HIV monoclonal antibodies: a new opportunity to further reduce mother-to-child HIV transmission.

Yegor Voronin and colleagues explore how monoclonal antibodies against HIV could provide a new opportunity to further reduce mother-to-child transmission of HIV and propose that new interventions should consider issues related to implementation, feasibility, and access. Please see later in the article for the Editors' Summary.

Risk factors for medication nonadherence in older adults with cognitive impairment who live alone.

OBJECTIVE: The aim of this study was to prospectively examine the influence of cognitive, medical, behavioral, and social risk factors on medication nonadherence in community-dwelling older adults with cognitive impairment. METHODS: A sample of 339 elderly participants with cognitive impairment, who lived alone and took at least one medication, underwent baseline assessment which included the five subscales of the Dementia Rating Scale (DRS), number of medications, retrospective medication nonadherence, amount of formal and informal assistance, functional impairment, depression, perception of social resources, comorbidity, and alcohol consumption. The outcome was medication nonadherence during the 12-month prospective period as reported by the participants' primary care physicians and caregivers at three-month intervals. RESULTS: Fifty-nine participants (17.4%) had, at least, one report of medication nonadherence. Logistic regression analyses indicated for every point increase on the DRS Conceptualization subscale (OR = 1.14; 95% CI = 1.02-1.27), there was a 14% increase in the odds of nonadherence. For every point increase on the DRS Memory subscale (OR = 0.89; 95% CI = 0.81-0.97) and DRS Initiation/Perseveration subscale (OR = 0.93; 95% CI = 0.87-1.00), there was an 11% decrease and 7% decrease in the odds, respectively. Having at least one previous occurrence of medication nonadherence (OR = 2.61; 95% CI = 1.18-5.62) and taking at least four medications (OR = 2.58; 95% CI = 1.31-5.29), both increased the odds by over 2.5-fold. CONCLUSIONS: Our unique finding that better conceptualization predicted nonadherence has important implications for healthcare providers' approaches to improve adherence in older adults with cognitive impairment. Replication in future studies is warranted.

HIV immunoprophylaxis: preparing the pathway from proof of concept to policy decision and use.

Various long-awaited efficacy studies of vaccines and broadly neutralising antibodies for prevention of HIV are now well underway in highly endemic settings. One broadly neutralising monoclonal antibody is being assessed for proof of concept, and combinations are in the pipeline. Two multicomponent prime-and-boost vaccine regimens are being evaluated, one of which is designed for global coverage. These multicomponent vaccines present a new level of complexity that will challenge health delivery systems. We recommend that while awaiting the results, which will appear in 2020-22, the target product profiles and full public value proposition for both categories of products should be defined, and the regulatory, policy, and implementation pathways should be prepared. Economic and health benefits, cost of goods, administrative complexity, and user perspectives will be key considerations for the roll-out of effective products. Investments in manufacturing capacity and public-sector delivery systems will be needed to prepare for product introduction and scale-up. We propose a prioritisation of activities on the basis of a broad stakeholder consultation organised by WHO and UNAIDS.

Transcriptional Profiling of Non-Human Primate Lymphoid Organ Responses to Total-Body Irradiation.

The global threat of exposure to radiation and its subsequent outcomes require the development of effective strategies to mitigate immune cell injury. In this study we explored transcriptional and immunophenotypic characteristics of lymphoid organs of a non-human primate model after total-body irradiation (TBI). Fifteen middle-aged adult, ovariectomized, female cynomolgus macaques received a single dose of 0, 2 or 5 Gy gamma radiation. Thymus, spleen and lymph node from three controls and 2 Gy (n = 2) and 5 Gy (n = 2) exposed animals were assessed for molecular responses to TBI through microarray-based transcriptional profiling at day 5 postirradiation, and cellular changes through immunohistochemical (IHC) characterization of markers for B and T lymphocytes and macrophages across all 15 animals at time points up to 6 months postirradiation. Irradiated macaques developed acute hematopoietic syndrome. Analysis of array data at day 5 postirradiation identified transcripts with ≥2-fold difference from control and a false discovery rate (FDR) of Padj < 0.05 in lymph node (n = 666), spleen (n = 493) and thymus (n=3,014). Increasing stringency of the FDR to P < 0.001 reduced the number of genes to 71 for spleen and 379 for thymus. IHC and gene expression data demonstrated that irradiated animals had reduced numbers of T and B lymphocytes along with relative elevations of macrophages. Transcriptional analysis revealed unique patterns in primary and secondary lymphoid organs of cynomolgus macaques. Among the many differentially regulated transcripts, upregulation of noncoding RNAs [MIR34A for spleen and thymus and NEAT1 (NCRNA00084) for thymus] showed potential as biomarkers of radiation injury and targets for mitigating the effects of radiation-induced hematopoietic syndrome-impaired lymphoid reconstitution.

