Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK.

OBJECTIVES: To assess the incidence, predictors, and outcomes of Kaposi sarcoma-associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings. DESIGN: Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK. METHODS: KS-IRIS case definition was standardized across sites. Cox regression and Kaplan-Meier survival analysis were used to identify the incidence and predictors of KS-IRIS and Kaposi sarcoma-associated mortality. RESULTS: Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (P=0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02-8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26-6.94); and plasma HIV-1 RNA more than 5 log₁₀ copies/ml (hazard ratio 2.14, 95% CI 1.25-3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23-7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62-48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09-5.05), pre-ART CD4 cell count less than 200 cells/μl (hazard ratio 2.04, 95% CI 0.99-4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94-4.77). CONCLUSION: KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa

Compartmentalized T cell profile in the lungs of patients with HIV-1-associated pulmonary Kaposi sarcoma.

Pulmonary Kaposi sarcoma (pKS) caused by Human herpesvirus 8 (HHV-8) is a devastating form of KS in patients with advanced acquired immunodeficiency syndrome (AIDS) and is associated with increased morbidity and mortality. Blood T cells play a central role in the response of HIV-1 and HHV-8. However, little information is available on T cells in the alveolar space of HIV-1-associated pKS patients.Therefore, we examined CD8+ and CD4+ T cells in the alveolar space in comparison with the blood of patients with pKS. We recruited 26 HIV-1 positive patients with KS, including 15 patients with pKS. Bronchoalveolar lavage (BAL) cells and blood mononuclear cells were analyzed for T cell memory phenotypes, surface markers associated with exhaustion, and intracellular cytokine staining (ICS) using flow cytometry. HIV-1 and HHV-8 viral loads were measured in plasma by quantitative PCR.BAL T cells showed reduced inflammatory capacities and significantly diminished polyfunctionality compared to blood T cells from patients with pKS. This was not accompanied by increased expression of exhaustion markers, such as TIM-3 and PD-1.More importantly, we found a negative correlation between the production of MIP1-β and TNF-α in T cells in BAL and blood, indicating compartmentalised immune responses to pKS and accentuated chronic HIV-1/HHV-8 pathogenesis via T cells in the lungs of people with pKS

Differential effects of antiretroviral treatment on immunity and gut microbiome composition in people living with HIV in rural versus urban Zimbabwe.

BACKGROUND: The widespread availability of antiretroviral therapy (ART) has dramatically reduced mortality and improved life expectancy for people living with HIV (PLWH). However, even with HIV-1 suppression, chronic immune activation and elevated inflammation persist and have been linked to a pro-inflammatory gut microbiome composition and compromised intestinal barrier integrity. PLWH in urban versus rural areas of sub-Saharan Africa experience differences in environmental factors that may impact the gut microbiome and immune system, in response to ART, yet this has not previously been investigated in these groups. To address this, we measured T cell activation/exhaustion/trafficking markers, plasma inflammatory markers, and fecal microbiome composition in PLWH and healthy participants recruited from an urban clinic in the city of Harare, Zimbabwe, and a district hospital that services surrounding rural villages. PLWH were either ART naïve at baseline and sampled again after 24 weeks of first-line ART and the antibiotic cotrimoxazole or were ART-experienced at both timepoints. RESULTS: Although expected reductions in the inflammatory marker IL-6, T-cell activation, and exhaustion were observed with ART-induced viral suppression, these changes were much more pronounced in the urban versus the rural area. Gut microbiome composition was the most highly altered from healthy controls in ART experienced PLWH, and characterized by both reduced alpha diversity and altered composition. However, gut microbiome composition showed a pronounced relationship with T cell activation and exhaustion in ART-naïve PLWH, suggesting a particularly significant role for the gut microbiome in disease progression in uncontrolled infection. Elevated immune exhaustion after 24 weeks of ART did correlate with both living in the rural location and a more Prevotella-rich/Bacteroides-poor microbiome type, suggesting a potential role for rural-associated microbiome differences or their co-variates in the muted improvements in immune exhaustion in the rural area. CONCLUSION: Successful ART was less effective at reducing gut microbiome-associated inflammation and T cell activation in PLWH in rural versus urban Zimbabwe, suggesting that individuals on ART in rural areas of Zimbabwe may be more vulnerable to co-morbidity related to sustained immune dysfunction in treated infection. Video Abstract

