Differential Reduction in Monocyte Activation and Vascular Inflammation With Integrase Inhibitor-Based Initial Antiretroviral Therapy Among HIV-Infected Individuals.

BACKGROUND: Little is known about how different antiretrovirals effect inflammation and monocyte activation in human immunodeficiency virus (HIV) infection. METHODS: We examined plasma specimens obtained during a randomized, double-blinded trial in antiretroviral therapy (ART)-naive HIV-infected adults which compared the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/c/FTC/TDF) with that of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). From a random sample achieving an HIV type 1 RNA load of <50 copies/mL by week 48, changes over 24 and 48 weeks in levels of biomarkers of monocyte activation (soluble CD14 [sCD14] and soluble CD163 [sCD163]), systemic inflammation (soluble tumor necrosis factor α receptor I [sTNF-RI], interleukin 6 [IL-6], and high-sensitivity C-reactive protein [hsCRP]), and vascular inflammation (lipoprotein-associated phospholipase A2 [Lp-PLA2]) were compared. Multivariable linear regression was used. RESULTS: A total of 200 participants were included. Significant differences favoring EVG/c/FTC/TDF were noted for changes in sCD14, hsCRP, and Lp-PLA2 levels. Factors independently associated with a larger decrease in the sCD14 level included random assignment to receive EVG/c/FTC/TDF, higher baseline sCD14 level, and larger decreases in hsCRP and sCD163 levels; factors associated with a larger Lp-PLA2 decrease included higher baseline Lp-PLA2 and IL-6 levels, smaller increases in total cholesterol and triglycerides levels, a larger decrease in the sCD14 level, and a smaller decrease in the sCD163 level. CONCLUSIONS: EVG/c/FTC/TDF led to greater decreases in sCD14, hsCRP, and Lp-PLA2 levels, compared with EFV/FTC/TDF. Randomization group independently predicted the change in sCD14 level, and changes in monocyte activation independently predicted the change in Lp-PLA2 level. There appears to be a more favorable effect of the integrase inhibitor EVG over efavirenz on immune activation, which may affect vascular inflammation.

Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection.

BACKGROUND: While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear. METHODS: We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4(+) T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency. RESULTS: Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4(+) T-cell count (all P ≤ .001). A higher percentage of CD38(+)HLA-DR(+) cells in the CD8(+) T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4(+) T-cell count. Frequencies of senescent (defined as CD28(-)CD57(+) cells), exhausted (defined as PD1(+) cells), naive, and CMV-specific T cells did not predict mortality. CONCLUSIONS: Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.

Sevelamer does not decrease lipopolysaccharide or soluble CD14 levels but decreases soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol levels in individuals with untreated HIV infection.

UNLABELLED: Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits. CLINICAL TRIALS REGISTRATION: NCT 01543958.

Rosuvastatin treatment reduces markers of monocyte activation in HIV-infected subjects on antiretroviral therapy.

BACKGROUND: Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects that are independent of their lipid-lowering properties. Despite suppressive antiretroviral therapy (ART), elevated levels of immune activation and inflammation often persist. METHODS: The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial is a randomized, double-blind, placebo-controlled study, designed to investigate the effects of rosuvastatin (10 mg/daily) on markers of cardiovascular disease risk in ART-treated human immunodeficiency virus (HIV)-infected subjects. A preplanned analysis was to assess changes in markers of immune activation at week 24. Subjects with low-density lipoprotein cholesterol <130 mg/dL and heightened immune activation (%CD8(+)CD38(+)HLA-DR(+) ≥19%, or plasma high-sensitivity C-reactive protein ≥2 mg/L) were randomized to receive rosuvastatin or placebo. We measured plasma (soluble CD14 and CD163) and cellular markers of monocyte activation (proportions of monocyte subsets and tissue factor expression) and T-cell activation (expression of CD38, HLA-DR, and PD1). RESULTS: After 24 weeks of rosuvastatin, we found significant decreases in plasma levels of soluble CD14 (-13.4% vs 1.2%, P = .002) and in proportions of tissue factor-positive patrolling (CD14(Dim)CD16(+)) monocytes (-38.8% vs -11.9%, P = .04) in rosuvastatin-treated vs placebo-treated subjects. These findings were independent of the lipid-lowering effect and the use of protease inhibitors. Rosuvastatin did not lead to any changes in levels of T-cell activation. CONCLUSIONS: Rosuvastatin treatment effectively lowered markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. CLINICAL TRIALS REGISTRATION: NCT01218802.

