Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Physicochemical Dynamics, Microbial Community Patterns, and Reef Growth in Coral Reefs of the Central Red Sea

Coral reefs in the Red Sea belong to the most diverse and productive reef ecosystems worldwide, although they are exposed to strong seasonal variability, high temperature, and high salinity. These factors are considered stressful for coral reef biota and challenge reef growth in other oceans, but coral reefs in the Red Sea thrive despite these challenges. In the central Red Sea high temperatures, high salinities, and low dissolved oxygen on the one hand reflect conditions that are predicted for ‘future oceans’ under global warming. On the other hand, alkalinity and other carbonate chemistry parameters are considered favourable for coral growth. In coral reefs of the central Red Sea, temperature and salinity follow a seasonal cycle, while chlorophyll and inorganic nutrients mostly vary spatially, and dissolved oxygen and pH fluctuate on the scale of hours to days. Within these strong environmental gradients micro- and macroscopic reef communities are dynamic and demonstrate plasticity and acclimatisation potential. Epilithic biofilm communities of bacteria and algae, crucial for the recruitment of reef-builders, undergo seasonal community shifts that are mainly driven by changes in temperature, salinity, and dissolved oxygen. These variables are predicted to change with the progression of global environmental change and suggest an immediate effect of climate change on the microbial community composition of biofilms. Corals are so-called holobionts and associate with a variety of microbial organisms that fulfill important functions in coral health and productivity. For instance, coral-associated bacterial communities are more specific and less diverse than those of marine biofilms, and in many coral species in the central Red Sea they are dominated by bacteria from the genus Endozoicomonas. Generally, coral microbiomes align with ecological differences between reef sites. They are similar at sites where these corals are abundant and successful. Coral microbiomes reveal a measurable footprint of anthropogenic influence at polluted sites. Coral-associated communities of endosymbiotic dinoflagellates in central Red Sea corals are dominated by Symbiodinium from clade C. Some corals harbour the same specific symbiont with a high physiological plasticity throughout their distribution range, while others maintain a more flexible association with varying symbionts of high physiological specificity over depths, seasons, or reef locations. The coral-Symbiodinium endosymbiosis drives calcification of the coral skeleton, which is a key process that provides maintenance and formation of the reef framework. Calcification rates and reef growth are not higher than in other coral reef regions, despite the beneficial carbonate chemistry in the central Red Sea. This may be related to the comparatively high temperatures, as indicated by reduced summer calcification and long-term slowing of growth rates that correlate with ocean warming trends. Indeed, thermal limits of abundant coral species in the central Red Sea may have been exceeded, as evidenced by repeated mass bleaching events during previous years. Recent comprehensive baseline data from central Red Sea reefs allow for insight into coral reef functioning and for quantification of the impacts of environmental change in the region