A mathematical model of comprehensive test-and-treat services and HIV incidence among men who have sex with men in the United States

Background

Early diagnosis and treatment of HIV infection and suppression of viral load are potentially powerful interventions for reducing HIV incidence. A test-and-treat strategy may have long-term effects on the epidemic among urban men who have sex with men (MSM) in the United States and may achieve the 5-year goals of the 2010 National AIDS Strategy that include: 1) lowering to 25% the annual number of new infections, 2) reducing by 30% the HIV transmission rate, 3) increasing to 90% the proportion of persons living with HIV infection who know their HIV status, 4) increasing to 85% the proportion of newly diagnosed patients linked to clinical care, and 5) increasing by 20% the proportion of HIV-infected MSM with an undetectable HIV RNA viral load.

Methods and Findings

We constructed a dynamic compartmental model among MSM in an urban population (based on New York City) that projects new HIV infections over time. We compared the cumulative number of HIV infections in 20 years, assuming current annual testing rate and treatment practices, with new infections after improvements in the annual HIV testing rate, notification of test results, linkage to care, initiation of antiretroviral therapy (ART) and viral load suppression. We also assessed whether five of the national HIV prevention goals could be met by the year 2015. Over a 20-year period, improvements in test-and-treat practice decreased the cumulative number of new infections by a predicted 39.3% to 69.1% in the urban population based on New York City. Institution of intermediate improvements in services would be predicted to meet at least four of the five goals of the National HIV/AIDS Strategy by the 2015 target.

Conclusions

Improving the five components of a test-and-treat strategy could substantially reduce HIV incidence among urban MSM, and meet most of the five goals of the National HIV/AIDS Strategy.     

Imaging radiation-induced normal tissue injury

Technological developments in radiation therapy and other cancer therapies have led to a progressive increase in five-year survival rates over the last few decades. Although acute effects have been largely minimized by both technical advances and medical interventions, late effects remain a concern. Indeed, the need to identify those individuals who will develop radiation-induced late effects, and to develop interventions to prevent or ameliorate these late effects is a critical area of radiobiology research. In the last two decades, preclinical studies have clearly established that late radiation injury can be prevented/ameliorated by pharmacological therapies aimed at modulating the cascade of events leading to the clinical expression of radiation-induced late effects. These insights have been accompanied by significant technological advances in imaging that are moving radiation oncology and normal tissue radiobiology from disciplines driven by anatomy and macrostructure to ones in which important quantitative functional, microstructural, and metabolic data can be noninvasively and serially determined. In the current article, we review use of positron emission tomography (PET), single photon emission tomography (SPECT), magnetic resonance (MR) imaging and MR spectroscopy to generate pathophysiological and functional data in the central nervous system, lung, and heart that offer the promise of, (1) identifying individuals who are at risk of developing radiation-induced late effects, and (2) monitoring the efficacy of interventions to prevent/ameliorate them.     

Detecting gustatory-olfactory flavor mixtures: models of probability summation

Odorants and flavorants typically contain many components. It is generally easier to detect multicomponent stimuli than to detect a single component, through either neural integration or probability summation (PS) (or both). PS assumes that the sensory effects of 2 (or more) stimulus components (e.g., gustatory and olfactory components of a flavorant) are detected in statistically independent channels, that each channel makes a separate decision whether a component is detected, and that the behavioral response depends solely on the separate decisions. Models of PS traditionally assume high thresholds for detecting each component, noise being irrelevant. The core assumptions may be adapted, however, to signal-detection theory, where noise limits detection. The present article derives predictions of high-threshold and signal-detection models of independent-decision PS in detecting gustatory-olfactory flavorants, comparing predictions in yes/no and 2-alternative forced-choice tasks using blocked and intermixed stimulus designs. The models also extend to measures of response times to suprathreshold flavorants. Predictions derived from high-threshold and signal-detection models differ markedly. Available empirical evidence on gustatory-olfactory flavor detection suggests that neither the high-threshold nor the signal-detection versions of PS can readily account for the results, which likely reflect neural integration in the flavor system.     

A comparative study of embryonic development of Japanese quail selected for different patterns of postnatal growth

Patterns of early embryonic development have traditionally been viewed as invariant within vertebrate taxa. It has been argued that the specific differences which are found arise during the later stages of development. These differences may be a result of allometry, heterochrony or changes in relative growth rates. To test whether early embryonic development is indeed invariant, or whether selection of adult characteristics can alter embryonic growth, we compared embryonic development in birds selected for different patterns of postnatal growth. Using quail lines selected for high and low body mass, we compared somite formation, and muscle and feather development. We obtained data that showed changes in the rate of myotome formation in the brachial somites which contribute to muscle formation in the limbs and thorax. We think these observations are connected with intraspecific changes in adult morphology, ie., breast muscle size. Our findings suggest that selection for late ontogenetic/adult stages affects early embryonic development.     