Cutting edge: spontaneous development of IL-17-producing gamma delta T cells in the thymus occurs via a TGF-beta 1-dependent mechanism.

In naive animals, gammadelta T cells are innate sources of IL-17, a potent proinflammatory cytokine mediating bacterial clearance as well as autoimmunity. However, mechanisms underlying the generation of these cells in vivo remain unclear. In this study, we show that TGF-beta1 plays a key role in the generation of IL-17(+) gammadelta T cells and that it mainly occurs in the thymus particularly during the postnatal period. Interestingly, IL-17(+) gammadelta TCR(+) thymocytes were mainly CD44(high)CD25(low) cells, which seem to derive from double-negative 4 gammadelta TCR(+) cells that acquired CD44 and IL-17 expression. Our findings identify a novel developmental pathway during which IL-17-competent gammadelta T cells arise in the thymus by a TGF-beta1-dependent mechanism.

Factors that dentists use to decide whether or not to render a patient edentulous. Part 2. An investigation using a postal questionnaire sent to dentists in East lancashire.

AIMS: To investigate the factors that dentists use to decide whether or not to make a patient edentulous. METHOD: A previous qualitative investigation identified factors that dentists would consider when making a patient edentulous. Using this information, a questionnaire was created and sent to all dentists practising in East Lancashire, asking them whether these factors would make them more or less likely to extract all remaining teeth for a patient. RESULTS: 123 usable questionnaires were returned from 187 dentists, a response rate of 67%. Dentists felt that clinical factors such as poor periodontal health and active decay were more likely to make them extract all remaining teeth. They were also concerned about retention and were keen to retain strategic teeth. Apart from their acknowledgment of the need to comply with the patient's wish to keep his or her teeth, the dentists had a neutral opinion of other factors such as poor health or their personal attitude to treatment. On average, respondents were rendering just over three patients per year edentulous. CONCLUSION: In this group of dentists, the key clinical factors that were considered when they decided whether or not to render a patient edentulous were periodontal disease, caries, and the attitude of the patient to tooth loss. Relatively few patients were rendered edentulous each year and if this pattern is common elsewhere in the United Kingdom, it may lead to a lack of skills within the dental workforce in managing patients' transition from dentate to edentulous.

Estimating HIV incidence in the Akwa Ibom AIDS indicator survey (AKAIS), Nigeria using the limiting antigen avidity recency assay.

