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

Predicting Precipitation over the Northwest: from Weather Forecasts to Climate Change

Cliff Mass will speak about the unique precipitation patterns in the Northwest. This has major societal impacts, such as flood control and damaging storms, usually associated with the "Pineapple Express." There has been major progress in understanding and predicting precipitation over this region during the past several decades. Mass will describe high resolution numerical simulations, which have become a central tool. He will also review the problems with these forecasts. He will describe the latest computer model prediction approaches, which use ensembles. Finally, he will consider the effects of global warming on Northwest precipitation

Aspects of effective mesoscale, . . .

This study developed and evaluated a short-range ensemble forecasting (SREF) system with the goal of producing useful, mesoscale forecast probability (FP). Real-time, 0 to 48-h SREF predictions were produced and analyzed for 129 cases over the Pacific Northwest. Eight analyses from different operational forecast centers were used as initial conditions for running the Fifth-Generation Pennsylvania State University−National Center of Atmospheric Research Mesoscale Model (MM5). Model error is a large source of forecast uncertainty and must be accounted for to maximize SREF utility, particularly for mesoscale, sensible weather phenomena. Although inclusion of model diversity improved FP skill (both reliability and resolution) and increased dispersion toward statistical consistency, dispersion remained inadequate. Conversely, systematic model errors (i.e., biases) must be removed from a SREF since they contribute to forecast error but not to forecast uncertainty. A grid-based, two-week, running-mean bias correction was shown to improve FP skill through: 1) better reliability by adjusting the ensemble mean toward the mean of the verification values, and 2) better resolution by removing unrepresentative ensemble variance. Comparison of the multimodel (each member uses a unique model) and varied-model (each member uses a unique version of MM5) approaches indicated that the multimodel SREF exhibited greater dispersion and superior performance. It was also found that an ensemble of unequally likely members can be skillful as long as each member occasionally performs well. Lastly, smaller grid spacing led to greater ensemble spread as smaller scales of motion were modeled. This study indicates substantial utility in current SREF systems and suggests several avenues for further improvement

F.: An evaluation of a high-resolution hydrometeorological modeling system for prediction of a coolseason flood event in a coastal mountainous watershed

ABSTRACT This study used the atmospheric Fifth-Generation Pennsylvania State University-National Center for Atmospheric Research Mesoscale Model (MM5) and the University of Washington Distributed Hydrology-SoilVegetation Model (DHSVM) for the simulation of a complex rain-on-snow flood event that occurred from 28 December 1996 to 3 January 1997 on the 1560-km 2 Snoqualmie River watershed in western Washington. Three control simulations were created with MM5 applied at 36-, 12-, and 4-km horizontal spacing and DHSVM at a horizontal spacing of 100 m. Results showed that the accuracy of the atmospheric fields increased with higher horizontal resolution, although underforecasting of precipitation was evident for all three resolutions. Simulated river flows captured 67% (36 km), 75% (12 km), and 72% (4 km) of the total flow and 52% (36 km), 58% (12 km), and 62% (4 km) of the event peak flow. Several sensitivity simulations of the modeling system (4-km spacing only) were conducted to improve on the control simulations. Adjusting the MM5 precipitation using observations led to a streamflow forecast that captured 90% of the total flow. Reduction of the model high-wind speed bias improved the simulated snowmelt, although the resulting effects on streamflow were relatively small. A sensitivity experiment that included the precipitation from an intense rainband that was not captured by MM5 revealed the importance of this highintensity, short-lived feature; simulated streamflow from this experiment captured 93% of the total flow and over 82% of the peak flow, with a 4-h timing error. A final set of sensitivity simulations, using both a higher-and lower-elevation observation as the sole forcing of DHSVM (no MM5), revealed strong sensitivity to the observation location; using a slightly displaced (ϳ8 km) lower-elevation observation produced river flows that differed by over 18%. Both of the resulting simulated river flows forced by the two-station method were significantly lower than both the observed flows (35% and 53% of total observed flow) and the flows simulated with the MM5 input fields. A major cause of this low flow was that the temperatures at the observation locations were located in gap regions of the Cascade Mountains, were not representative of the basin-average temperature, and therefore caused too much precipitation to fall as snow

Convection-Kelvin Wave Coupling in a Global Convection-Permitting Model

A convectively coupled equatorial Kelvin wave (CCKW) was observed over the equatorial Indian Ocean in early November 2011 during the DYNAMO field campaign. This study examines the structure of the CCKW event using two simulations made using the MPAS model: one with 3-km grid spacing without convective parameterization and another with a 15-km grid and parameterized convection. Both simulations qualitatively capture the observed structure of the CCKW, including its vertical tilt and progression of cloud/precipitation structures. The two simulations, however, differ substantially in the amplitude of the CCKW-Associated precipitation. While the 3-km run realistically captures the observed modulation of precipitation by the CCKW, the 15-km simulation severely underestimates its magnitude. To understand the difference between the two MPAS simulations regarding wave-convection coupling within the CCKW, the relationship of precipitation with convective inhibition, saturation fraction, and surface turbulent fluxes is investigated. Results show that the 15-km simulation underestimates the magnitude of the CCKW precipitation peak in association with its unrealistically linear relationship between moisture and precipitation. Precipitation, both in observations and the 3-km run, is predominantly controlled by saturation fraction and this relationship is exponential. In contrast, the parameterized convection in the 15-km run is overly sensitive to convective inhibition and not sensitive enough to environmental moisture. The implications of these results on CCKW theories are discussed.Y