Should expectations about the rate of new antiretroviral drug development impact the timing of HIV treatment initiation and expectations about treatment benefits?

Background: Many analyses of HIV treatment decisions assume a fixed formulary of HIV drugs. However, new drugs are approved nearly twice a year, and the rate of availability of new drugs may affect treatment decisions, particularly when to initiate antiretroviral therapy (ART). Objectives: To determine the impact of considering the availability of new drugs on the optimal initiation criteria for ART and outcomes in patients with HIV/AIDS. Methods: We enhanced a previously described simulation model of the optimal time to initiate ART to incorporate the rate of availability of new antiviral drugs. We assumed that the future rate of availability of new drugs would be similar to the past rate of availability of new drugs, and we estimated the past rate by fitting a statistical model to actual HIV drug approval data from 1982-2010. We then tested whether or not the future availability of new drugs affected the model-predicted optimal time to initiate ART based on clinical outcomes, considering treatment initiation thresholds of 200, 350, and 500 cells/mm 3. We also quantified the impact of the future availability of new drugs on life expectancy (LE) and quality-adjusted life expectancy (QALE). Results: In base case analysis, considering the availability of new drugs raised the optimal starting CD4 threshold for most patients to 500 cells/mm 3. The predicted gains in outcomes due to availability of pipeline drugs were generally small (less than 1%), but for young patients with a high viral load could add as much as a 4.9% (1.73 years) increase in LE and a 8% (2.43 QALY) increase in QALE, because these patients were particularly likely to exhaust currently available ART regimens before they died. In sensitivity analysis, increasing the rate of availability of new drugs did not substantially alter the results. Lowering the toxicity of future ART drugs had greater potential to increase benefit for many patient groups, increasing QALE by as much as 10%. Conclusions: The future availability of new ART drugs without lower toxicity raises optimal treatment initiation for most patients, and improves clinical outcomes, especially for younger patients with higher viral loads. Reductions in toxicity of future ART drugs could impact optimal treatment initiation and improve clinical outcomes for all HIV patients. © 2014 Khademi et al

SARS CoV subunit vaccine: Antibodymediated neutralisation and enhancement

1. A SARS vaccine was produced based on recombinant native full-length Spike-protein trimers (triSpike) and efficient establishment of a vaccination procedure in rodents. 2. Antibody-mediated enhancement of SARS-CoV infection with anti-SARS-CoV Spike immune-serum was observed in vitro. 3. Antibody-mediated infection of SARS-CoV triggers entry into human haematopoietic cells via an FcγR-dependent and ACE2-, pH-, cysteine-protease-independent pathways. 4. The antibody-mediated enhancement phenomenon is not a mandatory component of the humoral immune response elicited by SARS vaccines, as pure neutralising antibody only could be obtained. 5. Occurrence of immune-mediated enhancement of SARS-CoV infection raises safety concerns regarding the use of SARS-CoV vaccine in humans and enables new ways to investigate SARS pathogenesis (tropism and immune response deregulation)

Gray's time-varying coefficients model for posttransplant survival of pediatric liver transplant recipients with a diagnosis of cancer

Transplantation is often the only viable treatment for pediatric patients with end-stage liver disease. Making well-informed decisions on when to proceed with transplantation requires accurate predictors of transplant survival. The standard Cox proportional hazards (PH) model assumes that covariate effects are time-invariant on right-censored failure time; however, this assumption may not always hold. Gray's piecewise constant time-varying coefficients (PC-TVC) model offers greater flexibility to capture the temporal changes of covariate effects without losing the mathematical simplicity of Cox PH model. In the present work, we examined the Cox PH and Gray PC-TVC models on the posttransplant survival analysis of 288 pediatric liver transplant patients diagnosed with cancer. We obtained potential predictors through univariable (P < 0.15) and multivariable models with forward selection (P < 0.05) for the Cox PH and Gray PC-TVC models, which coincide. While the Cox PH model provided reasonable average results in estimating covariate effects on posttransplant survival, the Gray model using piecewise constant penalized splines showed more details of how those effects change over time. © 2013 Yi Ren et al

Current quark mass dependence of nucleon magnetic moments and radii

A calculation of the current-quark-mass-dependence of nucleon static electromagnetic properties is necessary in order to use observational data as a means to place constraints on the variation of Nature's fundamental parameters. A Poincare' covariant Faddeev equation, which describes baryons as composites of confined-quarks and -nonpointlike-diquarks, is used to calculate this dependence The results indicate that, like observables dependent on the nucleons' magnetic moments, quantities sensitive to their magnetic and charge radii, such as the energy levels and transition frequencies in Hydrogen and Deuterium, might also provide a tool with which to place limits on the allowed variation in Nature's constants.Comment: 23 pages, 2 figures, 4 tables, 4 appendice

Horizontal gene transfer converts non-toxigenic Clostridium difficile strains into toxin producers.

