Early prediction of median survival among a large AIDS surveillance cohort

<p>Abstract</p> <p>Background</p> <p>For individuals with AIDS, data exist relatively soon after diagnosis to allow estimation of "early" survival quantiles (<it>e.g.</it>, the 0.10, 0.15, 0.20 and 0.30 quantiles, etc.). Many years of additional observation must elapse before median survival, a summary measure of survival, can be estimated accurately. In this study, a new approach to predict AIDS median survival is presented and its accuracy tested using AIDS surveillance data.</p> <p>Methods</p> <p>The data consisted of 96,373 individuals who were reported to the HIV/AIDS Reporting System of the California Department of Health Services Office of AIDS as of December 31, 1996. We defined cohorts based on quarter year of diagnosis (<it>e.g.</it>, the "931" cohort consists of individuals diagnosed with AIDS in the first quarter of 1993). We used early quantiles (estimated using the Inverse Probability of Censoring Weighted estimator) of the survival distribution to estimate median survival by assuming a linear relationship between the earlier quantiles and median survival. From this model, median survival was predicted for cohorts for which a median could not be estimated empirically from the available data. This prediction was compared with the actual medians observed when using updated survival data reported at least five years later.</p> <p>Results</p> <p>Using the 0.15 quantile as the predictor and the data available as of December 31, 1996, we were able to predict the median survival of four cohorts (933, 934, 941, and 942) to be 34, 34, 31, and 29 months. Without this approach, there were insufficient data with which to make any estimate of median survival. The actual median survival of these four cohorts (using data as of December 31, 2001) was found to be 32, 40, 46, and 80 months, suggesting that the accuracy for this approach requires a minimum of three years to elapse from diagnosis to the time an accurate prediction can be made.</p> <p>Conclusion</p> <p>The results of this study suggest that early and accurate prediction of median survival time after AIDS diagnosis may be possible using early quantiles of the survival distribution. The methodology did not seem to work well during a period of significant change in survival as observed with highly active antiretroviral treatment, but results suggest that it may work well in a time of more gradual improvement in survival.</p

Prevalence of chronic kidney disease among people living with HIV/AIDS in Burundi: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Since little is known about chronic kidney disease (CKD) among people living with HIV/AIDS (PLWHA) in Sub-Saharan Africa, the prevalence and nature of CKD were assessed in Burundi through a multicenter cross-sectional study.</p> <p>Methods</p> <p>Patients underwent assessments at baseline and 3 months later. Glomerular Filtration Rate (GFR) was estimated using abbreviated 4-variable Modification of Diet in Renal Diseases (MDRD) and Cockroft-Gault estimation methods. Patients were classified at month 3 into various CKD stages using the National Kidney Foundation (NKF) definition, which combines GFR and urinary abnormalities. Risk factors for presence of proteinuria (PRO) and aseptic leukocyturia (LEU) were further analyzed using multiple logistic regression.</p> <p>Results</p> <p>Median age of the patients in the study (N = 300) was 40 years, 70.3% were female and 71.7% were on highly active antiretroviral therapy. Using the MDRD method, CKD prevalence in patients was 45.7%, 30.2% of whom being classified as stage 1 according to the NKF classification, 13.5% as stage 2 and 2% as stage 3. No patient was classified as stage 4 or 5. Among CKD patients with urinary abnormality, PRO accounted for 6.1% and LEU for 18.4%. Significant associations were found between LEU and non-steroidal anti-inflammatory drug (NSAID) use, previous history of tuberculosis, low body mass index and female gender and between PRO and high viral load.</p> <p>Conclusion</p> <p>Our study, using a very sensitive definition for CKD evaluation, suggests a potentially high prevalence of CKD among PLWHA in Burundi. Patients should be regularly monitored and preventative measures implemented, such as monitoring NSAID use and adjustment of drug dosages according to body weight. Urine dipsticks could be used as a screening tool to detect patients at risk of renal impairment.</p

