Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver

Hereditary hemochromatosis is the result of pathogenic variants in multiple genes that can result in increased body iron stores with excess iron deposited in various organs, including the liver, pancreas, and heart. The two most important advances in the field over the past 30 years have been the identification of the HFE gene (and the associated p.Cys282Tyr substitution), and the discovery of the hormone hepcidin, which is inappropriately low in this condition and is the pathophysiological basis of the increased iron absorption. The identification of mutations in the HFE gene and subsequent studies have reshaped diagnostic algorithms resulting in a marked reduction in the need for liver biopsy. The discovery of hepcidin has resulted in many studies that have dramatically improved our understanding of iron metabolism with clear potential therapeutic implications. The variable clinical expression of hemochromatosis has puzzled clinicians and scientists, and our understanding of the factors that influence the phenotype has increased over recent years. Nevertheless, increased clinician and patient awareness, early diagnosis, and therapeutic phlebotomy to restore normal life expectancy are still the cornerstones of management. The classic triad of cirrhosis, diabetes, and skin pigmentation is now uncommon, and many patients are diagnosed with minimal or no symptoms

Second-order corrections to slow-roll inflation in the brane cosmology

We calculate the power spectrum, spectral index, and running spectral index for the RS-II brane inflation in the high-energy regime using the slow-roll expansion. There exist several modifications. As an example, we take the power-law inflation by choosing an inverse power-law potential. When comparing these with those arisen in the standard inflation, we find that the power spectrum is enhanced and the spectral index is suppressed, while the running spectral index becomes zero as in the standard inflation. However, since second-order corrections are rather small, these could not play a role of distinguishing between standard and brane inflations.Comment: 6 page

Second-order corrections to noncommutative spacetime inflation

We investigate how the uncertainty of noncommutative spacetime affects on inflation. For this purpose, the noncommutative parameter $\mu_0$ is taken to be a zeroth order slow-roll parameter. We calculate the noncommutative power spectrum up to second order using the slow-roll expansion. We find corrections arisen from a change of the pivot scale and the presence of a variable noncommutative parameter, when comparing with the commutative power spectrum. The power-law inflation is chosen to obtain explicit forms for the power spectrum, spectral index, and running spectral index. In cases of the power spectrum and spectral index, the noncommutative effect of higher-order corrections compensates for a loss of higher-order corrections in the commutative case. However, for the running spectral index, all higher-order corrections to the commutative case always provide negative spectral indexes, which could explain the recent WMAP data.Comment: 15 pages, no figure, version published in PR

Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma

The global burden of hepatocellular carcinoma (HCC), one of the frequent causes of cancer-related deaths worldwide, is rapidly increasing partly due to the limited treatment options available for this disease and recurrence due to therapy resistance. Immune checkpoint inhibitors that are proved to be beneficial in the treatment of advanced melanoma and other cancer types are currently in clinical trials in HCC. These ongoing trials are testing the efficacy and safety of a few select checkpoints in HCC. Similar to observations in other cancers, these immune checkpoint blockade treatments as monotherapy may benefit only a fraction of HCC patients. Studies that assess the prevalence and distribution of other immune checkpoints/modulatory molecules in HCC have been limited. Moreover, robust predictors to identify which HCC patients will respond to immunotherapy are currently lacking. The objective of this study is to perform a comprehensive evaluation on different immune modulators as predictive biomarkers to monitor HCC patients at high risk for poor prognosis. We screened publically available HCC patient databases for the expression of previously well described immune checkpoint regulators and evaluated the usefulness of these immune modulators to predict high risk, patient overall survival and recurrence. We also identified the immune modulators that synergized with known immune evasion molecules programmed death receptor ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and correlated with worse patient outcomes. We evaluated the association between the expression of epithelial-to-mesenchymal transition (EMT) markers and PD-L1 in HCC patient tumors. We also examined the relationship of tumor mutational burden with HCC patient survival. Notably, expression of immune modulators B7-H4, PD-L2, TIM-3, and VISTA were independently associated with worse prognosis, while B7-H4, CD73, and VISTA predicted low recurrence-free survival. Moreover, the prognosis of patients expressing high PD-L1 with high B7-H4, TIM-3, VISTA, CD73, and PD-L2 expression was significantly worse. Interestingly, PD-L1 expression in HCC patients in the high-risk group was closely associated with EMT marker expression and prognosticates poor survival. In HCC patients, high tumor mutational burden (TMB) predicted worse patient outcomes than those with low TMB

