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Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of CD4+ T cells that contribute to viral rebound if treatment is interrupted. Identifying the cellular populations that contribute to the HIV-1 reservoir and understanding the mechanisms of viral persistence are necessary to achieve an effective cure. In this regard, through Full-Length Individual Proviral Sequencing, we observed that the HIV-1 proviral landscape was different and changed with time on ART across naive and memory CD4+ T cell subsets isolated from 24 participants. We found that the proportion of genetically intact HIV-1 proviruses was higher and persisted over time in effector memory CD4+ T cells when compared with naive, central, and transitional memory CD4+ T cells. Interestingly, we found that escape mutations remained stable over time within effector memory T cells during therapy. Finally, we provided evidence that Nef plays a role in the persistence of genetically intact HIV-1. These findings posit effector memory T cells as a key component of the HIV-1 reservoir and suggest Nef as an attractive therapeutic target.

The Portable Extensible Toolkit for Scientific computation (PETSc) library delivers scalable solvers for nonlinear time-dependent differential and algebraic equations and for numerical optimization. The PETSc design for performance portability addresses fundamental GPU accelerator challenges and stresses flexibility and extensibility by separating the programming model used by the application from that used by the library, and it enables application developers to use their preferred programming model, such as Kokkos, RAJA, SYCL, HIP, CUDA, or OpenCL, on upcoming exascale systems. A blueprint for using GPUs from PETSc-based codes is provided, and case studies emphasize the flexibility and high performance achieved on current GPU-based systems.

Aims: Digital living is now an integral part of many children and young people's (CYP) everyday experience. Practitioners who work with them are increasingly focused on effectively deploying technology to help those with social, emotional and mental health (SEMH) needs. Throughout all aspects and phases of work, practitioners must adhere to legal and professional best practice standards in involving service users, person-centred working and in enhancing accessibility for all. Methods: Measures introduced to reduce the spread of COVID-19 triggered significant service delivery change in a specialist multi-disciplinary child and adolescent mental health service (CAMHS) team. The majority of assessment and intervention work moved to an online audio and web conferencing platform. A shared decision-making approach was developed to support service user understanding of online appointments and to giving informed consent, in line with the i-THRIVE Framework for system change (Wolpert et al., 2019). Three Guides were developed and distributed ahead of online appointments: written, easy-read and video. Findings: Data collected within a Quality Improvement (QI) framework indicated that the Guides supported practitioners to prepare service users, as well as themselves, for digital working. The Guides supported service access, collaborative decision-making and increased CYP autonomy. Their introduction also led to conversations about equity and cultural responsiveness, as well as serving as a model for the development of aids to support shared decision-making for autism diagnostic assessments. Limitations: This paper outlines the first phase of the QI project with a small participant sample and requires further engagement with service users to review the use of Guides and shared decision-making decision aids. Conclusions: Digital approaches present new possibilities and are rapidly changing service delivery across CAMHS. The importance of involving service users in shared decision-making when developing digital practices must be held in mind as part of this change process.

Background: Despite repeated policy initiatives, an enduring number of people with learning disabilities remain resident in secure settings (also referred to as locked wards). The spatial and emotional distance from family and friends means that relationships with staff become central to people's lives, and are critical for a successful transition to making their home in the community. Methods: This article uses a synthesis of evidence from two qualitative studies. We re-analysed data from fieldnotes and interview transcripts with people with learning disabilities resident in secure settings and with staff who worked with them. The purpose of the original studies was service improvement however, relationships--particularly with between staff and residents--emerged as a significant theme in both studies. Therefore, the data were revisited to explore these relationships in more depth. Findings: The analysis identified that positive relationships with staff were critical in enabling residents to be "in a good space"--something they and staff viewed as a crucial factor for moving on. The analysis identified four main themes: (i) the characteristics of positive relationships, (ii) the challenges for positive relationships, (iii) how positive relationships can be encouraged and (iv) how positive relationships support people to move on. Conclusion: We conclude that flattening the hierarchy between staff and residents is key when supporting people with learning disabilities to move on. We stress the importance of the "soft skills" in enabling people to transition back to their community. There is a pressing need for research with people who have made the transition from hospital to generate retrospective narratives about what elements of these relationships are most significant in supporting a successful transition.

The investigation of Islamic archaeology in Ethiopia has until recently been neglected. Excavations at Harlaa, a large urban centre in eastern Ethiopia, are now beginning to redress this lack of research attention. By establishing occupation and material sequences, and by assessing the chronology and material markers of Islamisation, recent work provides important new insight on the presence and role of Muslims and Islamic practice at Harlaa, and in the Horn of Africa more generally. The results challenge previous assumptions of cultural homogeneity, instead indicating the development of cosmopolitanism. They also suggest a possible historical identity for Harlaa: as Hubat/ Hobat, the capital of the Harla sultanate. Keywords: Ethiopia, Harlaa, Islamic archaeology, Islamisation, cosmopolitanism, Introduction Archaeological research on Islamic sites in Ethiopia, and more generally in the Horn of Africa, has been limited. This is a significant omission, as Ethiopia was in contact with [...]