A comparison of nicotine dose estimates in smokers between filter analysis, salivary cotinine, and urinary excretion of nicotine metabolites

RATIONALE: Nicotine uptake during smoking was estimated by either analyzing the metabolites of nicotine in various body fluids or by analyzing filters from smoked cigarettes. However, no comparison of the filter analysis method with body fluid analysis methods has been published. OBJECTIVES: Correlate nicotine uptake estimates between filter analysis, salivary cotinine, and urinary excretion of selected nicotine metabolites to determine the suitability of these methods in estimating nicotine absorption in smokers of filtered cigarettes. MATERIALS AND METHODS: A 5-day clinical study was conducted with 74 smokers who smoked 1–19 mg Federal Trade Commission tar cigarettes, using their own brands ad libitum. Filters were analyzed to estimate the daily mouth exposure of nicotine. Twenty-four-hour urine samples were collected and analyzed for nicotine, cotinine, and 3′-hydroxycotinine plus their glucuronide conjugates. Saliva samples were collected daily for cotinine analysis. RESULTS: Each method correlated significantly (p < 0.01) with the other two. The best correlation was between the mouth exposure of nicotine, as estimated by filter analysis, and urinary nicotine plus metabolites. Multiple regression analysis implies that saliva cotinine and urinary output are dependent on nicotine mouth exposure for multiple days. Creatinine normalization of the urinary metabolites degrades the correlation with mouth exposure. CONCLUSIONS: The filter analysis method was shown to correlate with more traditional methods of estimating nicotine uptake. However, because filter analysis is less complicated and intrusive, subjects can collect samples easily and unsupervised. This should enable improvements in study compliance and future study designs

Dorstone Hill: A Neolithic timescape

Studies of early fourth-millennium BC Britain have typically focused on the Early Neolithic sites of Wessex and Orkney; what can the investigation of sites located in areas beyond these core regions add? The authors report on excavations (2011-2019) at Dorstone Hill in Herefordshire, which have revealed a remarkable complex of Early Neolithic monuments: three long barrows constructed on the footprints of three timber buildings that had been deliberately burned, plus a nearby causewayed enclosure. A Bayesian chronological model demonstrates the precocious character of many of the site's elements and strengthens the evidence for the role of tombs and houses/halls in the creation and commemoration of foundational social groups in Neolithic Britain

Internalization Dissociates β2-Adrenergic Receptors

G protein-coupled receptors (GPCRs) self-associate as dimers or higher-order oligomers in living cells. The stability of associated GPCRs has not been extensively studied, but it is generally thought that these receptors move between the plasma membrane and intracellular compartments as intact dimers or oligomers. Here we show that β2-adrenergic receptors (β2ARs) that self-associate at the plasma membrane can dissociate during agonist-induced internalization. We use bioluminescence-resonance energy transfer (BRET) to monitor movement of β2ARs between subcellular compartments. BRET between β2ARs and plasma membrane markers decreases in response to agonist activation, while at the same time BRET between β2ARs and endosome markers increases. Energy transfer between β2ARs is decreased in a similar manner if either the donor- or acceptor-labeled receptor is mutated to impair agonist binding and internalization. These changes take place over the course of 30 minutes, persist after agonist is removed, and are sensitive to several inhibitors of arrestin- and clathrin-mediated endocytosis. The magnitude of the decrease in BRET between donor- and acceptor-labeled β2ARs suggests that at least half of the receptors that contribute to the BRET signal are physically segregated by internalization. These results are consistent with the possibility that β2ARs associate transiently with each other in the plasma membrane, or that β2AR dimers or oligomers are actively disrupted during internalization

The Transmembrane Domain of CEACAM1-4S Is a Determinant of Anchorage Independent Growth and Tumorigenicity

