Impact of HIV drug resistance on HIV/AIDS associated mortality, new infections and antiretroviral therapy program costs in sub-Saharan Africa

To inform the level of attention to be given by antiretroviral therapy (ART) programs to HIV drug resistance (HIVDR), we used an individual-level model to estimate its impact on future AIDS deaths, HIV-incidence and ART program costs in sub-Saharan Africa (SSA) for a range of program situations. We applied this to SSA through the Spectrum-Goals model. In a situation in which current levels of pre-treatment HIVDR are over 10% (mean 15%), 16% of AIDS deaths (890,000 deaths) , 9% of new infections (450,000) and 8% ($6.5 billion) of ART program costs in SSA in 2016-2030 will be attributable to HIVDR

Disquieting Discretion: Race, Geography & the Colorado Death Penalty in the First Decade of the Twenty-First Century

This Article demonstrates through original statistical research that prosecutors in Colorado were more likely to seek the death penalty against minority defendants than against white defendants. Moreover, defendants in Colorado’s Eighteenth Judicial District were more likely to face a death prosecution than defendants elsewhere in the state. Our empirical analysis demonstrates that even when one controls for the differential rates at which different groups commit statutorily death-eligible murders, non-white defendants and defendants in the Eighteenth Judicial District were still more likely than others to face a death penalty prosecution. Even when the heinousness of the crime is accounted for, the race of the accused and the place of the crime are statistically significant predictors of whether prosecutors will seek the death penalty. We discuss the implications of this disparate impact on the constitutionality of Colorado’s death penalty regime, concluding that the Colorado statute does not meet the dictates of the Eighth Amendment to the Constitution

Differential adipose tissue gene expression profiles in abacavir treated patients that may contribute to the understanding of cardiovascular risk: a microarray study

OBJECTIVE:To compare changes in gene expression by microarray from subcutaneous adipose tissue from HIV treatment naïve patients treated with efavirenz based regimens containing abacavir (ABC), tenofovir (TDF) or zidovidine (AZT). DESIGN:Subcutaneous fat biopsies were obtained before, at 6- and 18-24-months after treatment, and from HIV negative controls. Groups were age, ethnicity, weight, biochemical profile, and pre-treatment CD4 count matched. Microarray data was generated using the Agilent Whole Human Genome Microarray. Identification of differentially expressed genes and genomic response pathways was performed using limma and gene set enrichment analysis. RESULTS:There were significant divergences between ABC and the other two groups 6 months after treatment in genes controlling cell adhesion and environmental information processing, with some convergence at 18-24 months. Compared to controls the ABC group, but not AZT or TDF showed enrichment of genes controlling adherence junction, at 6 months and 18-24 months (adjusted p<0.05) and focal adhesions and tight junction at 6 months (p<0.5). Genes controlling leukocyte transendothelial migration (p<0.05) and ECM-receptor interactions (p = 0.04) were over-expressed in ABC compared to TDF and AZT at 6 months but not at 18-24 months. Enrichment of pathways and individual genes controlling cell adhesion and environmental information processing were specifically dysregulated in the ABC group in comparison with other treatments. There was little difference between AZT and TDF. CONCLUSION:After initiating treatment, there is divergence in the expression of genes controlling cell adhesion and environmental information processing between ABC and both TDF and AZT in subcutaneous adipose tissue. If similar changes are also taking place in other tissues including the coronary vasculature they may contribute to the increased risk of cardiovascular events reported in patients recently started on abacavir-containing regimens

Stakeholder perspectives of a pilot multicomponent delirium prevention intervention for adult patients with advanced cancer in palliative care units: A behaviour change theory-based qualitative study

