Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression.

Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCR5 regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCR5 alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-delta32 and CCR2-641 polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-641 allele were found in African Americans but not in Caucasians, and the SDF1-3'A/3'A genotype was associated with an accelerated progression to death. In contrast, the CCR5-delta32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.

Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro.

Peripheral blood mononuclear cells (PBMCs) from many asymptomatic individuals infected with human immunodeficiency virus-type 1 (HIV) are unresponsive as measured by in vitro T cell proliferation and interleukin-2 (IL-2) production to influenza virus and synthetic peptides of HIV envelope (Env). Strong influenza virus- and Env-stimulated IL-2 responses and T cell proliferation were restored when cultures were stimulated in the presence of IL-12. Interferon-gamma production by PBMCs from HIV seropositive (HIV+) patients was also restored with IL-12. Furthermore, in vitro antigen-specific production of IL-2 and proliferation of PBMCs from HIV- donors were suppressed by antibody to IL-12, but were not enhanced by addition of exogenous IL-12. Thus, IL-12 may be limiting in PBMCs from HIV+ but not HIV- individuals. These findings demonstrate that IL-12 can restore HIV-specific cell-mediated immunity in vitro in HIV-infected individuals and suggest a potential use of IL-12 in augmenting the diminished immunologic functions associated with HIV infection.

Likelihood analysis of the pMSSM11 in light of LHC 13-TeV data.

We use MasterCode to perform a frequentist analysis of the constraints on a phenomenological MSSM model with 11 parameters, the pMSSM11, including constraints from ∼ 36 /fb of LHC data at 13 TeV and PICO, XENON1T and PandaX-II searches for dark matter scattering, as well as previous accelerator and astrophysical measurements, presenting fits both with and without the ( g - 2 ) µ constraint. The pMSSM11 is specified by the following parameters: 3 gaugino masses M 1 , 2 , 3 , a common mass for the first-and second-generation squarks m q ~ and a distinct third-generation squark mass m q ~ 3 , a common mass for the first-and second-generation sleptons m ℓ ~ and a distinct third-generation slepton mass m τ ~ , a common trilinear mixing parameter A, the Higgs mixing parameter µ , the pseudoscalar Higgs mass M A and tan ß . In the fit including ( g - 2 ) µ , a Bino-like χ ~ 1 0 is preferred, whereas a Higgsino-like χ ~ 1 0 is mildly favoured when the ( g - 2 ) µ constraint is dropped. We identify the mechanisms that operate in different regions of the pMSSM11 parameter space to bring the relic density of the lightest neutralino, χ ~ 1 0 , into the range indicated by cosmological data. In the fit including ( g - 2 ) µ , coannihilations with χ ~ 2 0 and the Wino-like χ ~ 1 ± or with nearly-degenerate first- and second-generation sleptons are active, whereas coannihilations with the χ ~ 2 0 and the Higgsino-like χ ~ 1 ± or with first- and second-generation squarks may be important when the ( g - 2 ) µ constraint is dropped. In the two cases, we present χ 2 functions in two-dimensional mass planes as well as their one-dimensional profile projections and best-fit spectra. Prospects remain for discovering strongly-interacting sparticles at the LHC, in both the scenarios with and without the ( g - 2 ) µ constraint, as well as for discovering electroweakly-interacting sparticles at a future linear e + e - collider such as the ILC or CLIC.

Likelihood analysis of the minimal AMSB model.