Pregnancy represents a stage during which maternal physiology and homeostatic regulation undergo dramatic change and adaptation. The fundamental purpose of these adaptations is to ensure the survival of her offspring through adequate nutrient provision and an environment that is tolerant to the semi-allogenic foetus. While poor maternal diet during pregnancy is associated with perturbed maternal adaptations during pregnancy, the influence of paternal diet on maternal well-being is less clearly defined. We fed C57BL/6 male mice either a control (CD), low protein diet (LPD), a high fat/sugar Western diet (WD) or the LPD or WD supplemented with methyl donors (MD-LPD and MD-WD, respectively) for a minimum of 8 weeks prior to mating with C57BL/6 females. Mated females were culled at day 17 of gestation for the analysis of maternal metabolic, gut, cardiac and bone health. Paternal diet had minimal influences on maternal serum and hepatic metabolite levels or gut microbiota diversity. However, analysis of the maternal hepatic transcriptome revealed distinct profiles of differential gene expression in response to the diet of the father. Paternal LPD and MD-LPD resulted in differential expression of genes associated with lipid metabolism, transcription, ubiquitin conjugation and immunity in dams, while paternal WD and MD-WD modified the expression of genes associated with ubiquitin conjugation and cardiac morphology. Finally, we observed changes in maternal femur length, volume of trabecular bone, trabecular connectivity, volume of the cortical medullar cavity and thickness of the cortical bone in response to the father's diets. Our current study demonstrates that poor paternal diet at the time of mating can influence the patterns of maternal metabolism and gestation-associated adaptations to her physiology. [ABSTRACT FROM AUTHOR]

Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of [CD4.sup.+] T cells that contribute to viral rebound if treatment is interrupted. Identifying the cellular populations that contribute to the HIV-1 reservoir and understanding the mechanisms of viral persistence are necessary to achieve an effective cure. In this regard, through Full-Length Individual Proviral Sequencing, we observed that the HIV-1 proviral landscape was different and changed with time on ART across naive and memory [CD4.sup.+] T cell subsets isolated from 24 participants. We found that the proportion of genetically intact HIV-1 proviruses was higher and persisted over time in effector memory [CD4.sup.+] T cells when compared with naive, central, and transitional memory [CD4.sup.+] T cells. Interestingly, we found that escape mutations remained stable over time within effector memory T cells during therapy. Finally, we provided evidence that Nef plays a role in the persistence of genetically intact HIV-1. These findings posit effector memory T cells as a key component of the HIV-1 reservoir and suggest Nef as an attractive therapeutic target., Introduction Genetic characterization of HIV-1 proviruses isolated from individuals on suppressive antiretroviral therapy (ART) has revealed that 2%-8% of persistent HIV-1 is genetically intact and potentially replication competent (1-6). Replication-competent [...]

Background Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials. Methods A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid. Results Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3–4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid. Conclusions Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB. [ABSTRACT FROM AUTHOR]

Encounters with, within and between digital technologies have become characteristic of life in the contemporary moment. This is, often, no different for displaced individuals seeking asylum across European states. Smartphones have become part of the everyday ‘doing’ of life for individuals governed through asylum systems which now includes routinely encountering the state. Whilst smartphones are commonly said to offer the promised affordances of increased connection or communication, this paper aims to explore how everyday encounters with the UK asylum state fall short of these imagined expectations. In its place, the paper identifies how a series of ongoing (non)encounters—encounters that fail to manifest in expected ways; characterised by pauses, delays or voids—become characteristic of the everyday experience of being a digitally connected asylum seeker in the UK. Drawing upon a year‐long ethnographic research project with people actively seeking asylum in the UK between 2022 and 2023, this paper thus explores how the increased uptake of smartphone affordances within the UK asylum system contributes to the ongoing administration of state slow violence: experienced as exhaustion through everyday digital (non)encounters. Developing the concept of the (non)encounter for geographic research, this paper outlines how forms of dis/connection become characteristic of the state encounter for asylum‐seeking individuals. These modes of dis/connection are traced as slow violence along the contours of neoliberalisation and hostile assemblages of asylum governance within the UK context. [ABSTRACT FROM AUTHOR]

In the lesson on which this practical article is based, third grade students constructed a "lift-the-flap" page to explore food webs on the prairie. The moveable papercraft focused student attention on prairie animals' external structures and how the inferred functions of those structures could support further inferences about the animals' diets. In general, most students made simple causal connections between an animal's observable characteristics and the food it would probably eat. Some students were also able to make multi-agent connections to develop a more complex mental model of a food web. Ultimately, the lift-the flap project was engaging to students and motivated them to focus their attention on the characteristics of animals of different ecosystems to infer their probable diets.