INTRODUCTION: HIV incidence estimates are important to characterize the status of an epidemic, identify locations and populations at high risk and to guide and evaluate HIV prevention interventions. We used the limiting antigen avidity assay (LAg) as part of a recent infection testing algorithm to estimate HIV incidence in the Akwa Ibom AIDS Indicator Survey (AKAIS), Nigeria. METHODS: In 2017, AKAIS, a cross-sectional population-based study was conducted at the household (HH) level in 31 local government areas (LGAs) of Akwa Ibom state. Of the 8963 participants aged ≥15 years who were administered questionnaires for demographic and behavioural data, 8306 consented to HIV rapid testing. Whole-blood specimens were collected from 394 preliminary HIV-seropositive individuals for CD4+ cell count determination and plasma storage. Samples were shipped to a central quality laboratory for HIV confirmatory testing and viral load determination. A total of 370 HIV-positive specimens were tested for the recent HIV infection using the LAg assay. RESULTS: Of the 8306 consenting adults, the HIV prevalence was 4.8%. Of the 370 HIV-positive samples tested for HIV recency, the median age was 35 years, 48.8% had CD4+ cell count >500/mm3 and 81.3% was not virally suppressed. Viral suppression was greater among females (21%) than for males (13%). A total of 11 specimens were classified as recent based on the LAg assay and HIV viral load ≥1000 copies/mL. The weighted, adjusted HIV-1 incidence was 0.41/100 person-years (95% CI 0.16 to 0.66); translating to 13,000 new cases of HIV infections annually in Akwa Ibom, a state with a population of 5.5 million. The HIV incidence rate was similar in females and males (0.41% and 0.42% respectively). The incidence rate was the highest among participants aged 15 to 49 years (0.44%, 95% CI 0.15 to 0.74) translating to 11,000 new infections annually, about 85% of all new infections in the state. CONCLUSIONS: The finding of the high HIV incidence among the 15 to 49-year age group calls for renewed and innovative efforts to prevent HIV infection among young adults in Akwa Ibom state.

TGF beta-mediated BIM expression and apoptosis are regulated through SMAD3-dependent expression of the MAPK phosphatase MKP2.

Transforming growth factor-beta (TGFbeta) induces the expression of the pro-apoptotic protein BIM, and mediates apoptosis in hepatocytes and B lymphocytes. BIM is regulated through a post-translational mechanism involving ERK-dependent phosphorylation and ubiquitin-mediated proteasomal degradation. Here, we show that TGFbeta induces BIM through its rapid inhibition of ERK, thereby preventing the phosphorylation and degradation of BIM. TGFbeta, through a SMAD3-dependent mechanism, transcriptionally induces the mitogen-activated protein kinase (MAPK) phosphatase MKP2, encoded by an immediate early gene, to attenuate ERK and promote the accumulation of BIM protein. Overexpression of MKP2 in hepatocytes modulates ERK-mediated phosphorylation of BIM and apoptosis in the absence of TGFbeta, whereas its ablation in pro-B cells, derived from MKP2-deficient mice, protects cells from TGFbeta-mediated apoptosis, and blocks TGFbeta-induced ERK inhibition and BIM induction. Furthermore, in pro-B cells derived from SMAD3-deficient mice, induction of MKP2 by TGFbeta, inhibition of ERK, induction of BIM and apoptosis do not occur. Our results indicate that MKP2 mediates TGFbeta-dependent apoptosis by linking SMAD3 to the modulation of ERK activity and mitochondrial-mediated pro-apoptotic events.

Effect of an inpatient nurse-directed smoking cessation program.

The purpose of this study was to evaluate the effect of a nurse-directed smoking cessation intervention for adults hospitalized in a small community hospital using a quasiexperimental, prospective, longitudinal design with biochemical validation of self-reported tobacco abstinence. Sixty-eight inpatients were assigned to either a control (n = 30) or an intervention group (n = 38). The control group received smoking cessation literature. The intervention group received smoking cessation literature and a nursing intervention. Each member of the intervention group was randomly assigned to a one or four telephone call subgroup for post discharge nurse follow-up at 3 months. Fifty-five participants completed the study. Smokers receiving the nurse-directed intervention were significantly more likely to be tobacco abstinent at 3 months (n = 17, 55%) than smokers in the control group (n = 5, 21%). Within the intervention group, tobacco abstinence at 3 months was not significantly different between the one and four telephone call groups. For the total sample, smoking relapse was significantly higher for participants who lived with another smoker.

Acceptability of a home monitor used to aid in conception: psychosocial factors and couple dynamics.