The extraordinary universe of Peter Apian: technical investigation of five copies of a 16th-century astronomical book

AbstractIn 1540, in Ingolstadt, Germany, the influential astronomer and printer Peter Apian produced the Astronomicum Caesareum: a printed and hand-coloured astronomical book visualising the Ptolemaic universe through the use of diagrams and wheelcharts, worthy of his imperial patron, Charles V. About 130 copies have survived to this day, with varying degrees of paper quality and level of decoration, and only eleven volumes are considered deluxe copies. We thoroughly analysed one deluxe volume held at the Fitzwilliam Museum, Cambridge, and compared the results with four (one deluxe and three standard) other copies from institutions in the UK. A non-invasive analytical protocol was applied, including extensive microscopy, fibre-optic reflectance spectroscopy (FORS), X-ray spectroscopy (XRF), macroscale XRF (MA-XRF) and Raman spectroscopy. The most interesting pages were chosen based on art-historical evidence and the variety of the colour palette, including on volvelles (wheelcharts) and coats of arms. Following a systematic approach, we analysed the same pages in each volume, gathering information on the colour palette in all the volumes. The type of paper and the presence of watermarks were also documented. A wide range of materials was identified in the five copies, including red, purple and yellow organic dyes, lead white, verdigris, vermilion, azurite, indigo, smalt, and lead–tin yellow. Mosaic gold was used to embellish certain paint passages in the deluxe volumes and metals (gold and silver) were applied on some pages. The comprehensive findings were essential to identify specific traits related to Apian’s workshop, to differentiate deluxe from standard copies, to suggest an order of production of the copies, and to provide new information on this landmark book and more generally in an under-researched field of study.</jats:p

The extraordinary universe of Peter Apian: technical investigation of five copies of a 16th-century astronomical book

Funder: Cambridge Humanities Research GrantsIn 1540, in Ingolstadt, Germany, the influential astronomer and printer Peter Apian produced the Astronomicum Caesareum: a printed and hand-coloured astronomical book visualising the Ptolemaic universe through the use of diagrams and wheelcharts, worthy of his imperial patron, Charles V. About 130 copies have survived to this day, with varying degrees of paper quality and level of decoration, and only eleven volumes are considered deluxe copies. We thoroughly analysed one deluxe volume held at the Fitzwilliam Museum, Cambridge, and compared the results with four (one deluxe and three standard) other copies from institutions in the UK. A non-invasive analytical protocol was applied, including extensive microscopy, fibre-optic reflectance spectroscopy (FORS), X-ray spectroscopy (XRF), macroscale XRF (MA-XRF) and Raman spectroscopy. The most interesting pages were chosen based on art-historical evidence and the variety of the colour palette, including on volvelles (wheelcharts) and coats of arms. Following a systematic approach, we analysed the same pages in each volume, gathering information on the colour palette in all the volumes. The type of paper and the presence of watermarks were also documented. A wide range of materials was identified in the five copies, including red, purple and yellow organic dyes, lead white, verdigris, vermilion, azurite, indigo, smalt, and lead-tin yellow. Mosaic gold was used to embellish certain paint passages in the deluxe volumes and metals (gold and silver) were applied on some pages. The comprehensive findings were essential to identify specific traits related to Apian’s workshop, to differentiate deluxe from standard copies, to suggest an order of production of the copies, and to provide new information on this landmark book and more generally in an under-researched field of study

The Pigments of British Medieval Illuminators: A Scientific and Cultural Study

This comprehensive and richly illustrated volume is the first-ever history of British medieval illuminators’ pigments. It rests on first-hand investigation, with optimal scientific techniques, of a wide selection of manuscripts, ranging in date from the seventh century to the fifteenth. It provides an authoritative, engaging and accessible guide to this understudied field, for historians, art historians, librarians, conservators, heritage scientists, and anyone interested in the art, culture and techniques of book illumination

Strengthening research governance for sustainable research: experiences from three Zimbabwean universities

