Limited Durability of Viral Control following Treated Acute HIV Infection

BACKGROUND: Early treatment of acute HIV infection with highly active antiretroviral therapy, followed by supervised treatment interruption (STI), has been associated with at least transient control of viremia. However, the durability of such control remains unclear. Here we present longitudinal follow-up of a single-arm, open-label study assessing the impact of STI in the setting of acute HIV-1 infection. METHODS AND FINDINGS: Fourteen patients were treated during acute HIV-1 infection and subsequently subjected to an STI protocol that required retreatment if viral load exceeded 50,000 RNA copies/ml plasma or remained above 5,000 copies/ml for more than three consecutive weeks. Eleven of 14 (79%) patients were able to achieve viral loads of less than 5,000 RNA copies/ml for at least 90 d following one, two, or three interruptions of treatment. However, a gradual increase in viremia and decline in CD4+ T cell counts was observed in most individuals. By an intention-to-treat analysis, eight (57%), six (43%), and three (21%) of 14 patients achieved a maximal period of control of 180, 360, and 720 d, respectively, despite augmentation of HIV-specific CD4+ and CD8+ T cell responses. The magnitude of HIV-1-specific cellular immune responses before treatment interruption did not predict duration of viremia control. The small sample size and lack of concurrent untreated controls preclude assessment of possible clinical benefit despite failure to control viremia by study criteria. CONCLUSIONS: These data indicate that despite initial control of viremia, durable viral control to less than 5,000 RNA copies/ml plasma in patients following treated acute HIV-1 infection occurs infrequently. Determination of whether early treatment leads to overall clinical benefit will require a larger and randomized clinical trial. These data may be relevant to current efforts to develop an HIV-1 vaccine designed to retard disease progression rather than prevent infection since they indicate that durable maintenance of low-level viremia may be difficult to achieve

A review of wildland fire spread modelling, 1990-present 3: Mathematical analogues and simulation models

In recent years, advances in computational power and spatial data analysis (GIS, remote sensing, etc) have led to an increase in attempts to model the spread and behvaiour of wildland fires across the landscape. This series of review papers endeavours to critically and comprehensively review all types of surface fire spread models developed since 1990. This paper reviews models of a simulation or mathematical analogue nature. Most simulation models are implementations of existing empirical or quasi-empirical models and their primary function is to convert these generally one dimensional models to two dimensions and then propagate a fire perimeter across a modelled landscape. Mathematical analogue models are those that are based on some mathematical conceit (rather than a physical representation of fire spread) that coincidentally simulates the spread of fire. Other papers in the series review models of an physical or quasi-physical nature and empirical or quasi-empirical nature. Many models are extensions or refinements of models developed before 1990. Where this is the case, these models are also discussed but much less comprehensively.Comment: 20 pages + 9 pages references + 1 page figures. Submitted to the International Journal of Wildland Fir

Isospin-tracing: A probe of non-equilibrium in central heavy-ion collisions

Four different combinations of $^{96}_{44}$Ru and $^{96}_{40}$Zr nuclei, both as projectile and target, were investigated at the same bombarding energy of 400$A$ MeV using a $4 \pi$ detector. The degree of isospin mixing between projectile and target nucleons is mapped across a large portion of the phase space using two different isospin-tracer observables, the number of measured protons and the ${\rm t}/^{3}{\rm He}$ yield ratio. The experimental results show that the global equilibrium is not reached even in the most central collisions. Quantitative measures of stopping and mixing are extracted from the data. They are found to exhibit a quite strong sensitivity to the in-medium (n,n) cross section used in microscopic transport calculations.Comment: 4 pages RevTeX, 3 figures (ps files), submitted to Phys. Rev. Let

Medication Complications in Extracorporeal Membrane Oxygenation.