BACKGROUND: Assessing the psychological acceptability of technologies designed to assist couples in achieving pregnancy is complex. OBJECTIVE: The current study developed measures relating to the impact of one such technology on 52 couples' relationships, their feelings relating to pregnancy status and their feelings about the technology itself. METHODS: Pregnancy status and daily logs of sexual activity were recorded for four menstrual cycles, in addition to the completion of acceptability questionnaires. RESULTS: Baseline acceptability measures were more favorable among couples eventually achieving pregnancy. For couples not becoming pregnant, acceptability declined over time and relationships became more strained. Behavioral data clearly indicated a "targeting" and focusing of sexual activity in response to the information displayed by the monitor. CONCLUSION: Expectations of success, couple disagreements about prior failure and partner communication patterns appear to be related to pregnancy success when using such technology.

Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIV-infected subjects on antiretroviral therapy.

BACKGROUND: Despite suppressive antiretroviral therapy (ART), increased levels of immune activation persist in HIV-infected subjects. Statins have anti-inflammatory effects and may reduce immune activation in HIV disease. METHODS: Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN in HIV (SATURN-HIV) is a randomized, double-blind placebo-controlled trial assessing the effect of rosuvastatin (10 mg daily) on markers of cardiovascular risk and immune activation in ART-treated patients. T-cell activation was measured by expression of CD38, HLA-DR, and PD1. Monocyte activation was measured with soluble markers (sCD14 and sCD163) and by enumeration of monocyte subpopulations and tissue factor expression. Markers of systemic and vascular inflammation and coagulation were also measured. SATURN-HIV is registered on clinicaltrials.gov (identifier: NCT01218802). RESULTS: Rosuvastatin, compared with placebo, reduced sCD14 (-10.4% vs 0.5%, P = 0.006), lipoprotein-associated phospholipase A2 (-12.2% vs -1.7%, P = 0.0007), and IP-10 (-27.5 vs -8.2%, P = 0.03) levels after 48 weeks. The proportion of tissue factor-positive patrolling (CD14CD16) monocytes was also reduced by rosuvastatin (-41.6%) compared with placebo (-18.8%, P = 0.005). There was also a greater decrease in the proportions of activated (CD38HLA-DR) T cells between the arms (-38.1% vs -17.8%, P = 0.009 for CD4 cells, and -44.8% vs -27.4%, P = 0.003 for CD8 cells). CONCLUSIONS: Forty-eight weeks of rosuvastatin treatment reduced significantly several markers of inflammation and lymphocyte and monocyte activation in ART-treated subjects.

Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis.

Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression of prostaglandin metabolism. Agents that both enhance 15-PGDH expression and suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are a class of small molecules that suppress COX-2 as well as inflammatory cytokine signaling. Here, we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester (CDDO-Me) suppresses CAC in mice. In a spontaneous, inflammation-driven intestinal neoplasia model, deletion of Smad4 specifically in T cells led to progressive production of inflammatory cytokines, including TNF-α, IFN-γ, iNOS, IL-6, IL-1ß; as well as activation of STAT1 and STAT3; along with suppression of 15-PGDH expression. Oral administration of CDDO-Me to mice with SMAD4-deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of 15-PGDH. Induction of 15-PGDH by CDDO-Me was dose dependent in epithelial cells and was abrogated following treatment with TGF-ß signaling inhibitors in vitro. Furthermore, CDDO-Me-dependent 15-PGDH induction was not observed in Smad3-/- mice. Similarly, CDDO-Me suppressed azoxymethane plus dextran sodium sulfate-induced carcinogenesis in wild-type animals, highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans.

Microbial IgA protease removes IgA immune complexes from mouse glomeruli in vivo: potential therapy for IgA nephropathy.

The hallmark of IgA nephropathy (IgAN), the most common form of glomerulonephritis, is the presence of mesangial deposits containing IgA, specifically the IgA1 subclass, as the most prominent component. The deposited IgA is considered to be part of an immune complex. The family of enzymes known as bacterial IgA proteases exhibits substrate specificity that is essentially limited to the hinge region of IgA1. Here we demonstrate the ability of systemically administered IgA protease to remove glomerular IgA immune complexes, both the antigen and antibody components, in a passive mouse model of IgAN. Thus, IgA protease may have potential as a therapeutic agent for human IgAN.