Clostridium difficile is a major nosocomial pathogen and the main causative agent of antibiotic-associated diarrhoea. The organism produces two potent toxins, A and B, which are its major virulence factors. These are chromosomally encoded on a region termed the pathogenicity locus (PaLoc), which also contains regulatory genes, and is absent in non-toxigenic strains. Here we show that the PaLoc can be transferred from the toxin-producing strain, 630Δerm, to three non-toxigenic strains of different ribotypes. One of the transconjugants is shown by cytotoxicity assay to produce toxin B at a similar level to the donor strain, demonstrating that a toxigenic C. difficile strain is capable of converting a non-toxigenic strain to a toxin producer by horizontal gene transfer. This has implications for the treatment of C. difficile infections, as non-toxigenic strains are being tested as treatments in clinical trials

Analysis of a Clostridium difficile PCR ribotype 078 100 kilobase island reveals the presence of a novel transposon, Tn6164.

Clostridium difficile is the main cause of antibiotic associated diarrhea. In the past decade, the number of C. difficile patients has increased dramatically, coinciding with the emergence of two PCR ribotypes 027 and 078. PCR ribotype 078 is also frequently found during C. difficile outbreaks in pigfarms. Previously, the genome of the PCR ribotype 078 strain M120, a human isolate, was described to contain a unique insert of 100 kilobases

Higgs Mass from D-Terms: a Litmus Test

We explore supersymmetric theories in which the Higgs mass is boosted by the non-decoupling D-terms of an extended $U(1)_X$ gauge symmetry, defined here to be a general linear combination of hypercharge, baryon number, and lepton number. Crucially, the gauge coupling, $g_X$, is bounded from below to accommodate the Higgs mass, while the quarks and leptons are required by gauge invariance to carry non-zero charge under $U(1)_X$. This induces an irreducible rate, $\sigma$BR, for $pp \rightarrow X \rightarrow \ell\ell$ relevant to existing and future resonance searches, and gives rise to higher dimension operators that are stringently constrained by precision electroweak measurements. Combined, these bounds define a maximally allowed region in the space of observables, ($\sigma$BR, $m_X$), outside of which is excluded by naturalness and experimental limits. If natural supersymmetry utilizes non-decoupling D-terms, then the associated $X$ boson can only be observed within this window, providing a model independent `litmus test' for this broad class of scenarios at the LHC. Comparing limits, we find that current LHC results only exclude regions in parameter space which were already disfavored by precision electroweak data.Comment: 7 pages, 9 figure

A Critical Appraisal of Guidelines for Antenatal Care: Components of Care and Priorities in Prenatal Education

There are a variety of published prenatal care (PNC) guidelines that claim a scientific basis for the information included. Four sets of PNC guidelines published between 2005 and 2009 were examined and critiqued. The recommendations for assessment procedures, laboratory testing, and education/counseling topics were analyzed within and between these guidelines. The PNC components were synthesized to provide an organized, comprehensive appendix that can guide providers of antepartum care. The appendix may be used to locate which guidelines addressed which topics to assist practitioners to identify evidence sources. The suggested timing for introducing and reinforcing specific topics is also presented in the appendix. Although education is often assumed to be a vital component of PNC, it was inconsistently included in the guidelines that were reviewed. Even when education was included, important detail was lacking. Addressing each woman\u27s needs as the first priority was suggested historically and remains relevant in current practice to systematically provide care while maintaining the woman as the central player. More attention to gaps in current research is important for the development of comprehensive prenatal guidelines that contribute effectively to the long‐term health and well‐being of women, families, and their communities

Some remarks on PM2.5

Since 1970, the General Physics Department of «Università degli Studi di Torino» has carried out a project research, on inorganic solid particulate matter. The special issue of Annals of Geophysics, published for Professor Giorgio Fiocco’s 70th birthday, gives us the possibility to make some important remarks on this topic, focusing on PM2.5. This has been possible using all the old and new experimental data of the measures made by the authors of this paper since 1970

Limit on the mass of a long-lived or stable gluino

We reinterpret the generic CDF charged massive particle limit to obtain a limit on the mass of a stable or long-lived gluino. Various sources of uncertainty are examined. The $R$-hadron spectrum and scattering cross sections are modeled based on known low-energy hadron physics and the resultant uncertainties are quantified and found to be small compared to uncertainties from the scale dependence of the NLO pQCD production cross sections. The largest uncertainty in the limit comes from the unknown squark mass: when the squark -- gluino mass splitting is small, we obtain a gluino mass limit of 407 GeV, while in the limit of heavy squarks the gluino mass limit is 397 GeV. For arbitrary (degenerate) squark masses, we obtain a lower limit of 322 GeV on the gluino mass. These limits apply for any gluino lifetime longer than $\sim 30$ ns, and are the most stringent limits for such a long-lived or stable gluino.Comment: 15 pages, 5 figures, accepted for publication in JHE