Characterisation of protease resistance mutations in a South African paediatric cohort with virological failure, 2011 - 2017

Background. Advances in HIV management have improved treatment outcomes in the HIV-infected population. However, these advances have not been without multifaceted challenges. In sub-Saharan Africa, their impact is reflected in the increased emergence of HIV drug resistance mutations. With the rise in exposure of children to protease inhibitors (PIs), the possibility of increasing PI resistance remains a concern.Objectives. To describe a group of antiretroviral-experienced children with PI drug resistance mutations after failure on first- or second-line regimens in a public sector setting in South Africa.Methods. This was a retrospective cohort study of 22 children perinatally infected with HIV who had HIV genotyping conducted between January 2011 and December 2017.Results. Of the 236 children who had HIV genotyping conducted, 22 (9.3%) had evidence of HIV PI resistance mutations. Twenty-one of the 22 children (95.5%) had major mutations in the protease region of the HIV genome. Of these children, 66.7% (14/21) had loss of response to both boosted lopinavir and atazanavir, with boosted darunavir remaining susceptible in only 12 (57.1%). The most frequent major PI mutations were V82A (76.2%), M46I/M46L (76.2%), I54V (62.0%) and L76V (33.3%).Conclusions. We observed a high rate of PI resistance mutations, with a resulting loss of PIs that could be used in construction of third-line regimens. To build on improvements from the introduction of antiretroviral therapy, increased efforts are needed by both health professionals and caregivers to improve adherence measures in children perinatally infected with HIV.

AC ship microgrids: control and power management optimization

At sea, the electrical power system of a ship can be considered as an islanded microgrid. When connected to shore power at berth, the same power system acts as a grid connected microgrid or an extension of the grid. Therefore, ship microgrids show some resemblance to terrestrial microgrids. Nevertheless, due to the presence of large dynamic loads, such as electric propulsion loads, keeping the voltage and frequency within a permissible range and ensuring the continuity of supply are more challenging in ship microgrids. Moreover, with the growing demand for emission reductions and fuel efficiency improvements, alternative energy sources and energy storage technologies are becoming popular in ship microgrids. In this context, the integration of multiple energy sources and storage systems in ship microgrids requires an efficient power management system (PMS). These challenging environments and trends demand advanced control and power management solutions that are customized for ship microgrids. This paper presents a review on recent developments of control technologies and power management strategies proposed for AC ship microgrids

Selectively Cross-Linked Tetra-PEG Hydrogels Provide Control over Mechanical Strength with Minimal Impact on Diffusivity.

Synthetic hydrogels formed from poly(ethylene glycol) (PEG) are widely used to study how cells interact with their extracellular matrix. These in vivo-like 3D environments provide a basis for tissue engineering and cell therapies but also for research into fundamental biological questions and disease modeling. The physical properties of PEG hydrogels can be modulated to provide mechanical cues to encapsulated cells; however, the impact of changing hydrogel stiffness on the diffusivity of solutes to and from encapsulated cells has received only limited attention. This is particularly true in selectively cross-linked "tetra-PEG" hydrogels, whose design limits network inhomogeneities. Here, we used a combination of theoretical calculations, predictive modeling, and experimental measurements of hydrogel swelling, rheological behavior, and diffusion kinetics to characterize tetra-PEG hydrogels' permissiveness to the diffusion of molecules of biologically relevant size as we changed polymer concentration, and thus hydrogel mechanical strength. Our models predict that hydrogel mesh size has little effect on the diffusivity of model molecules and instead predicts that diffusion rates are more highly dependent on solute size. Indeed, our model predicts that changes in hydrogel mesh size only begin to have a non-negligible impact on the concentration of a solute that diffuses out of hydrogels for the smallest mesh sizes and largest diffusing solutes. Experimental measurements characterizing the diffusion of fluorescein isothiocyanate (FITC)-labeled dextran molecules of known size aligned well with modeling predictions and suggest that doubling the polymer concentration from 2.5% (w/v) to 5% produces stiffer gels with faster gelling kinetics without affecting the diffusivity of solutes of biologically relevant size but that 10% hydrogels can slow their diffusion. Our findings provide confidence that the stiffness of tetra-PEG hydrogels can be modulated over a physiological range without significantly impacting the transport rates of solutes to and from encapsulated cells