Grand Unified Inflation Confronts WMAP

In a class of realistic four and five dimensional supersymmetric grand unified models, the scalar spectral index is found to be $n_s=0.98 (\pm 0.01)$, in excellent agreement with the values determined by several previous experiments and most recently by the Wilkinson Microwave Anisotropy Probe (WMAP). The models predict $dn_s/d{\rm ln}k\sim 10^{-3}$ and a negligible tensor-to-scalar ratio $r\sim 10^{-8}$. A new five dimensional supersymmetric SO(10) model along these is presented in which inflation is associated with the breaking of SO(10) to SU(5) at scale $M$, with $\delta T/T\propto (M/M_{\rm Planck})^2$, so that $M\simeq 10^{16}$ GeV. The inflaton decay leads to the observed baryon asymmetry via leptogenesis. We also discuss how the monopole problem is solved without the use of non-renormalizable terms.Comment: A new resolution of the monopole problem proposed. 1+9 page

Supermodel Analysis of Galaxy Clusters

[abridged] We present the analysis of the X-ray brightness and temperature profiles for six clusters belonging to both the Cool Core and Non Cool Core classes, in terms of the Supermodel (SM) developed by Cavaliere, Lapi & Fusco-Femiano (2009). Based on the gravitational wells set by the dark matter halos, the SM straightforwardly expresses the equilibrium of the IntraCluster Plasma (ICP) modulated by the entropy deposited at the boundary by standing shocks from gravitational accretion, and injected at the center by outgoing blastwaves from mergers or from outbursts of Active Galactic Nuclei. The cluster set analyzed here highlights not only how simply the SM represents the main dichotomy Cool vs. Non Cool Core clusters in terms of a few ICP parameters governing the radial entropy run, but also how accurately it fits even complex brightness and temperature profiles. For Cool Core clusters like A2199 and A2597, the SM with a low level of central entropy straightforwardly yields the characteristic peaked profile of the temperature marked by a decline toward the center, without requiring currently strong radiative cooling and high mass deposition rates. Non Cool Core clusters like A1656 require instead a central entropy floor of a substantial level, and some like A2256 and even more A644 feature structured temperature profiles that also call for a definite floor extension; in such conditions the SM accurately fits the observations, and suggests that in these clusters the ICP has been just remolded by a merger event, in the way of a remnant cool core. The SM also predicts that dark matter halos with high concentration should correlate with flatter entropy profiles and steeper brightness in the outskirts; this is indeed the case with A1689.Comment: 12 pages, 11 figures, uses RevTeX4 + emulateapj.cls and apjfonts.sty. Accepted by Ap

Planck 2013 results. XXII. Constraints on inflation

We analyse the implications of the Planck data for cosmic inflation. The Planck nominal mission temperature anisotropy measurements, combined with the WMAP large-angle polarization, constrain the scalar spectral index to be ns = 0:9603 _ 0:0073, ruling out exact scale invariance at over 5_: Planck establishes an upper bound on the tensor-to-scalar ratio of r < 0:11 (95% CL). The Planck data thus shrink the space of allowed standard inflationary models, preferring potentials with V00 < 0. Exponential potential models, the simplest hybrid inflationary models, and monomial potential models of degree n _ 2 do not provide a good fit to the data. Planck does not find statistically significant running of the scalar spectral index, obtaining dns=dln k = 0:0134 _ 0:0090. We verify these conclusions through a numerical analysis, which makes no slowroll approximation, and carry out a Bayesian parameter estimation and model-selection analysis for a number of inflationary models including monomial, natural, and hilltop potentials. For each model, we present the Planck constraints on the parameters of the potential and explore several possibilities for the post-inflationary entropy generation epoch, thus obtaining nontrivial data-driven constraints. We also present a direct reconstruction of the observable range of the inflaton potential. Unless a quartic term is allowed in the potential, we find results consistent with second-order slow-roll predictions. We also investigate whether the primordial power spectrum contains any features. We find that models with a parameterized oscillatory feature improve the fit by __2 e_ _ 10; however, Bayesian evidence does not prefer these models. We constrain several single-field inflation models with generalized Lagrangians by combining power spectrum data with Planck bounds on fNL. Planck constrains with unprecedented accuracy the amplitude and possible correlation (with the adiabatic mode) of non-decaying isocurvature fluctuations. The fractional primordial contributions of cold dark matter (CDM) isocurvature modes of the types expected in the curvaton and axion scenarios have upper bounds of 0.25% and 3.9% (95% CL), respectively. In models with arbitrarily correlated CDM or neutrino isocurvature modes, an anticorrelated isocurvature component can improve the _2 e_ by approximately 4 as a result of slightly lowering the theoretical prediction for the ` <_ 40 multipoles relative to the higher multipoles. Nonetheless, the data are consistent with adiabatic initial conditions