Background: Theory-based and qualitative evaluations in pilot trials of complex clinical interventions help to understand quantitative results, as well as inform the feasibility and design of subsequent effectiveness and implementation trials. Aim: To explore patient, family, clinician and volunteer (‘stakeholder’) perspectives of the feasibility and acceptability of a multicomponent non-pharmacological delirium prevention intervention for adult patients with advanced cancer in four Australian palliative care units that participated in a phase II trial, the ‘PRESERVE pilot study’. Design: A trial-embedded qualitative study via semi-structured interviews and directed content analysis using Michie’s Behaviour Change Wheel and the Theoretical Domains Framework. Setting/participants: Thirty-nine people involved in the trial: nurses (n = 17), physicians (n = 6), patients (n = 6), family caregivers (n = 4), physiotherapists (n = 3), a social worker, a pastoral care worker and a volunteer. Results: Participants’ perspectives aligned with the ‘capability’, ‘opportunity’ and ‘motivation’ domains of the applied frameworks. Of seven themes, three were around the alignment of the delirium prevention intervention with palliative care (intervention was considered routine care; intervention aligned with the compassionate and collaborative culture of palliative care; and differing views of palliative care priorities influenced perspectives of the intervention) and four were about study processes more directly related to adherence to the intervention (shared knowledge increased engagement with the intervention; impact of the intervention checklist on attention, delivery and documentation of the delirium prevention strategies; clinical roles and responsibilities; and addressing environmental barriers to delirium prevention). Conclusion: This theory-informed qualitative study identified multiple influences on the delivery and documentation of a pilot multicomponent non-pharmacological delirium prevention intervention in four palliative care units. Findings inform future definitive studies of delirium prevention in palliative care

Potential impact and cost-effectiveness of long-acting injectable lenacapavir plus cabotegravir as HIV treatment in Africa

Although viral suppression is attained for most adults living with diagnosed HIV in East, Central, Southern and West Africa (ECSWA), challenges remain with sustained adherence to daily oral pill taking for some in the population. Here, we evaluate the potential effectiveness and cost-effectiveness of introduction of a new combination of long-acting injectable drugs of lenacapavir + cabotegravir to increase levels of sustained viral suppression. We find there is potential for a significant impact on HIV deaths and disability adjusted life years, including due to a decrease in mother to child transmission. If lenacapavir + cabotegravir can be sourced at a cost of around $ 80 per year or less, our analysis suggests there is potential for a policy to introduce it to be cost-effective in settings in ECSWA. Recognising the limitations of a modelling study, we suggest that implementation studies be conducted to confirm the viability of these approaches

Structural and Functional Insights into the Malaria Parasite Moving Junction Complex

Members of the phylum Apicomplexa, which include the malaria parasite Plasmodium, share many features in their invasion mechanism in spite of their diverse host cell specificities and life cycle characteristics. The formation of a moving junction (MJ) between the membranes of the invading apicomplexan parasite and the host cell is common to these intracellular pathogens. The MJ contains two key parasite components: the surface protein Apical Membrane Antigen 1 (AMA1) and its receptor, the Rhoptry Neck Protein (RON) complex, which is targeted to the host cell membrane during invasion. In particular, RON2, a transmembrane component of the RON complex, interacts directly with AMA1. Here, we report the crystal structure of AMA1 from Plasmodium falciparum in complex with a peptide derived from the extracellular region of PfRON2, highlighting clear specificities of the P. falciparum RON2-AMA1 interaction. The receptor-binding site of PfAMA1 comprises the hydrophobic groove and a region that becomes exposed by displacement of the flexible Domain II loop. Mutations of key contact residues of PfRON2 and PfAMA1 abrogate binding between the recombinant proteins. Although PfRON2 contacts some polymorphic residues, binding studies with PfAMA1 from different strains show that these have little effect on affinity. Moreover, we demonstrate that the PfRON2 peptide inhibits erythrocyte invasion by P. falciparum merozoites and that this strong inhibitory potency is not affected by AMA1 polymorphisms. In parallel, we have determined the crystal structure of PfAMA1 in complex with the invasion-inhibitory peptide R1 derived by phage display, revealing an unexpected structural mimicry of the PfRON2 peptide. These results identify the key residues governing the interactions between AMA1 and RON2 in P. falciparum and suggest novel approaches to antimalarial therapeutics