“Ndiyindoda” [I am a man]: theorising Xhosa masculinity

Masculinity studies in South Africa depend on Western gender theories to frame research questions and fieldwork. This article argues that such theories offer a limited understanding of Xhosa constructions of masculinity. Xhosa notions of masculinity are embodied in the concept of indoda, meaning a traditionally circumcised person. This article explores the nuanced meanings of indoda and its relationship to other masculinities, like uncircumcised boys [inkwenkwe] and medically circumcised men. The discussion reveals that indoda is the most “honoured” form of masculinity. A traditionally circumcised individual is regarded as indoda, a real man, irrespective of his sexual orientation or class, and this affords him certain rights and privileges. Inkwenkwe and medically circumcised men embody “subordinate” forms of masculinity and are victims of stigma and discrimination by indoda. This requires us to revisit some Western theories of masculinity which place heterosexual men at the top of a masculine hierarchy and gay men at the bottom. It furthermore requires us to pay attention to the body when theorising Xhosa masculinity, since it is a principal way of “proving” and “defending” Xhosa manhood.IBS

Voicing ambiguities in the Ilizwi Lenyaniso Lomhlaba co-creator collective

This article considers youth co-production in the context of Global Challenges Research funded project, Changing the Story. The participatory project conceives of ‘voice' as research data, turn of phrase, and character by engaging with the work produced by South African co-creator collective Ilizwi Lenyaniso Lomhlaba, who contribute to voicing issues related to land, stewardship and futures. Developing Linda Tuhiwai Smith's five dimensions of decolonial theorisation, the article considers ‘voice' as a complex and dynamic formulation including regimes of power: funding, legacies of dispossession and ongoing marginalisation and highlighting the achievements of young people’s formulation of the stories of their world

Analgesic and Anti-Inflammatory Effects of the Novel Semicarbazide-Sensitive Amine-Oxidase Inhibitor SzV-1287 in Chronic Arthritis Models of the Mouse.

Semicarbazide-sensitive amine oxidase (SSAO) catalyses oxidative deamination of primary amines. Since there is no data about its function in pain and arthritis mechanisms, we investigated the effects of our novel SSAO inhibitor SzV-1287 in chronic mouse models of joint inflammation. Effects of SzV-1287 (20 mg/kg i.p./day) were investigated in the K/BxN serum-transfer and complete Freund's adjuvant (CFA)-evoked active immunization models compared to the reference SSAO inhibitor LJP-1207. Mechanonociception was assessed by aesthesiometry, oedema by plethysmometry, clinical severity by scoring, joint function by grid test, myeloperoxidase activity by luminescence, vascular leakage by fluorescence in vivo imaging, histopathological changes by semiquantitative evaluation, and cytokines by Luminex assay. SzV-1287 significantly inhibited hyperalgesia and oedema in both models. Plasma leakage and keratinocyte chemoattractant production in the tibiotarsal joint, but not myeloperoxidase activity was significantly reduced by SzV-1287 in K/BxN-arthritis. SzV-1287 did not influence vascular and cellular mechanisms in CFA-arthritis, but significantly decreased histopathological alterations. There was no difference in the anti-hyperalgesic and anti-inflammatory actions of SzV-1287 and LJP-1207, but only SzV-1287 decreased CFA-induced tissue damage. Unlike SzV-1287, LJP-1207 induced cartilage destruction, which was confirmed in vitro. SzV-1287 exerts potent analgesic and anti-inflammatory actions in chronic arthritis models of distinct mechanisms, without inducing cartilage damage

Human Nasal Challenge with Streptococcus pneumoniae Is Immunising in the Absence of Carriage

Infectious challenge of the human nasal mucosa elicits immune responses that determine the fate of the host-bacterial interaction; leading either to clearance, colonisation and/or disease. Persistent antigenic exposure from pneumococcal colonisation can induce both humoral and cellular defences that are protective against carriage and disease. We challenged healthy adults intra-nasally with live 23F or 6B Streptococcus pneumoniae in two sequential cohorts and collected nasal wash, bronchoalveolar lavage (BAL) and blood before and 6 weeks after challenge. We hypothesised that both cohorts would successfully become colonised but this did not occur except for one volunteer. The effect of bacterial challenge without colonisation in healthy adults has not been previously assessed. We measured the antigen-specific humoral and cellular immune responses in challenged but not colonised volunteers by ELISA and Flow Cytometry. Antigen-specific responses were seen in each compartment both before and after bacterial challenge for both cohorts. Antigen-specific IgG and IgA levels were significantly elevated in nasal wash 6 weeks after challenge compared to baseline. Immunoglobulin responses to pneumococci were directed towards various protein targets but not capsular polysaccharide. 23F but not 6B challenge elevated IgG anti-PspA in BAL. Serum immunoglobulins did not increase in response to challenge. In neither challenge cohort was there any alteration in the frequencies of TNF, IL-17 or IFNγ producing CD4 T cells before or after challenge in BAL or blood. We show that simple, low dose mucosal exposure with pneumococci may immunise mucosal surfaces by augmenting anti-protein immunoglobulin responses; but not capsular or cellular responses. We hypothesise that mucosal exposure alone may not replicate the systemic immunising effect of experimental or natural carriage in humans