Estimated dates of detectable infection (EDDIs) as an improvement upon Fiebig staging for HIV infection dating.

Accurate methods for determining the duration of HIV infection at the individual level are valuable in many settings, including many critical research studies and in clinical practice (especially for acute infection). Since first published in 2003, the 'Fiebig staging system' has been used as the primary way of classifying early HIV infection into five sequential stages based on HIV test result patterns in newly diagnosed individuals. However, Fiebig stages can only be assigned to individuals who produce both a negative and a positive test result on the same day, on specific pairs of tests of varying 'sensitivity'. Further, in the past 16 years HIV-testing technology has evolved substantially, and three of the five key assays used to define Fiebig stages are no longer widely used. To address these limitations, we developed an improved and more general framework for estimating the duration of HIV infection by interpreting any combination of diagnostic test results, whether obtained on single or multiple days, into an estimated date of detectable infection, or EDDI. A key advantage of the EDDI method over Fiebig staging is that it allows for the generation of a point estimate, as well as an associated credibility interval for the date of first detectable infection, for any person who has at least one positive and one negative HIV test of any kind. The tests do not have to be run on the same day; they do not have to be run during the acute phase of infection and the method does not rely on any special pairing of tests to define 'stages' of infection. The size of the interval surrounding the EDDI (and therefore the precision of the estimate itself) depends largely on the length of time between negative and positive tests. The EDDI approach is also flexible, seamlessly incorporating any assay for which there is a reasonable diagnostic delay estimate. An open-source, free online tool includes a user-updatable curated database of published diagnostic delays. HIV diagnostics have evolved tremendously since that original publication more than 15 years ago, and it is time to similarly evolve the methods used to estimate timing of infection. The EDDI method is a flexible and rigorous way to estimate the timing of HIV infection in a continuously evolving diagnostic landscape.

Detection of IgG3 antibodies specific to the human immunodeficiency virus type 1 (HIV-1) p24 protein as marker for recently acquired infection.

Reducing the risk of human immunodeficiency virus type 1 (HIV-1) transmission is still a public health priority. The development of effective control strategies relies on the quantification of the effects of prophylactic and therapeutic measures in disease incidence. Although several assays can be used to estimate HIV incidence, these estimates are limited by the poor performance of these assays in distinguishing recent from long-standing infections. To address such limitation, we have developed an assay to titrate p24-specific IgG3 antibodies as a marker of recent infection. The assay is based on a recombinant p24 protein capable to detect total IgG antibodies in sera using a liquid micro array and enzyme-linked immunosorbent assay. Subsequently, the assay was optimised to detect and titrate anti-p24 IgG3 responses in a panel of sequential specimens from seroconverters over 24 months. The kinetics of p24-specific IgG3 titres revealed a transient peak in the 4 to 5-month period after seroconversion. It was followed by a sharp decline, allowing infections with less than 6 months to be distinguished from older ones. The developed assay exhibited a mean duration of recent infection of 144 days and a false-recent rate of ca. 14%. Our findings show that HIV-1 p24-specific IgG3 titres can be used as a tool to evaluate HIV incidence in serosurveys and to monitor the efficacy of vaccines and other transmission control strategies.

Moving towards a reliable HIV incidence test - current status, resources available, future directions and challenges ahead.

In 2011 the Incidence Assay Critical Path Working Group reviewed the current state of HIV incidence assays and helped to determine a critical path to the introduction of an HIV incidence assay. At that time the Consortium for Evaluation and Performance of HIV Incidence Assays (CEPHIA) was formed to spur progress and raise standards among assay developers, scientists and laboratories involved in HIV incidence measurement and to structure and conduct a direct independent comparative evaluation of the performance of 10 existing HIV incidence assays, to be considered singly and in combinations as recent infection test algorithms. In this paper we report on a new framework for HIV incidence assay evaluation that has emerged from this effort over the past 5 years, which includes a preliminary target product profile for an incidence assay, a consensus around key performance metrics along with analytical tools and deployment of a standardized approach for incidence assay evaluation. The specimen panels for this evaluation have been collected in large volumes, characterized using a novel approach for infection dating rules and assembled into panels designed to assess the impact of important sources of measurement error with incidence assays such as viral subtype, elite host control of viraemia and antiretroviral treatment. We present the specific rationale for several of these innovations, and discuss important resources for assay developers and researchers that have recently become available. Finally, we summarize the key remaining steps on the path to development and implementation of reliable assays for monitoring HIV incidence at a population level.