Progress on the BL2 beam measurement of the neutron lifetime.

A precise value of the neutron lifetime is important in several areas of physics, including determinations of the quark-mixing matrix element │V ud│, related tests of the Standard Model, and predictions of light element abundances in Big Bang Nucleosynthesis models. We report the progress on a new measurement of the neutron lifetime utilizing the cold neutron beam technique. Several experimental improvements in both neutron and proton counting that have been developed over the last decade are presented. This new effort should yield a final uncertainty on the lifetime of 1 s with an improved understanding of the systematic effects.

The Fundamental Neutron Physics Beamline at the Spallation Neutron Source.

The Spallation Neutron Source (SNS), currently under construction at Oak Ridge National Laboratory with an anticipated start-up in early 2006, will provide the most intense pulsed beams of cold neutrons in the world. At a projected power of 1.4 MW, the time averaged fluxes and fluences of the SNS will approach those of high flux reactors. One of the flight paths on the cold, coupled moderator will be devoted to fundamental neutron physics. The fundamental neutron physics beamline is anticipated to include two beam-lines; a broad band cold beam, and a monochromatic beam of 0.89 nm neutrons for ultracold neutron (UCN) experiments. The fundamental neutron physics beamline will be operated as a user facility with experiment selection based on a peer reviewed proposal process. An initial program of five experiments in neutron decay, hadronic weak interaction and time reversal symmetry violation have been proposed.

The fate of biodegradable microspheres injected into rat brain.

Biodegradable microspheres made with poly-[D,L-lactide-co-glycolide] represent an evolving technology for drug delivery into the central nervous system. Even though these microspheres have been shown to be engulfed by astrocytes in vitro, the purpose of the present study was to track the fate of biodegradable microspheres in vivo. This was accomplished using microspheres containing the fluorescent dye coumarin-6 followed 1 day, 1 week and 1 month after intracerebral injections of this material were made into the rat brain. Using dual color immunohistochemistry and antisera against glial fibrillary acidic protein for astrocytes versus phosphotyrosine for microglia, results demonstrate that phagocytosis of small coumarin-containing microspheres <7.5 microm in diameter was primarily by microglia in vivo during the first week post-injection. In contrast, only a small minority of these microspheres appeared to be engulfed by astrocytes.

The immune space: a concept and template for rationalizing vaccine development.

Empirical testing of candidate vaccines has led to the successful development of a number of lifesaving vaccines. The advent of new tools to manipulate antigens and new methods and vectors for vaccine delivery has led to a veritable explosion of potential vaccine designs. As a result, selection of candidate vaccines suitable for large-scale efficacy testing has become more challenging. This is especially true for diseases such as dengue, HIV, and tuberculosis where there is no validated animal model or correlate of immune protection. Establishing guidelines for the selection of vaccine candidates for advanced testing has become a necessity. A number of factors could be considered in making these decisions, including, for example, safety in animal and human studies, immune profile, protection in animal studies, production processes with product quality and stability, availability of resources, and estimated cost of goods. The "immune space template" proposed here provides a standardized approach by which the quality, level, and durability of immune responses elicited in early human trials by a candidate vaccine can be described. The immune response profile will demonstrate if and how the candidate is unique relative to other candidates, especially those that have preceded it into efficacy testing and, thus, what new information concerning potential immune correlates could be learned from an efficacy trial. A thorough characterization of immune responses should also provide insight into a developer's rationale for the vaccine's proposed mechanism of action. HIV vaccine researchers plan to include this general approach in up-selecting candidates for the next large efficacy trial. This "immune space" approach may also be applicable to other vaccine development endeavors where correlates of vaccine-induced immune protection remain unknown.

Organizing the HIV vaccine development effort.

PURPOSE OF REVIEW: To describe and compare the diverse organizational structures and funding mechanisms applied to advance HIV preventive vaccine research and development and to help explain and inform evolving infrastructures and collaborative funding models. RECENT FINDINGS: On the basis of models that have been tried, improved or abandoned over three decades, the field seems to have settled into a relatively stable set of diverse initiatives, each with its own organizational signature. At the same time, this set of organizations is forging cross-organizational collaborations, which promise to acquire newly emergent beneficial properties. SUMMARY: Strong motivation to expedite HIV vaccine R&D has driven a diversity of customized and inventive organizational approaches, largely government and foundation funded. Although no one approach has proven a panacea, the field has evolved into a constellation of often overlapping organizations that complement or reinforce one another. The Global HIV Vaccine Enterprise, a responsive, rapidly evolving loose infrastructure, is an innovative collaboration to catalyze that evolution.