The need for extracorporeal membrane oxygenation (ECMO) therapy is a marker of disease severity for which multiple medications are required. The therapy causes physiologic changes that impact drug pharmacokinetics. These changes can lead to exposure-driven decreases in efficacy or increased incidence of side effects. The pharmacokinetic changes are drug specific and largely undefined for most drugs. We review available drug dosing data and provide guidance for use in the ECMO patient population

The Hubble Space Telescope Cluster Supernova Survey: V. Improving the Dark Energy Constraints Above z>1 and Building an Early-Type-Hosted Supernova Sample

We present ACS, NICMOS, and Keck AO-assisted photometry of 20 Type Ia supernovae SNe Ia from the HST Cluster Supernova Survey. The SNe Ia were discovered over the redshift interval 0.623 < z < 1.415. Fourteen of these SNe Ia pass our strict selection cuts and are used in combination with the world's sample of SNe Ia to derive the best current constraints on dark energy. Ten of our new SNe Ia are beyond redshift $z=1$, thereby nearly doubling the statistical weight of HST-discovered SNe Ia beyond this redshift. Our detailed analysis corrects for the recently identified correlation between SN Ia luminosity and host galaxy mass and corrects the NICMOS zeropoint at the count rates appropriate for very distant SNe Ia. Adding these supernovae improves the best combined constraint on the dark energy density \rho_{DE}(z) at redshifts 1.0 < z < 1.6 by 18% (including systematic errors). For a LambdaCDM universe, we find \Omega_\Lambda = 0.724 +0.015/-0.016 (68% CL including systematic errors). For a flat wCDM model, we measure a constant dark energy equation-of-state parameter w = -0.985 +0.071/-0.077 (68% CL). Curvature is constrained to ~0.7% in the owCDM model and to ~2% in a model in which dark energy is allowed to vary with parameters w_0 and w_a. Tightening further the constraints on the time evolution of dark energy will require several improvements, including high-quality multi-passband photometry of a sample of several dozen z>1 SNe Ia. We describe how such a sample could be efficiently obtained by targeting cluster fields with WFC3 on HST.Comment: 27 pages, 11 figures. Submitted to ApJ. This first posting includes updates in response to comments from the referee. See http://www.supernova.lbl.gov for other papers in the series pertaining to the HST Cluster SN Survey. The updated supernova Union2.1 compilation of 580 SNe is available at http://supernova.lbl.gov/Unio

Daily Rhythms of Plasma Melatonin, but Not Plasma Leptin or Leptin mRNA, Vary between Lean, Obese and Type 2 Diabetic Men

Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physiology. It remains unclear, however, whether this rhythmicity is altered in obesity or type 2 diabetes (T2DM). We tested the hypothesis that 24-hour profiles of melatonin, leptin and leptin mRNA are altered by metabolic status in laboratory conditions. Men between 45–65 years old were recruited into lean, obese-non-diabetic or obese-T2DM groups. Volunteers followed strict sleep-wake and dietary regimes for 1 week before the laboratory study. They were then maintained in controlled light-dark conditions, semi-recumbent posture and fed hourly iso-energetic drinks during wake periods. Hourly blood samples were collected for hormone analysis. Subcutaneous adipose biopsies were collected 6-hourly for gene expression analysis. Although there was no effect of subject group on the timing of dim light melatonin onset (DLMO), nocturnal plasma melatonin concentration was significantly higher in obese-non-diabetic subjects compared to weight-matched T2DM subjects (p<0.01) and lean controls (p<0.05). Two T2DM subjects failed to produce any detectable melatonin, although did exhibit plasma cortisol rhythms comparable to others in the group. Consistent with the literature, there was a significant (p<0.001) effect of subject group on absolute plasma leptin concentration and, when expressed relative to an individual’s 24-hour mean, plasma leptin showed significant (p<0.001) diurnal variation. However, there was no difference in amplitude or timing of leptin rhythms between experimental groups. There was also no significant effect of time on leptin mRNA expression. Despite an overall effect (p<0.05) of experimental group, post-hoc analysis revealed no significant pair-wise effects of group on leptin mRNA expression. Altered plasma melatonin rhythms in weight-matched T2DM and non-diabetic individuals supports a possible role of melatonin in T2DM aetiology. However, neither obesity nor T2DM changed 24-hour rhythms of plasma leptin relative to cycle mean, or expression of subcutaneous adipose leptin gene expression, compared with lean subjects