[A 31-year-old pregnant woman with refractory hypercalcemia]. / 31-jährige Schwangere mit refraktärer Hyperkalzämie.

A 31-year-old pregnant woman presented with refractory severe hypercalcemia due to an advanced neuroendocrine tumor masquerading as hyperemesis gravidarum. Octreotide therapy and extensive tumor debulking surgery resulted in symptom control. After a prolonged stay in the intensive care unit due to parapneumonic acute respiratory distress syndrome, the patient delivered a healthy child. Neuroendocrine tumors are a rare complication of pregnancy and a seldom cause of refractory hypercalcemia.

Images of Jupiter's Sulfur Ring.

Images of the ring of singly ionized sulfur encircling Jupiter obtained on two successive nights in April 1979 show that the ring characteristics may change dramatically in approximately 24 hours. On the first night the ring was narrow and confined to the magnetic equator inside Io's orbit. On the second it was confined symmetrically about the centrifugal symmetry surface and showed considerable radial structure, including a "fan" extending to Io's orbit. Many of the differences in the ring on the two nights can be explained in terms of differences in sulfur plasma temperature.

Detection of singly ionized oxygen around jupiter.

Forbidden emission from singly ionized oxygen at wavelengths of 3726 and 3729 angstroms has been detected in the inner Jovian magnetosphere. The emission is present between approximately 4 and approximately 7 to 8 Jovian radii from the planet and appears concentrated in the magnetic equator. The line intensity ratio indicates the same plasma characteristics as those derived from observations of forbidden sulfur emission.

Galilean satellites: identification of water frost.

Water frost absorptions have been detected in the infrared reflectivities of Jupiter's Galilean satellites JII (Europa) and JIII (Ganymede). We have determined the percentage of frost-covered surface area to be 50 to 100 percent for JII, 20 to 65 percent for JIII, and possibly 5 to 25 percent for JIV (Callisto). The leading side of JIII has 20 percent more frost cover than the trailing side, which explains the visible geometric albedo differences between the two sides. The reflectivity of the material underlying the frost on JII, JIII, and JIV resembles that of silicates. The surface of JI (Io) may be covered by frost particles much smaller than those on JII and JIII.

Saturn's Rings: Identification of Water Frost.

A recently published infrared spectrum of Saturn's rings resembles our laboratory spectra of water frosts. Furthermore, there are discrepancies between the ring spectrum and ammonia frost spectra in the 2- to 2.5-micro region. These discrepancies render unlikely a reported ideti tification of ammonia frost in the ring spectrum.

Images from galileo of the venus cloud deck.

Images of Venus taken at 418 (violet) and 986 [near-infrared (NIR)] nanometers show that the morphology and motions of large-scale features change with depth in the cloud deck. Poleward meridional velocities, seen in both spectral regions, are much reduced in the NIR In the south polar region the markings in the two wavelength bands are strongly anticorrelated. The images follow the changing state of the upper cloud layer downwind of the subsolar point, and the zonal flow field shows a longitudinal periodicity that may be coupled to the formation of large-scale planetary waves. No optical lightning was detected.

First images of asteroid 243 ida.

The first images of the asteroid 243 Ida from Galileo show an irregular object measuring 56-kilometers by 24 kilometers by 21 kilometers. Its surface is rich in geologic features, including systems of grooves, blocks, chutes, albedo features, crater chains, and a full range of crater morphologies. The largest blocks may be distributed nonuniformly across the surface; lineaments and dark-floored craters also have preferential locations. Ida is interpreted to have a substantial regolith. The high crater density and size-frequency distribution (-3 differential power-law index) indicate a surface in equilibrium with saturated cratering. A minimum model crater age for Ida-and therefore for the Koronis family to which Ida belongs-is estimated at 1 billion years, older than expected.

Lunar impact basins and crustal heterogeneity: new Western limb and far side data from galileo.

Multispectral images of the lunar western limb and far side obtained from Galileo reveal the compositional nature of several prominent lunar features and provide new information on lunar evolution. The data reveal that the ejecta from the Orientale impact basin (900 kilometers in diameter) lying outside the Cordillera Mountains was excavated from the crust, not the mantle, and covers pre-Orientale terrain that consisted of both highland materials and relatively large expanses of ancient mare basalts. The inside of the far side South Pole-Aitken basin (>2000 kilometers in diameter) has low albedo, red color, and a relatively high abundance of iron- and magnesium-rich materials. These features suggest that the impact may have penetrated into the deep crust or lunar mantle or that the basin contains ancient mare basalts that were later covered by highlands ejecta.