A Markov chain Monte Carlo analysis of the CMSSM

We perform a comprehensive exploration of the Constrained MSSM parameter space employing a Markov Chain Monte Carlo technique and a Bayesian analysis. We compute superpartner masses and other collider observables, as well as a cold dark matter abundance, and compare them with experimental data. We include uncertainties arising from theoretical approximations as well as from residual experimental errors of relevant Standard Model parameters. We delineate probability distributions of the CMSSM parameters, the collider and cosmological observables as well as a dark matter direct detection cross section. The 68% probability intervals of the CMSSM parameters are: 0.52 TeV &lt; m1/2 &lt; 1.26 TeV, m0 &lt; 2.10 TeV, -0.34 TeV &lt; A0 &lt; 2.41 TeV and 38.5 &lt; tan \u3b2 &lt; 54.6. Generally, large fractions of high probability ranges of the superpartner masses will be probed at the LHC. For example, we find that the probability of mg &lt; 2.7TeV is 78%, of mqR &lt; 2.5TeV is 85% and of m\u3c7\ub11 &lt; 0.8TeV is 65%. As regards the other observables, for example at 68% probability we find 3.5 710-9 &lt; BR(Bs \u2192 \u3bc+\u3bc-) &lt; 1.7 710-8, 1.9 710-10 &lt; \u3b4a SUSY \u3bc &lt; 9.9 710-10 and 1 7 10 -10 pb &lt; \u3c3SIp &lt; 1 7 10 -8 pb for direct WIMP detection. We highlight a complementarity between LHC and WIMP dark matter searches in exploring the CMSSM parameter space. We further expose a number of correlations among the observables, in particular between BR(Bs \u2192 \u3bc+\u3bc-) and BR(B \u2192 X s\u3b3) or \u3c3SIp. Once SUSY is discovered, this and other correlations may prove helpful in distinguishing the CMSSM from other supersymmetric models. We investigate the robustness of our results in terms of the assumed ranges of CMSSM parameters and the effect of the (g - 2)\u3bc anomaly which shows some tension with the other observables. We find that the results for m0, and the observables which strongly depend on it, are sensitive to our assumptions, while our conclusions for the other variables are robust

The soft X-ray properties of AGN from the CJF sample; A correlation analysis between soft X-ray and VLBI properties

Context: We present the soft X-ray properties obtained in the ROSAT All-Sky survey and from pointed PSPC observations for the AGN in the complete flux-density limited Caltech-Jodrell Bank flat spectrum sample (hereafter CJF). CJF is a VLBI survey (VLBA observations at 5 GHz) of 293 AGN with detailed information on jet component motion. Aims: We investigate and discuss the soft X-ray properties of this AGN sample and examine the correlations between X-ray and VLBI properties, test beaming scenarios, and search for the discriminating properties between the sub-samples detected and not detected by ROSAT. Methods: Comparing the observed and the predicted X-ray fluxes by assuming an Inverse Compton (IC) origin for the observed X-rays, we compute the beaming or Doppler factor and contrast the Doppler factors with other beaming indicators derived from the VLBI observations, such as the value of the expansion velocity, and the observed and intrinsic brightness temperature. In addition, we investigate the large-scale radio structure of the AGN and the difference between the pc- and kpc-scale structure (misalignment) with regard to the X-ray observations.Results: We find a nearly linear relation between X-ray and radio luminosities, and a similar but less stringent behaviour for the relation between optical and X-ray luminosities. The quasars detected by ROSAT have a different $\beta_{\rm app}$-redshift relationship compared to the non-detected ones. ROSAT-detected sources tend to reveal extended large-scale radio structures more often. Conclusions: We conclude that beaming alone cannot explain the observed dichotomy of ROSAT detection or non-detection and assume that the large-scale jet structure plays a decisive role