Golgi recruitment of GRIP domain proteins by Arf-like GTPase 1 is regulated by Arf-like GTPase 3

Golgins are Golgi-localized proteins present in all molecularly characterized eukaryotes that function in Golgi transport and maintenance of Golgi structure. Some peripheral membrane Golgins, including the yeast Imh1 protein, contain the recently described GRIP domain that can independently mediate Golgi localization by an unknown mechanism. To identify candidate Golgi receptors for GRIP domain proteins, a collection of Saccharomyces cerevisiae deletion mutants was visually screened by using yeast, mouse, and human GFP-GRIP domain fusion proteins for defects in Golgi localization. GFP-GRIP reporters were localized to the cytosol in cells lacking either of two ARF-like (ARL) GTPases, Arl1p and Arl3p. In vitro binding experiments demonstrated that activated Arl1p-GTP binds specifically and directly to the Imh1p GRIP domain. Arl1p colocalized with Imh1p-GRIP at the Golgi, and Golgi localization of Arl1p was regulated by the GTPase cycle of Arl3p. These results suggest a cascade in which the GTPase cycle of Arl3p regulates Golgi localization of Arl1p, which in turn binds to the GRIP domain of Imh1p and recruits it to the Golgi. The similar requirements for localization of GRIP domains from yeast, mouse, and human when expressed in yeast, and the presence of Arl1p and Arl3p homologs in these species, suggest that this is an evolutionarily conserved mechanism.     

The Human Milk Protein-Lipid Complex HAMLET Sensitizes Bacterial Pathogens to Traditional Antimicrobial Agents

The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend the lifetime of the current treatment arsenal.     

Correlation of serotype-specific dengue virus infection with clinical manifestations

Background

Disease caused by the dengue virus (DENV) is a significant cause of morbidity throughout the world. Although prior research has focused on the association of specific DENV serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) with the development of severe outcomes such as dengue hemorrhagic fever and dengue shock syndrome, relatively little work has correlated other clinical manifestations with a particular DENV serotype. The goal of this study was to estimate and compare the prevalence of non-hemorrhagic clinical manifestations of DENV infection by serotype.

Methodology and Principal Findings

Between the years 2005–2010, individuals with febrile disease from Peru, Bolivia, Ecuador, and Paraguay were enrolled in an outpatient passive surveillance study. Detailed information regarding clinical signs and symptoms, as well as demographic information, was collected. DENV infection was confirmed in patient sera with polyclonal antibodies in a culture-based immunofluorescence assay, and the infecting serotype was determined by serotype-specific monoclonal antibodies. Differences in the prevalence of individual and organ-system manifestations were compared across DENV serotypes. One thousand seven hundred and sixteen individuals were identified as being infected with DENV-1 (39.8%), DENV-2 (4.3%), DENV-3 (41.5%), or DENV-4 (14.4%). When all four DENV serotypes were compared with each other, individuals infected with DENV-3 had a higher prevalence of musculoskeletal and gastrointestinal manifestations, and individuals infected with DENV-4 had a higher prevalence of respiratory and cutaneous manifestations.

Conclusions/Significance

Specific clinical manifestations, as well as groups of clinical manifestations, are often overrepresented by an individual DENV serotype.     

A functional dual-coated (FDC) microtiter plate method to replace the botulinum toxin LD50 test

Conventional capture ("Sandwich") ELISAs equally detect denatured inactive and native active botulinum type A toxin. Light chain endoprotease activity assays also fail to distinguish between various inactive molecules including partially denatured and fragmented material still retaining this protease activity. By co-coating microtiter plates with SNAP25 substrate and a monoclonal antibody specific for a conformational epitope of the toxin's Hc domain, it was possible to develop a highly sensitive (130 aM LoD), precise (1.4% GCV) new assay specific for the biologically active toxin molecule. Capture was performed in phosphate buffer with a fixed optimal concentration of chaotropic agent (e.g., 1.2 M urea) to differentially isolate functional toxin molecules. Addition of enzymatically favorable buffer containing zinc and DTT reduced the interchain disulfide bond releasing and activating the captured L-chain with subsequent specific cleavage of the SNAP25(1-206) substrate. A neoepitope antibody specific for the newly exposed Q(197) epitope was used to quantify the cleaved SNAP25(1-197). The assay's requirement for the intact toxin molecule was demonstrated with pre-reduced toxin (heavy and light chains), recombinant LHn fragments, and stressed samples containing partially or fully denatured material. This is the first known immunobiochemical assay that correlates with in vivo potency and provides a realistic alternative.     

Domain-based assays of individual antibody concentrations in an oligoclonal combination targeting a single protein

Quantitation of individual monoclonal antibodies (mAbs) within a combined antibody drug product is required for preclinical and clinical drug development, including pharmacokinetic (PK), toxicology, stability, and biochemical characterization studies of such drugs. We have developed an antitoxin, XOMA 3AB, consisting of three recombinant mAbs that potently neutralize the known subtypes of type A botulinum neurotoxin (BoNT/A). The three mAbs bind nonoverlapping BoNT/A epitopes with high affinity. XOMA 3AB is being developed as a treatment for botulism resulting from BoNT/A. To develop antibody-specific assays, we cloned, expressed, and purified BoNT/A domains from Escherichia coli. Each mAb bound only to its specific domain with affinity comparable to the binding to holotoxin. mAb-specific domains were used to develop an enzyme-linked immunosorbent assay (ELISA) for characterization of the integrity and binding activity of the three mAbs in the drug product. An electrochemiluminescence bridging assay that is robust to interference from components in serum was also developed, and we demonstrate that it can be used for PK assays. This type of antigen engineering to generate mAb-specific domains is a general method allowing quantitation and characterization of individual mAbs in a mAb cocktail that binds the same protein and is superior to anti-idiotype approaches.