CEACAM1 is a multifunctional Ig-like cell adhesion molecule expressed by epithelial cells in many organs. CEACAM1-4L and CEACAM1-4S, two isoforms produced by differential splicing, are predominant in rat liver. Previous work has shown that downregulation of both isoforms occurs in rat hepatocellular carcinomas. Here, we have isolated an anchorage dependent clone, designated 253T-NT that does not express detectable levels of CEACAM1. Stable transfection of 253-NT cells with a wild type CEACAM1-4S expression vector induced an anchorage independent growth in vitro and a tumorigenic phenotype in vivo. These phenotypes were used as quantifiable end points to examine the functionality of the CEACAM1-4S transmembrane domain. Examination of the CEACAM1 transmembrane domain showed N-terminal GXXXG dimerization sequences and C-terminal tyrosine residues shown in related studies to stabilize transmembrane domain helix-helix interactions. To examine the effects of transmembrane domain mutations, 253-NT cells were transfected with transmembrane domain mutants carrying glycine to leucine or tyrosine to valine substitutions. Results showed that mutation of transmembrane tyrosine residues greatly enhanced growth in vitro and in vivo. Mutation of transmembrane dimerization motifs, in contrast, significantly reduced anchorage independent growth and tumorigenicity. 253-NT cells expressing CEACAM1-4S with both glycine to leucine and tyrosine to valine mutations displayed the growth-enhanced phenotype of tyrosine mutants. The dramatic effect of transmembrane domain mutations constitutes strong evidence that the transmembrane domain is an important determinant of CEACAM1-4S functionality and most likely by other proteins with transmembrane domains containing dimerization sequences and/or C-terminal tyrosine residues

The effect of disgust-related side-effects on symptoms of depression and anxiety in people treated for cancer: a moderated mediation model

As maladaptive disgust responses are linked to mental health problems, and cancer patients may experience heightened disgust as a result of treatments they receive, we explored the associations between disgust-related side-effects and symptoms of depression and anxiety in people treated for cancer. One hundred and thirty two (83 women, Mage = 57.48 years) participants answered questions about their treatments, side-effects, disgust responding, and mental health. Experiencing bowel and/or bladder problems, sickness and/or nausea (referred to here as “core” disgust-related side-effects) was significantly related to greater symptoms of depression and borderline increased anxiety. Further, these links were explained by a moderated mediation model, whereby the effects of core disgust side-effects on depression and anxiety were mediated by (physical and behavioural) self-directed disgust, and disgust propensity moderated the effect of core disgust side-effects on self-disgust. These findings stress the importance of emotional responses, like disgust, in psychological adaptation to the side-effects of cancer treatments

Structural Alterations in a Component of Cytochrome c Oxidase and Molecular Evolution of Pathogenic Neisseria in Humans

Three closely related bacterial species within the genus Neisseria are of importance to human disease and health. Neisseria meningitidis is a major cause of meningitis, while Neisseria gonorrhoeae is the agent of the sexually transmitted disease gonorrhea and Neisseria lactamica is a common, harmless commensal of children. Comparative genomics have yet to yield clear insights into which factors dictate the unique host-parasite relationships exhibited by each since, as a group, they display remarkable conservation at the levels of nucleotide sequence, gene content and synteny. Here, we discovered two rare alterations in the gene encoding the CcoP protein component of cytochrome cbb3 oxidase that are phylogenetically informative. One is a single nucleotide polymorphism resulting in CcoP truncation that acts as a molecular signature for the species N. meningitidis. We go on to show that the ancestral ccoP gene arose by a unique gene duplication and fusion event and is specifically and completely distributed within species of the genus Neisseria. Surprisingly, we found that strains engineered to express either of the two CcoP forms conditionally differed in their capacity to support nitrite-dependent, microaerobic growth mediated by NirK, a nitrite reductase. Thus, we propose that changes in CcoP domain architecture and ensuing alterations in function are key traits in successive, adaptive radiations within these metapopulations. These findings provide a dramatic example of how rare changes in core metabolic proteins can be connected to significant macroevolutionary shifts. They also show how evolutionary change at the molecular level can be linked to metabolic innovation and its reversal as well as demonstrating how genotype can be used to infer alterations of the fitness landscape within a single host