We perform a likelihood analysis of the minimal anomaly-mediated supersymmetry-breaking (mAMSB) model using constraints from cosmology and accelerator experiments. We find that either a wino-like or a Higgsino-like neutralino LSP, [Formula: see text], may provide the cold dark matter (DM), both with similar likelihoods. The upper limit on the DM density from Planck and other experiments enforces [Formula: see text] after the inclusion of Sommerfeld enhancement in its annihilations. If most of the cold DM density is provided by the [Formula: see text], the measured value of the Higgs mass favours a limited range of [Formula: see text] (and also for [Formula: see text] if [Formula: see text]) but the scalar mass [Formula: see text] is poorly constrained. In the wino-LSP case, [Formula: see text] is constrained to about [Formula: see text] and [Formula: see text] to [Formula: see text], whereas in the Higgsino-LSP case [Formula: see text] has just a lower limit [Formula: see text] ([Formula: see text]) and [Formula: see text] is constrained to [Formula: see text] in the [Formula: see text] ([Formula: see text]) scenario. In neither case can the anomalous magnetic moment of the muon, [Formula: see text], be improved significantly relative to its Standard Model (SM) value, nor do flavour measurements constrain the model significantly, and there are poor prospects for discovering supersymmetric particles at the LHC, though there are some prospects for direct DM detection. On the other hand, if the [Formula: see text] contributes only a fraction of the cold DM density, future LHC [Formula: see text]-based searches for gluinos, squarks and heavier chargino and neutralino states as well as disappearing track searches in the wino-like LSP region will be relevant, and interference effects enable [Formula: see text] to agree with the data better than in the SM in the case of wino-like DM with [Formula: see text].

Likelihood analysis of supersymmetric SU(5) GUTs.

We perform a likelihood analysis of the constraints from accelerator experiments and astrophysical observations on supersymmetric (SUSY) models with SU(5) boundary conditions on soft SUSY-breaking parameters at the GUT scale. The parameter space of the models studied has seven parameters: a universal gaugino mass [Formula: see text], distinct masses for the scalar partners of matter fermions in five- and ten-dimensional representations of SU(5), [Formula: see text] and [Formula: see text], and for the [Formula: see text] and [Formula: see text] Higgs representations [Formula: see text] and [Formula: see text], a universal trilinear soft SUSY-breaking parameter [Formula: see text], and the ratio of Higgs vevs [Formula: see text]. In addition to previous constraints from direct sparticle searches, low-energy and flavour observables, we incorporate constraints based on preliminary results from 13 TeV LHC searches for jets + [Formula: see text] events and long-lived particles, as well as the latest PandaX-II and LUX searches for direct Dark Matter detection. In addition to previously identified mechanisms for bringing the supersymmetric relic density into the range allowed by cosmology, we identify a novel [Formula: see text] coannihilation mechanism that appears in the supersymmetric SU(5) GUT model and discuss the role of [Formula: see text] coannihilation. We find complementarity between the prospects for direct Dark Matter detection and SUSY searches at the LHC.

Supersymmetric dark matter after LHC run 1.

Different mechanisms operate in various regions of the MSSM parameter space to bring the relic density of the lightest neutralino, [Formula: see text], assumed here to be the lightest SUSY particle (LSP) and thus the dark matter (DM) particle, into the range allowed by astrophysics and cosmology. These mechanisms include coannihilation with some nearly degenerate next-to-lightest supersymmetric particle such as the lighter stau [Formula: see text], stop [Formula: see text] or chargino [Formula: see text], resonant annihilation via direct-channel heavy Higgs bosons H / A, the light Higgs boson h or the Z boson, and enhanced annihilation via a larger Higgsino component of the LSP in the focus-point region. These mechanisms typically select lower-dimensional subspaces in MSSM scenarios such as the CMSSM, NUHM1, NUHM2, and pMSSM10. We analyze how future LHC and direct DM searches can complement each other in the exploration of the different DM mechanisms within these scenarios. We find that the [Formula: see text] coannihilation regions of the CMSSM, NUHM1, NUHM2 can largely be explored at the LHC via searches for [Formula: see text] events and long-lived charged particles, whereas their H / A funnel, focus-point and [Formula: see text] coannihilation regions can largely be explored by the LZ and Darwin DM direct detection experiments. We find that the dominant DM mechanism in our pMSSM10 analysis is [Formula: see text] coannihilation: parts of its parameter space can be explored by the LHC, and a larger portion by future direct DM searches.

The pMSSM10 after LHC run 1.

We present a frequentist analysis of the parameter space of the pMSSM10, in which the following ten soft SUSY-breaking parameters are specified independently at the mean scalar top mass scale [Formula: see text]: the gaugino masses [Formula: see text], the first-and second-generation squark masses [Formula: see text], the third-generation squark mass [Formula: see text], a common slepton mass [Formula: see text] and a common trilinear mixing parameter A, as well as the Higgs mixing parameter [Formula: see text], the pseudoscalar Higgs mass [Formula: see text] and [Formula: see text], the ratio of the two Higgs vacuum expectation values. We use the MultiNest sampling algorithm with [Formula: see text]1.2 [Formula: see text] points to sample the pMSSM10 parameter space. A dedicated study shows that the sensitivities to strongly interacting sparticle masses of ATLAS and CMS searches for jets, leptons [Formula: see text][Formula: see text] signals depend only weakly on many of the other pMSSM10 parameters. With the aid of the Atom and Scorpion codes, we also implement the LHC searches for electroweakly interacting sparticles and light stops, so as to confront the pMSSM10 parameter space with all relevant SUSY searches. In addition, our analysis includes Higgs mass and rate measurements using the HiggsSignals code, SUSY Higgs exclusion bounds, the measurements of [Formula: see text] by LHCb and CMS, other B-physics observables, electroweak precision observables, the cold dark matter density and the XENON100 and LUX searches for spin-independent dark matter scattering, assuming that the cold dark matter is mainly provided by the lightest neutralino [Formula: see text]. We show that the pMSSM10 is able to provide a supersymmetric interpretation of [Formula: see text], unlike the CMSSM, NUHM1 and NUHM2. As a result, we find (omitting Higgs rates) that the minimum [Formula: see text] with 18 degrees of freedom (d.o.f.) in the pMSSM10, corresponding to a [Formula: see text] probability of 30.8 %, to be compared with [Formula: see text] in the CMSSM (NUHM1) (NUHM2). We display the one-dimensional likelihood functions for sparticle masses, and we show that they may be significantly lighter in the pMSSM10 than in the other models, e.g., the gluino may be as light as [Formula: see text]1250 [Formula: see text] at the 68 % CL, and squarks, stops, electroweak gauginos and sleptons may be much lighter than in the CMSSM, NUHM1 and NUHM2. We discuss the discovery potential of future LHC runs, [Formula: see text] colliders and direct detection experiments.

Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin.

OBJECTIVE: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. DESIGN AND METHODS: PBMC from HIV-1 infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-gamma, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. RESULTS: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-gamma, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiment indicated that antigen-stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. CONCLUSIONS: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.

Anti-CCR5 antibodies in sera of HIV-positive individuals.

One of the proposed mechanisms for resistance to human immunodeficiency virus-1 (HIV-1) infection is the presence of antibodies against receptor for CC-chemokines (CCR5). These antibodies, detected in sera of uninfected individuals exposed to HIV, have been shown to downmodulate surface CCR5 in vivo and are able to neutralize the infectivity of CCR5 strains in vitro. To address the potential role of anti-CCR5 antibodies in HIV infection, we analyzed anti-CCR5 antibody levels in plasma from HIV-infected patients who present a wide range of CD4(+) T-cell counts and viral load. Increased levels of anti-CCR5 antibodies were found in plasma from 13/46 HIV-positive donors compared with healthy controls (0/36). However, antibody levels were not associated with disease stage evaluated by CD4(+) T-cell counts and viral load.

A close look at alcohol gel as an antimicrobial sanitizing agent.

BACKGROUND: Hand transmission of microbes by health care workers is a primary cause of nosocomial infections in both long-term and acute care facilities. Compliance with effective handwashing and hand sanitization regimens can break this cycle. METHODS: We investigated the antimicrobial efficacy and irritation potential of 5 handwash product regimens: a nonantimicrobial lotion soap, an antimicrobial lotion soap, an alcohol gel sanitizer, a nonantimicrobial lotion soap with an alcohol gel sanitizer, and an antimicrobial lotion soap with an alcohol gel sanitizer. The regimens were evaluated by using a Healthcare Personnel Handwash procedure, and irritation was assessed by using expert hand evaluation after 25 consecutive washes. RESULTS: The Healthcare Personnel Handwash data showed that the mean log reductions from baseline were greatest for the lotion soaps with alcohol gel sanitizer, less for the alcohol and the antimicrobial soap alone, and least for the bland soap. All of the product regimens showed a low potential for skin irritation. CONCLUSION: In terms of both microorganism reduction and skin irritation, the most effective product regimens were the use of alcohol gel sanitizer in combination with either an antimicrobial or a plain lotion soap.

Static in situ calibration of force plates.

An in situ calibration protocol for ground-to-foot force measuring platforms is described. The methodology allows verification of the function of the force plate and allows accurate calibration for three force and moment channels. The effect of cross-sensitivity on recorded data is discussed along with the need for improvements in methodology to quantify this property.

Near-drowning-associated Aeromonas pneumonia.

Aeromonas is increasingly recognized as a human pathogen that causes a variety of different infections. Aeromonas has rarely been reported as a cause of respiratory infection, and it has been described in near-drowning-associated pneumonia. This article reviews a case of Aeromonas sobria pneumonia associated with a near drowning and considers the clinical and epidemiological characteristics of 10 previously reported cases. Nearly all of the cases involved young healthy men, a rapid development of pneumonia and sepsis after a brief stable period postimmersion, and bilateral infiltrates on chest radiography. A very high rate of positive blood cultures and mortality was also noted. The epidemiological and clinical data in this review may be helpful to the clinician caring for near-drowning victims. Although prophylactic antibiotics are not recommended for near-drowning victims, broad-spectrum antibiotics should be rapidly instituted with any evidence of infection.

Quality framework for force plate testing.

Following work done in C.E.C. project AIM 2002 CAMARC II, a framework of the relevant standards for testing equipment used in laboratories analysing human movement is presented. In particular, gait analysis laboratories may provide a service for a clinical team considering treatment such as surgical intervention or provision of orthoses. In this case the analysis and equipment used in the analysis must have assured quality so that the correct clinical interpretation of the results is possible. The operation of a gait analysis laboratory may be described in quality standards terminology as the operation of a 'special process'. The operation of a special process requires that particular attention be paid to procedures including confirmation of the equipment and regular testing to ensure correct operation of the equipment. In general this is difficult to achieve since equipment manufacturers still have to address this technical requirement. Although difficult, these procedures must be accomplished in the operation of a special process. Passages of the most pertinent standards are presented and a methodology of a periodic confirmation and regular spot checking of equipment suggested to ensure its correct operation. Although force plates are specifically addressed, the framework could be applied to other dynamometers and measurement equipment.

Clinical prognosis of patients with early-stage human immunodeficiency virus (HIV) disease: contribution of HIV-1 RNA and T lymphocyte subset quantitation.

Systems for the staging of individuals with human immunodeficiency virus type 1 (HIV-1) infection were developed 15 years ago. Subsequently, assays for quantitating HIV-1 RNA and immunophenotyping of lymphocyte subsets have been developed and validated. The utility of these assays for improved staging in early disease was evaluated in 256 HIV-infected adults (52% minority) with CD4 counts > or = 400 cells/microL followed in U.S. military medical centers before the highly active anti-retroviral therapy era. HIV viral load (RNA) was quantitated; the frequencies of select CD4+ immunophenotypes were determined in 112 subjects. The results were analyzed in relation to three outcome measures: death, first acquired immunodeficiency syndrome-defining opportunistic infection, and CD4 count < or = 200 cells/microL. Serum RNA level and CD4 count were each found to be predictive of all three outcomes. In addition, increases in the T-cell subsets CD28-CD4+ and CD29+CD26-CD4+ were found to be independently predictive of more rapid progression. The classification of early-stage HIV patients is improved by the quantitation of both viral RNA and T-lymphocyte subsets.

Implications of improved Higgs mass calculations for supersymmetric models.

We discuss the allowed parameter spaces of supersymmetric scenarios in light of improved Higgs mass predictions provided by FeynHiggs 2.10.0. The Higgs mass predictions combine Feynman-diagrammatic results with a resummation of leading and subleading logarithmic corrections from the stop/top sector, which yield a significant improvement in the region of large stop masses. Scans in the pMSSM parameter space show that, for given values of the soft supersymmetry-breaking parameters, the new logarithmic contributions beyond the two-loop order implemented in FeynHiggs tend to give larger values of the light CP-even Higgs mass, [Formula: see text], in the region of large stop masses than previous predictions that were based on a fixed-order Feynman-diagrammatic result, though the differences are generally consistent with the previous estimates of theoretical uncertainties. We re-analyse the parameter spaces of the CMSSM, NUHM1 and NUHM2, taking into account also the constraints from CMS and LHCb measurements of [Formula: see text]and ATLAS searches for [Formula: see text] events using 20/fb of LHC data at 8 TeV. Within the CMSSM, the Higgs mass constraint disfavours [Formula: see text], though not in the NUHM1 or NUHM2.

