced DNA from diverse ecosystems and found hundreds of phage genomes with lengths of more than 200&nbsp;kilobases (kb), including a genome of 735&nbsp;kb, which is-to our knowledge-the largest phage genome to be described to date. Thirty-five genomes were manually curated to completion (circular and no gaps). Expanded genetic repertoires include diverse and previously undescribed CRISPR-Cas systems, transfer RNAs (tRNAs), tRNA synthetases, tRNA-modification enzymes, translation-initiation and elongation factors, and ribosomal proteins. The CRISPR-Cas systems of phages have the capacity to silence host transcription factors and translational genes, potentially as part of a larger interaction network that intercepts translation to redirect biosynthesis to phage-encoded functions. In addition, some phages may repurpose bacterial CRISPR-Cas systems to eliminate competing phages. We phylogenetically define the major clades of huge phages from human and other animal microbiomes, as well as from oceans, lakes, sediments, soils and the built environment. We conclude that the large gene inventories of huge phages reflect a conserved biological strategy, and that the phages are distributed across a broad bacterial host range and across Earth's ecosystems

Limits and barriers to adaptation to climate variability and change in Bangladeshi coastal fishing communities

Limits and barriers to adaptation restrict people’s ability to address the negative impacts of climate change or manage risks in a way that maximises their wellbeing. There is a lack of evidence of this on small-scale fishing communities in developing countries. This study identifies and characterises limits and barriers to adaptation of fishing activities to cyclones and examines interactions between them in two fishing communities in Bangladesh, using household questionnaires, oral history interviews, vulnerability matrices and focus group discussions. The limits include physical characteristics of climate and sea like higher frequency and duration of cyclones, and hidden sandbars. Barriers include technologically poor boats, inaccurate weather forecast, poor radio signal, lack of access to credit, low incomes, underestimation of cyclone occurrence, coercion of fishermen by the boat owners and captains, lack of education, skills and livelihood alternatives, unfavourable credit schemes, lack of enforcement of fishing regulations and maritime laws, and lack of access to fish markets. These local and wider scale factors interact in complex ways and constrain completion of fishing trips, coping with cyclones at sea, safe return of boats from sea, timely responses to cyclones and livelihood diversification. The findings indicate a need for further detailed research into the determinants and implications of such limits and barriers, in order to move towards an improved characterisation of adaptation and to identify most suitable means to overcome the limits and barriers

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The biogeographic differentiation of algal microbiomes in the upper ocean from pole to pole

Eukaryotic phytoplankton are responsible for at least 20% of annual global carbon fixation. Their diversity and activity are shaped by interactions with prokaryotes as part of complex microbiomes. Although differences in their local species diversity have been estimated, we still have a limited understanding of environmental conditions responsible for compositional differences between local species communities on a large scale from pole to pole. Here, we show, based on pole-to-pole phytoplankton metatranscriptomes and microbial rDNA sequencing, that environmental differences between polar and non-polar upper oceans most strongly impact the large-scale spatial pattern of biodiversity and gene activity in algal microbiomes. The geographic differentiation of co-occurring microbes in algal microbiomes can be well explained by the latitudinal temperature gradient and associated break points in their beta diversity, with an average breakpoint at 14 °C ± 4.3, separating cold and warm upper oceans. As global warming impacts upper ocean temperatures, we project that break points of beta diversity move markedly pole-wards. Hence, abrupt regime shifts in algal microbiomes could be caused by anthropogenic climate change

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention