Endothelin-1 Predicts Hemodynamically Assessed Pulmonary Arterial Hypertension in HIV Infection.

BackgroundHIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. ET-1 is a robust vasoconstrictor and key mediator of pulmonary vascular homeostasis. Higher levels of ET-1 predict disease severity and mortality in other forms of PAH, and endothelin receptor antagonists are central to treatment, including in HIV-associated PAH. The direct relationship between ET-1 and PAH in HIV-infected individuals is not well described.MethodsWe measured ET-1 and estimated pulmonary artery systolic pressure (PASP) with transthoracic echocardiography (TTE) in 106 HIV-infected individuals. Participants with a PASP ≥ 30 mmHg (n = 65) underwent right heart catheterization (RHC) to definitively diagnose PAH. We conducted multivariable analysis to identify factors associated with PAH.ResultsAmong 106 HIV-infected participants, 80% were male, the median age was 52 years and 77% were on antiretroviral therapy. ET-1 was significantly associated with higher values of PASP [14% per 0.1 pg/mL increase in ET-1, p = 0.05] and PASP ≥ 30 mmHg [PR (prevalence ratio) = 1.24, p = 0.012] on TTE after multivariable adjustment for PAH risk factors. Similarly, among the 65 individuals who underwent RHC, ET-1 was significantly associated with higher values of mean pulmonary artery pressure and PAH (34%, p = 0.003 and PR = 2.43, p = 0.032, respectively) in the multivariable analyses.ConclusionsHigher levels of ET-1 are independently associated with HIV-associated PAH as hemodynamically assessed by RHC. Our findings suggest that excessive ET-1 production in the setting of HIV infection impairs pulmonary endothelial function and contributes to the development of PAH

Physician Accuracy in Interpreting Potential ST‐Segment Elevation Myocardial Infarction Electrocardiograms

Background: With adoption of telemedicine, physicians are increasingly asked to diagnose ST‐segment elevation myocardial infarctions (STEMIs) based on electrocardiograms (ECGs) with minimal associated clinical information. We sought to determine physicians' diagnostic agreement and accuracy when interpreting potential STEMI ECGs. Methods and Results: A cross‐sectional survey was performed consisting of 36 deidentified ECGs that had previously resulted in putative STEMI diagnoses. Emergency physicians, cardiologists, and interventional cardiologists participated in the survey. For each ECG, physicians were asked, “based on the ECG above, is there a blocked coronary artery present causing a STEMI?” The reference standard for ascertaining the STEMI diagnosis was subsequent emergent coronary arteriography. Responses were analyzed with generalized estimating equations to account for nested and repeated measures. One hundred twenty‐four physicians interpreted a total of 4392 ECGs. Among all physicians, interreader agreement (kappa) for ECG interpretation was 0.33, reflecting poor agreement. The sensitivity to identify “true” STEMIs was 65% (95% CI: 63 to 67) and the specificity was 79% (95% CI: 77 to 81). There was a 6% increase in the odds of accurate ECG interpretation for every 5 years of experience since medical school graduation (OR 1.06, 95% CI: 1.02 to 1.10, P=0.01). After adjusting for experience, there was no significant difference in the odds of accurate interpretation by specialty—Emergency Medicine (reference), General Cardiology (AOR 0.97, 95% CI: 0.79 to 1.2, P=0.80), or Interventional Cardiology physicians (AOR 1.24, 95% CI: 0.93 to 1.7, P=0.15). Conclusions: There is significant physician disagreement in interpreting ECGs with features concerning for STEMI. Such ECGs lack the necessary sensitivity and specificity to act as a suitable “stand‐alone” diagnostic test

Renormalization of Hamiltonian Field Theory; a non-perturbative and non-unitarity approach

Renormalization of Hamiltonian field theory is usually a rather painful algebraic or numerical exercise. By combining a method based on the coupled cluster method, analysed in detail by Suzuki and Okamoto, with a Wilsonian approach to renormalization, we show that a powerful and elegant method exist to solve such problems. The method is in principle non-perturbative, and is not necessarily unitary.Comment: 16 pages, version shortened and improved, references added. To appear in JHE

Sigma model approach to string theory effective actions with tachyons

Motivated by recent discussions of actions for tachyon and vector fields related to tachyon condensation in open string theory we review and clarify some aspects of their derivation within sigma model approach. In particular, we demonstrate that the renormalized partition function $Z(T,A)$ of boundary sigma model gives the effective action for massless vectors which is consistent with string S-matrix and beta function, resolving an old problem with this suggestion in bosonic string case at the level of the leading $F^2 (dF)^2$ derivative corrections to Born-Infeld action. We give manifestly gauge invariant definition of $Z(T,A)$ in non-abelian NSR open string theory and check that its derivative reproduces the tachyon beta function in a particular scheme. We also discuss derivation of similar actions for tachyon and massless modes in closed bosonic and NSR (type 0) string theories.Comment: 26 pages, harvmac. To appear in the special issue of J. Math. Phys. on Strings, Branes and M-theory. v4: minor editorial changes, version to appear in JM

HIV Infection and the Risk of World Health Organization-Defined Sudden Cardiac Death

Background People living with HIV have higher sudden cardiac death (SCD) rates compared with the general population. Whether HIV infection is an independent SCD risk factor is unclear. Methods and Results This study evaluated participants from the Veterans Aging Cohort Study, an observational, longitudinal cohort of veterans with and without HIV infection matched 1:2 on age, sex, race/ethnicity, and clinical site. Baseline for this study was a participant\u27s first clinical visit on or after April 1, 2003. Participants were followed through December 31, 2014. Using Cox proportional hazards regression, we assessed whether HIV infection, CD4 cell counts, and/or HIV viral load were associated with World Health Organization (WHO)–defined SCD risk. Among 144 336 participants (30% people living with HIV), the mean (SD) baseline age was 50.0 years (10.6 years), 97% were men, and 47% were of Black race. During follow‐up (median, 9.0 years), 3035 SCDs occurred. HIV infection was associated with increased SCD risk (hazard ratio [HR], 1.14; 95% CI, 1.04–1.25), adjusting for possible confounders. In analyses with time‐varying CD4 and HIV viral load, people living with HIV with CD4 counts \u3c 200 cells/mm3 (HR, 1.57; 95% CI, 1.28–1.92) or viral load \u3e 500 copies/mL (HR, 1.70; 95% CI, 1.46–1.98) had increased SCD risk versus veterans without HIV. In contrast, people living with HIV who had CD4 cell counts \u3e 500 cells/mm3 (HR, 1.03; 95% CI, 0.90–1.18) or HIV viral load \u3c 500 copies/mL (HR, 0.97; 95% CI, 0.87–1.09) were not at increased SCD risk. Conclusions HIV infection is associated with increased risk of WHO‐defined SCD among those with elevated HIV viral load or low CD4 cell counts

Antiphospholipid antibodies in black south africans with hiv and acute coronary syndromes: prevalence and clinical correlates

<p>Abstract</p> <p>Background</p> <p>HIV infection is associated with a high prevalence of antiphospholipid antibodies (aPL) and increased thrombotic events but the aetiopathogenic link between the two is unclear.</p> <p>Findings</p> <p>Prospective single centre study from Soweto, South Africa, comparing the prevalence of aPL in highly active anti-retroviral therapy (HAART) naïve HIV positive and negative patients presenting with Acute Coronary Syndromes (ACS). Between March 2004 and February 2008, 30 consecutive black South African HIV patients with ACS were compared to 30 black HIV negative patients with ACS. The HIV patients were younger (43 ± 7 vs. 54 ± 13, p = 0.004) and besides smoking (73% vs. 33%, p = 0.002) and lower HDL levels (0.8 ± 0.3 vs. 1.1 ± 0.4, p = 0.001) had fewer risk factors than the control group. HIV patients had a higher prevalence of anticardiolipin (aCL) IgG (47% vs. 10%, p = 0.003) and anti-prothrombin (aPT) IgG antibodies (87% vs. 21%, p < 0.001) but there was no difference in the prevalence of the antiphospholipid syndrome (44% vs. 24%, p = N/S) and aPL were not predictive of clinical or angiographic outcomes.</p> <p>Conclusions</p> <p>Treatment naïve black South African HIV patients with ACS are younger with fewer traditional coronary risk factors than HIV negative patients but have a higher prevalence and different expression of aPL which is likely to be an epiphenomenon of the HIV infection rather than causally linked to thrombosis and the pathogenesis of ACS.</p

The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts

Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al

HIV patients stable on ART retain evidence of a high CMV load but changes to Natural Killer cell phenotypes reflect both HIV and CMV

Background: Whilst ART corrects many effects of HIV disease, T cell populations retain features of accelerated immunological aging. Methods: Here we analyse phenotypic changes to natural killer (NK) cells in HIV patients who began ART with <200 CD4 T-cells/µl and maintained virological control for 12-17 years, compared with CMV seropositive and seronegative healthy control donors. Results: Humoral responses to CMV antigens (lysate, gB, IE-1) remain elevated in the patients (P <0.0001) despite the long duration of ART. Patient's NK cells responded poorly to K562 cells when assessed by CD107a and IFNγ, but this could not be attributed to CMV as responses were low in CMV-seronegative controls. Moreover HIV (and not CMV) increased expression of CD57 on CD56lo cells. Conclusions: Comparisons with published studies suggest that CMV accelerates age-related increases in CD57 expression but levels plateau by 60-70 years of age, so the effect of CMV disappears. In HIV patients the plateau is higher and perhaps reached sooner