The NUHM2 after LHC Run 1.

We make a frequentist analysis of the parameter space of the NUHM2, in which the soft supersymmetry (SUSY)-breaking contributions to the masses of the two Higgs multiplets, [Formula: see text], vary independently from the universal soft SUSY-breaking contributions [Formula: see text] to the masses of squarks and sleptons. Our analysis uses the MultiNest sampling algorithm with over [Formula: see text] points to sample the NUHM2 parameter space. It includes the ATLAS and CMS Higgs mass measurements as well as the ATLAS search for supersymmetric jets + [Formula: see text] signals using the full LHC Run 1 data, the measurements of [Formula: see text] by LHCb and CMS together with other B-physics observables, electroweak precision observables and the XENON100 and LUX searches for spin-independent dark-matter scattering. We find that the preferred regions of the NUHM2 parameter space have negative SUSY-breaking scalar masses squared at the GUT scale for squarks and sleptons, [Formula: see text], as well as [Formula: see text]. The tension present in the CMSSM and NUHM1 between the supersymmetric interpretation of [Formula: see text] and the absence to date of SUSY at the LHC is not significantly alleviated in the NUHM2. We find that the minimum [Formula: see text] with 21 degrees of freedom (dof) in the NUHM2, to be compared with [Formula: see text] in the CMSSM, and [Formula: see text] in the NUHM1. We find that the one-dimensional likelihood functions for sparticle masses and other observables are similar to those found previously in the CMSSM and NUHM1.

The CMSSM and NUHM1 after LHC Run 1.

We analyze the impact of data from the full Run 1 of the LHC at 7 and 8 TeV on the CMSSM with [Formula: see text] and [Formula: see text] and the NUHM1 with [Formula: see text], incorporating the constraints imposed by other experiments such as precision electroweak measurements, flavour measurements, the cosmological density of cold dark matter and the direct search for the scattering of dark matter particles in the LUX experiment. We use the following results from the LHC experiments: ATLAS searches for events with [Formula: see text] accompanied by jets with the full 7 and 8 TeV data, the ATLAS and CMS measurements of the mass of the Higgs boson, the CMS searches for heavy neutral Higgs bosons and a combination of the LHCb and CMS measurements of [Formula: see text] and [Formula: see text]. Our results are based on samplings of the parameter spaces of the CMSSM for both [Formula: see text] and [Formula: see text] and of the NUHM1 for [Formula: see text] with 6.8[Formula: see text], 6.2[Formula: see text] and 1.6[Formula: see text] points, respectively, obtained using the MultiNest tool. The impact of the Higgs-mass constraint is assessed using FeynHiggs 2.10.0, which provides an improved prediction for the masses of the MSSM Higgs bosons in the region of heavy squark masses. It yields in general larger values of [Formula: see text] than previous versions of FeynHiggs, reducing the pressure on the CMSSM and NUHM1. We find that the global [Formula: see text] functions for the supersymmetric models vary slowly over most of the parameter spaces allowed by the Higgs-mass and the [Formula: see text] searches, with best-fit values that are comparable to the [Formula: see text] for the best Standard Model fit. We provide 95 % CL lower limits on the masses of various sparticles and assess the prospects for observing them during Run 2 of the LHC.

Q fever meningoencephalitis in a soldier returning from the Persian Gulf War.

Acute infection with Coxiella burnetti usually results in a self-limited illness requiring a high index of clinical suspicion for diagnosis. Although headache is a common presentation of acute infection with this agent, focal neurological deficits are considered to be limited to chronic infection, most commonly caused by emboli from endocarditis. We report the case of a soldier returning from Desert Storm who presented with headache and a crescendo pattern of transient ischemic attacks and had serology consistent with an acute Q fever infection. The English-language literature on central nervous system infection caused by Coxiella burnetti is reviewed.