Has the Rate of CD4 Cell Count Decline before Initiation of Antiretroviral Therapy Changed over the Course of the Dutch HIV Epidemic among MSM?

Introduction:Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline.Methods:Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

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

Rapport van het Veluwe-onderzoek : een onderzoek van natuur, landschap en cultuurhistorie ten behoeve van de ruimtelijke ordening en het recreatie beleid

Onderzoek Stibok

Schema cyclohexanon uit phenol

Document(en) uit de collectie Chemische ProcestechnologieDelftChemTechApplied Science

Dawn Aerospace Mk-III Spaceplane Aerothermodynamic Analysis

Dawn Aerospace is developing a horizontal take-off and landing two stage to orbit partially-reusable launcher concept. The re-usable first stage spaceplane operates on a return to launch site trajectory and integrates into the existing airspace, flying as an UAV. For any re-entry vehicle the design needs to account for aerothermodynamic behaviour around the vehicle, to ensure the structure can survive the re-entry temperatures. The unique mission of the Mk-III means the thermal design considerations are unique and provide a new engineering challenge and research topic. This thesis investigates the aerothermodynamic behaviour of the Mk-III flow and structure. A loosely coupled model was created for this purpose, which couples engineering methods to predict the aerothermodynamics and the thermal behaviour of the structure. The coupling is done by transferring the external skin temperature and convective heat flux between the two simulations. The primary research question for this thesis is “What thermal protection systems have potential to be implemented on the Dawn Aerospace Mk-III spaceplane for a range of different design trajectories.” Two thermal protection systems (TPS) and material choices have been identified as potential solutions. The first is a fully titanium structure, which can handle the temperature experienced by the Mk-III for all trajectories at every point along the vehicle. The second is a combined titanium and BMI CF structure with an insulation layer on the BMI CF. The titanium is required for the temperatures experienced on the vehicle’s leading edges, while the BMI CF has been identified as suitable in areas away from the leading edge if protected by an insulation TPS. A benefit this option produces is that the insulation layer can be changed in thickness to lighten the vehicle for lower design trajectories, therefore creating different vehicles for different trajectories. However, combining a metal with a composite could pose manufacturing issues such as cost for different manufacturing processes and joining problems. This thesis could not properly trade-off between these two options due to it being outside the scope of this thesis and due to limitations in detailed structural knowledge. These two material choices were chosen from four materials analysed in the thesis and four different TPS. Other TPS were not suitable at decreasing the structural temperature for the Mk-III mission or had an unjustifiable weight penalty. The other material choices would have been suitable in certain situations but were heavier than the current proposed options and might have required a TPS. This thesis provides valuable insight in what suitable material and TPS choices could be for the Mk-III mission. It also shows that for any future material and TPS choice to be made, a comprehensive structural analysis is required. Mass is a key trade-off parameter between the two proposed solutions and a better structural analysis is required for any further trade-off.Aerospace Engineerin