Galileo encounter with 951 gaspra: first pictures of an asteroid.

Galileo images of Gaspra reveal it to be an irregularly shaped object (19 by 12 by 11 kilometers) that appears to have been created by a catastrophic collisional disruption of a precursor parent body. The cratering age of the surface is about 200 million years. Subtle albedo and color variations appear to correlate with morphological features: Brighter materials are associated with craters especially along the crests of ridges, have a stronger 1-micrometer absorption, and may represent freshly excavated mafic materials; darker materials exhibiting a significantly weaker 1-micrometer absorption appear concentrated in interridge areas. One explanation of these patterns is that Gaspra is covered with a thin regolith and that some of this material has migrated downslope in some areas.

Galileo multispectral imaging of the north polar and eastern limb regions of the moon.

Multispectral images obtained during the Galileo probe's second encounter with the moon reveal the compositional nature of the north polar regions and the northeastern limb. Mare deposits in these regions are found to be primarily low to medium titanium lavas and, as on the western limb, show only slight spectral heterogeneity. The northern light plains are found to have the spectral characteristics of highlands materials, show little evidence for the presence of cryptomaria, and were most likely emplaced by impact processes regardless of their age.

Galileo's First Images of Jupiter and the Galilean Satellites

The first images of Jupiter, Io, Europa, and Ganymede from the Galileo spacecraft reveal new information about Jupiter's Great Red Spot (GRS) and the surfaces of the Galilean satellites. Features similar to clusters of thunderstorms were found in the GRS. Nearby wave structures suggest that the GRS may be a shallow atmospheric feature. Changes in surface color and plume distribution indicate differences in resurfacing processes near hot spots on Io. Patchy emissions were seen while Io was in eclipse by Jupiter. The outer margins of prominent linear markings (triple bands) on Europa are diffuse, suggesting that material has been vented from fractures. Numerous small circular craters indicate localized areas of relatively old surface. Pervasive brittle deformation of an ice layer appears to have formed grooves on Ganymede. Dark terrain unexpectedly shows distinctive albedo variations to the limit of resolution.

Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes: Combinatorial Islet Autoantibody Workshop.

The aim of this workshop was to assess the ability of individual autoantibody (ab) assays and their use in combination to discriminate between type 1 diabetic and control sera. Coded aliquots of sera were measured in a total of 119 assays by 49 participating laboratories in 17 countries. The sera were from 51 patients with new onset type 1 diabetes and 101 healthy control subjects with no family history of diabetes. In the final analysis, data on diabetic sera were restricted to 43 subjects younger than age 30 years. The laboratories were asked to report results for these sera using their currently available anti-islet autoantibody assays. In addition, they were asked to combine information from their assays to classify sera as having high, moderate, or low probability of originating from a patient with type 1 diabetes. Actual strategies for combining assays were determined by each laboratory. There were no significant differences in sensitivity among 19 radioimmunoassays (RIAs) for IA-2 autoantibodies (cytoplasmic islet cell antibody [ICA] 512) using different constructs that included the intracellular portion of the molecule (mean sensitivity 73%). However, an enzyme-linked immunosorbent assay (ELISA) using the extracellular portion of the IA-2 molecule did not discriminate between diabetic and control sera. Among GAD autoantibody assays that achieved sensitivity >70%, 26 were RIAs and one was an ELISA. When the sera were ranked according to their autoantibody levels, the concordance for insulin autoantibodies (IAAs) in different laboratories was markedly less than for IA-2ab and GADab. Using a combination of autoantibody assays, several laboratories achieved excellent discrimination between diabetic and control sera (sensitivity up to 80% with false-positive rate of 0%). A variety of strategies for combining information from different assays were successful (e.g., those including and excluding ICA), and no one strategy emerged as clearly superior. In conclusion, IA-2/ICA512 autoantibodies are a marker of type 1 diabetes and can be measured consistently by most assays. Several different strategies for combining assays achieved high sensitivity with a low false-positive rate.

The interaction of fiber, supplied by distillers dried grains with solubles, with an antimicrobial and a nutrient partitioning agent on nitrogen balance, water utilization, and energy digestibility in finishing pigs.