A robust research system requires a robust governance framework. As part of the Medical Education Partnership Initiative, three Zimbabwean universities partnered with two US universities in a project to strengthen research governance in the Zimbabwean universities. The project aimed at (1) developing research policies; (2) strengthening central research management offices; (3) developing a research administration curriculum; and (4) enhancing awareness about the role and relevance of research administration in other universities and research institutions in Zimbabwe. Through the efforts of the partners, a generic research policy was developed and successfully adapted by the institutions. A curriculum was drafted, and module development experts are helping to finalize the curriculum to meet university requirements for accreditation of training research administrators. The Association of Research Managers of Zimbabwe was established to promote information sharing and professionalize research administration. The consortium approach enabled rapid and smooth development and adoption of research policies in the institutions. It also helped researchers and managers accept research administration as an essential structure and function. The experiences and lessons learned are reported here to benefit other institutions and consortia

Differential effects of antiretroviral treatment on immunity and gut microbiome composition in people living with HIV in rural versus urban Zimbabwe

The widespread availability of antiretroviral therapy (ART) for people living with HIV (PLWH) has dramatically reduced mortality and improved life expectancy. However, even with suppression of HIV-1 replication, chronic immune activation and elevated inflammation persist. Chronic immune activation has been linked to a pro-inflammatory gut microbiome composition, exacerbated by compromised intestinal barrier integrity that occurs after HIV infection. Individuals living in urban versus rural areas of sub-Saharan Africa have differences in environmental factors that may impact gut microbiome composition, yet immune phenotype and gut microbiome composition response to ART in PLWH living in rural versus urban areas of sub-Saharan Africa have not been compared. Here, we measured immune phenotypes and fecal microbiome composition in PLWH and healthy participants recruited from the urban Mabvuku polyclinic in the city of Harare, Zimbabwe and the Mutoko District hospital located in a district 146 km from Harare that services surrounding rural villages. PLWH were either ART naïve at baseline and sampled again after 24 weeks of treatment with efavirenz/lamivudine/tenofovir disoproxil fumarate (EFV/3TC/TDF) and the prophylactic antibiotic cotrimoxazole or were ART experienced at both timepoints. Although expected reductions in the inflammatory marker IL-6, T-cell activation, and exhaustion were observed in individuals who had suppressed HIV-1 with treatment, these changes were much more pronounced when considering individuals in the urban and not the rural area. Gut microbiome composition showed more marked differences from healthy controls in the ART experienced compared to ART naïve cohort, and consistent longitudinal changes were also observed in ART naïve PLWH after 24 weeks of treatment, including a reduction in alpha diversity and altered composition. However, gut microbiome composition showed a more pronounced relationship with chronic immune activation and exhaustion phenotypes in the ART naïve compared to ART experienced PLWH, suggesting a particularly significant role for the gut microbiome in disease progression in uncontrolled infection

Antiretroviral initiation is associated with increased skeletal muscle area and fat content.

ObjectiveA greater burden of physical function impairment occurs in HIV-infected adults; the impact of antiretroviral therapy (ART) initiation on muscle density (less dense = more fat), a measure of muscle quality, is unknown.DesignAIDS Clinical Trials Group Study A5260s, a cardiometabolic substudy of A5257, randomized HIV-infected, ART-naive adults to ritonavir-boosted atazanavir, darunavir, or raltegravir with tenofovir/emtricitabine backbone. Single-slice abdominal computed tomography scans from baseline and week 96 were reanalyzed for total and lean muscle area and density.MethodsTwo-sample t-tests described the differences between baseline and week 96 variables. Linear regression analysis was used to explore the role of a priori identified variables and potential confounders.ResultsParticipants (n = 235) were mostly men (90%); 31% were Black non-Hispanic; 21% were Hispanic. Over 96 weeks, small but significant increases were seen in oblique/transverse abdominal, rectus, and psoas muscle total area (range 0.21-0.83 cm; P &lt; 0.05) but not the lean muscle component (all P ≥ 0.33). Significant decreases in overall density, consistent with increases in fat, were seen in all muscle groups (range -0.87 to -2.4 HU; P &lt; 0.01); for the lean muscle component, only decreases in oblique/transverse abdominal and rectus reached statistical significance (P &lt; 0.05). In multivariable analyses, Black race was associated with increased muscle density and female sex with decreased density; treatment arm was not associated with changes in mass or density.ConclusionThe ART-associated increase in muscle area, regardless of regimen, is likely a reflection of increased fat within the muscle. The consequences of fatty infiltration of muscle on subsequent muscle function require further investigation