Multiwavelength Observations of LS I +61 303 with VERITAS, Swift and RXTE

We present results from a long-term monitoring campaign on the TeV binary LSI +61 303 with VERITAS at energies above 500 GeV, and in the 2-10 keV hard X-ray bands with RXTE and Swift, sampling nine 26.5 day orbital cycles between September 2006 and February 2008. The binary was observed by VERITAS to be variable, with all integrated observations resulting in a detection at the 8.8 sigma (2006/2007) and 7.3 sigma (2007/2008) significance level for emission above 500 GeV. The source was detected during active periods with flux values ranging from 5 to 20% of the Crab Nebula, varying over the course of a single orbital cycle. Additionally, the observations conducted in the 2007-2008 observing season show marginal evidence (at the 3.6 sigma significance level) for TeV emission outside of the apastron passage of the compact object around the Be star. Contemporaneous hard X-ray observations with RXTE and Swift show large variability with flux values typically varying between 0.5 and 3.0*10^-11 ergs cm^-2 s^-1 over a single orbital cycle. The contemporaneous X-ray and TeV data are examined and it is shown that the TeV sampling is not dense enough to detect a correlation between the two bands.Comment: 30 pages, 5 figures, 2 table, Accepted for publication in The Astrophysical Journa

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Discovery of the Binary Pulsar PSR B1259-63 in Very-High-Energy Gamma Rays around Periastron with H.E.S.S

We report the discovery of very-high-energy (VHE) gamma-ray emission of the binary system PSR B1259-63/SS 2883 of a radio pulsar orbiting a massive, luminous Be star in a highly eccentric orbit. The observations around the 2004 periastron passage of the pulsar were performed with the four 13 m Cherenkov telescopes of the H.E.S.S. experiment, recently installed in Namibia and in full operation since December 2003. Between February and June 2004, a gamma-ray signal from the binary system was detected with a total significance above 13 sigma. The flux was found to vary significantly on timescales of days which makes PSR B1259-63 the first variable galactic source of VHE gamma-rays observed so far. Strong emission signals were observed in pre- and post-periastron phases with a flux minimum around periastron, followed by a gradual flux decrease in the months after. The measured time-averaged energy spectrum above a mean threshold energy of 380 GeV can be fitted by a simple power law F_0(E/1 TeV)^-Gamma with a photon index Gamma = 2.7+-0.2_stat+-0.2_sys and flux normalisation F_0 = (1.3+-0.1_stat+-0.3_sys) 10^-12 TeV^-1 cm^-2 s^-1. This detection of VHE gamma-rays provides unambiguous evidence for particle acceleration to multi-TeV energies in the binary system. In combination with coeval observations of the X-ray synchrotron emission by the RXTE and INTEGRAL instruments, and assuming the VHE gamma-ray emission to be produced by the inverse Compton mechanism, the magnetic field strength can be directly estimated to be of the order of 1 G.Comment: 10 pages, 8 figures, accepted in Astronomy and Astrophysics on 2 June 2005, replace: document unchanged, replaced author field in astro-ph entry - authors are all members of the H.E.S.S. collaboration and three additional authors (99+3, see document

The impact of regional and neighbourhood deprivation on physical health in Germany: a multilevel study

Voigtländer S, Berger U, Razum O. The impact of regional and neighbourhood deprivation on physical health in Germany: a multilevel study. BMC Public Health. 2010;10(1): 403.Background There is increasing evidence that individual health is at least partly determined by neighbourhood and regional factors. Mechanisms, however, remain poorly understood, and evidence from Germany is scant. This study explores whether regional as well as neighbourhood deprivation are associated with physical health and to what extent this association can be explained by specific neighbourhood exposures. Methods Using 2004 data from the German Socio-Economic Panel Study (SOEP) merged with regional and neighbourhood characteristics, we fitted multilevel linear regression models with subjective physical health, as measured by the SF-12, as the dependent variable. The models include regional and neighbourhood proxies of deprivation (i.e. regional unemployment quota, average purchasing power of the street section) as well as specific neighbourhood exposures (i.e. perceived air pollution). Individual characteristics including socioeconomic status and health behaviour have been controlled for. Results This study finds a significant association between area deprivation and physical health which is independent of compositional factors and consistent across different spatial scales. Furthermore the association between neighbourhood deprivation and physical health can be partly explained by specific features of the neighbourhood environment. Among these perceived air pollution shows the strongest association with physical health (-2.4 points for very strong and -1.5 points for strong disturbance by air pollution, standard error (SE) = 0.8 and 0.4, respectively). Beta coefficients for perceived air pollution, perceived noise and the perceived distance to recreational resources do not diminish when including individual health behaviour in the models. Conclusions This study highlights the difference regional and in particular neighbourhood deprivation make to the physical health of individuals in Germany. The results support the argument that specific neighbourhood exposures serve as an intermediary step between deprivation and health. As people with a low socioeconomic status were more likely to be exposed to unfavourable neighbourhood characteristics these conditions plausibly contribute towards generating health inequalities