The objective of this study was to determine if a higher-fiber diet alters the response of finishing pigs to an antimicrobial (tylosin phosphate [TP]) and a nutrient partitioning agent (ractopamine HCl [RAC]) in terms of N and water utilization and energy digestibility. Seventy-two gilts (initial BW = 107.4 ± 4.2 kg) were blocked by weight and allotted to 1 of 8 dietary treatments. Treatments were arranged as a 2 × 2 × 2 factorial: distillers dried grains with solubles (DDGS; 0 vs. 30%), RAC (0 mg of RAC/kg and 0.70% standardized ileal digestible [SID] Lys vs. 5 mg of RAC/kg and 0.95% SID Lys) and TP (0 vs. 44 mg of TP/kg). Pig was the experimental unit, with 9 replications per treatment. Pigs were housed in individual metabolism crates and fed treatment diets for 17 d. Feed was provided twice daily, as much as the pigs could consume within 1 h per meal, and water was provided to the pigs between feeding periods, ad libitum. Fecal and urine collection occurred on d 7 and 8 and on d 15 and 16, for sampling periods 1 and 2, respectively. Pigs fed the DDGS diets had reduced ADG ( < 0.001) and ADFI ( < 0.0001). The apparent total tract digestibility (ATTD) of N and GE were lower for the 30% DDGS diets than the 0% DDGS diets ( < 0.0001). Ractopamine improved ADG ( < 0.0001), G:F ( < 0.0001), and N retention ( < 0.001) and tended to increase daily water intake ( < 0.10). Pigs fed RAC had higher N intake and urinary excretion and lower N retention in Period 2 than in Period 1 ( < 0.05), indicating a decline in the response to RAC over time. Tylosin phosphate did not affect ADFI or G:F but did improve ATTD of N ( < 0.05). There was a tendency for a TP × DDGS interaction ( < 0.10) for ADG, where TP tended to increase ADG in pigs fed 0% DDGS diets ( < 0.10) but not in pigs fed 30% DDGS diets ( > 0.10). Pigs fed DDGS diets had higher N intake ( < 0.01) and higher fecal ( < 0.0001) and urinary ( < 0.01) N excretion with no difference in N retention (g/d). Overall, RAC increased N retention by 33% ( < 0.0001) and the response to RAC was similar in both corn-soybean meal-based and corn-soybean meal-DDGS-based diets. Tylosin phosphate tended to improve growth performance in pigs fed corn-soybean meal-based diets but not in diets containing 30% DDGS; however, this response was not explained by changes in N balance or in energy digestibility.

Transcript profiles in longissimus dorsi muscle and subcutaneous adipose tissue: a comparison of pigs with different postweaning growth rates.

Although most pigs recover rapidly from stresses associated with the transition of weaning, a portion of the population lags behind their contemporaries in growth performance. The underlying biological and molecular mechanisms involved in postweaning differences in growth performance are poorly understood. The objective of this experiment was to use transcriptional profiling of skeletal muscle and adipose tissue to develop a better understanding of the metabolic basis for poor weaned-pig transition. A total of 1,054 pigs was reared in commercial conditions and weighed at birth, weaning, and 3 wk postweaning. Transition ADG (tADG) was calculated as the ADG for the 3-wk period postweaning. Nine pigs from both the lowest 10th percentile (low tADG) and the 60th to 70th percentile (high tADG) were harvested at 3 wk postweaning. Differential expression analysis was conducted in longissimus dorsi muscle (LM) and subcutaneous adipose tissue using RNA-Seq methodology. In LM, 768 transcripts were differentially expressed (DE), 327 with higher expression in low tADG and 441 with higher expression in high tADG pigs (q < 0.10). Expression patterns measured in LM by RNA-Seq were verified in 30 of 32 transcripts using quantitative PCR. No DE transcripts were identified in adipose tissue. To identify biological functions potentially underlying the effects of tADG on skeletal muscle metabolism and physiology, functional annotation analysis of the DE transcripts was conducted using DAVID and Pathway Studio analytic tools. The group of DE genes with lower expression in LM of low tADG pigs was enriched in genes with functions related to muscle contraction, glucose metabolism, cytoskeleton organization, muscle development, and response to hormone stimulus (enrichment score > 1.3). The list of DE genes with higher expression in low tADG LM was enriched in genes with functions related to protein catabolism (enrichment score > 1.3). Analysis of known gene-gene interactions identified possible regulators of these differences in gene expression in LM of high and low tADG pigs; these include forkhead box O1 (FOXO1), growth hormone (GH1), and the glucocorticoid receptor (NR3C1). Differences in gene expression between poor transitioning pigs and their contemporaries indicate a shift to decreased protein synthesis, increased protein degradation, and reduced glucose metabolism in the LM of low tADG pigs.

Effect of feeding ractopamine hydrochloride on growth performance and responses to handling and transport in heavy-weight pigs.

The impact of feeding ractopamine hydrochloride (RAC) on growth performance and responses to handling and transport in heavy BW pigs was evaluated in a study performed as a split-plot design with a 3 × 3 factorial arrangement of treatments: 1) RAC level (0 vs. 5 vs. 7.5 mg/kg of feed) and 2) handling intensity (HI; gentle vs. moderate vs. aggressive); RAC level was the main plot and HI was the subplot. A total of 288 pigs housed in groups of 8 were used to evaluate growth performance over a 28-d RAC feeding period (98.5 ± 4.58 to 131.5 ± 7.45 kg BW). On d 29 of the study, the HI treatment was applied to 216 pigs (6/pen; 2/pen on each HI). This was followed by transportation for 1 h on a livestock trailer at the end of which pigs were subjected to a final handling procedure. Blood samples (to measure acid-base, cortisol, and catecholamine levels) were collected and rectal temperature was measured 2 h before the HI treatment (baseline) and after the final handling procedure (final). Feeding RAC (5 and 7.5 mg/kg) improved ( < 0.01) ADG (9.9 and 9.0% for 5 and 7.5 mg/kg RAC, respectively) and G:F (8.8 and 11.8%, respectively) compared to controls, with no differences ( > 0.05) between the 2 RAC levels. Increasing the intensity of handling decreased ( < 0.001) final blood pH, bicarbonate, and base excess and increased ( < 0.001) final blood lactate and plasma cortisol and norepinephrine levels. Aggressive compared to gentle handling increased ( < 0.05) the incidence of pigs exhibiting open-mouth breathing and skin discoloration after the final handling procedure but had no effect ( > 0.05) on the incidence on nonambulatory, noninjured pigs. There was no effect ( > 0.05) of feeding RAC on final rectal temperature or blood acid-base measurements. Feeding 7.5, but not 5, compared to 0 mg/kg RAC increased ( < 0.05) final plasma epinephrine levels and the incidence of nonambulatory, noninjured pigs. This study confirms the improved growth performance of pigs fed RAC and the negative effects of aggressive handling on physical, metabolic, and physiological responses of pigs. It also suggests that pigs fed 5 compared to 0 mg/kg RAC showed similar responses to transport and handling. However, pigs fed 7.5 mg/kg of RAC had a greater incidence of nonambulatory, noninjured pigs when subjected to the handling/transport model and this warrants further investigation.

Detectable HIV-1 RNA at levels below quantifiable limits by amplicor HIV-1 monitor is associated with virologic relapse on antiretroviral therapy.

OBJECTIVE: To assess the clinical significance of HIV-1 RNA levels detectable using the Amplicor HIV-1 Monitor method but < 400 copies/ml versus levels undetectable by this method. DESIGN: Retrospective cohort study. METHODS: All plasma HIV-1 RNA results over 13 months in our institution were reviewed. The study population comprised all individuals that achieved an HIV-1 RNA level < 400 copies/ml and remained on stable antiretroviral therapy. Results of < 400 copies/ml were stratified as 'below quantifiable limits' (BQL) or 'below detectable limits' (BDL). We examined the incidence of virologic relapse, defined as an HIV-1 RNA level > 400 copies/ml, for individuals with viral loads of BQL or BDL. Cox proportional hazards regression analyses were performed to control for baseline CD4 cell count, the number of antiretroviral medications, and the use of protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI). RESULTS: Virologic relapse occurred in 52 of 168 individuals over 29,576 person-days overall (incidence rate 1.8 cases/1,000 person-days). The relapse rate was three times greater following HIV-1 RNA levels of BQL rather than BDL [crude rate ratio 3.2; 95% confidence interval (CI) 1.8-5.8]. After adjusting for baseline CD4 cell count, number of antiretroviral medications, and use of PI and/or NNRTI, the rate of relapse was nearly four times greater for individuals with HIV-1 RNA levels of BQL (hazard ratio 3.7; 95% CI 2.0-6.7). CONCLUSIONS: In a large clinic population, low-level HIV-1 RNA detected in plasma below the 400 copies/ml limit of quantifiability for Amplicor HIV-1 Monitor was associated with an increased rate of virologic relapse on therapy.