Naildex: pilot evaluation of an onychodystrophy severity instrument.

A valid and reliable measure that captures onychodystrophy disease severity is important for both clinical and research applications. Three hundred and twenty-two patients at two Veterans Affairs Medical Centers with clinical evidence of onychodystrophy suggesting onychomycosis (at least 25% in a distal subungual pattern) were examined using Naildex parameters. Naildex scores were calculated by a combination of: per cent of each nail infected, area of each nail and number of infected nails. Patients also completed a nail-specific quality of life questionnaire (NailQoL) and nail samples were collected and examined mycologically. Data was analysed for all enrolled patients (n = 322) and patients with mycologically-confirmed onychomycosis (n = 243). Inter-rater reliability was calculated from two examiners who each evaluated 17 patients with mycologically-confirmed onychomycosis. Significant correlations (P < 0.01) between Naildex and NailQoL as well as proxy measures (duration of infection) indicated construct validity of the instrument for all patients as well as mycologically-confirmed cases. Strong correlation (r = 0.754, P < 0.01, n = 17) indicated high inter-rate reliability. This pilot evaluation suggests that Naildex is a valid and reliable measure of onychomycosis severity.

Mistiming of intercourse as a primary cause of failure to conceive: results of a survey on use of a home-use fertility monitor.

OBJECTIVE: To assess demographics, fecundity characteristics and fertility history of couples who successfully conceived using a home-use Fertility Monitor. STUDY DESIGN: This was a retrospective US observational study of couples who successfully conceived using a Fertility Monitor. Data were self-reported by volunteers using a questionnaire supplied and collected by mail. Of 276 surveys distributed, 196 (71.0%) were returned and evaluated. RESULTS: Length of time trying to conceive was < 12 months for 70% of women; proportions were similar across age groupings. After switching to the Fertility Monitor, 49.5% and 91.9% of women had conceived within first and third cycles, respectively. Prior to Fertility Monitor use, conception aids were used by 84.2% and 64.3% had consulted a physician to seek help in attempting to conceive. Average costs of prior treatment were (in US dollars) 6637 dollars; median costs for infertility evaluation were 1075 dollars per cycle. Fertility Monitor costs ranged from 250 dollars for one cycle to 550 dollars after 10 cycles. CONCLUSIONS: A probable cause for failure to conceive appeared to be mistiming of intercourse. The issue of early intervention with tests and medications were highlighted, resulting in escalating costs and strain on the couple. The use of a home Fertility Monitor that identifies all fertile days of the cycle and allows couples to target intercourse accordingly, should be considered as an alternative choice for couples seeking to conceive during the first year, before other attempts at infertility diagnosis are made, unless there are conflicting clinical reasons.

Increased pregnancy rate with use of the Clearblue Easy Fertility Monitor.

OBJECTIVE: To determine the effect on pregnancy rates through use of the Clearblue Easy Fertility Monitor (CEFM) in women trying to conceive. DESIGN: Prospective study, in which volunteers were randomly assigned either to use or not to use the CEFM. All participants could also use other aids to conception. Data were self-reported by volunteers using daily diaries, supplied and collected by mail. SETTING: Home use, under conditions normally experienced by over-the-counter purchasers of the marketed device. PATIENT(S): Women who were trying to conceive; 653 (CEFM 305, control 348) provided evaluable information. INTERVENTION(S): CEFM was used for two cycles. MAIN OUTCOME MEASURE(S): Cumulative pregnancy rates over two cycles of use. RESULT(S): The cumulative pregnancy rate for 2 cycles was significantly higher in the CEFM group (22.7%) compared with the control group (14.4%). More women who had been trying to conceive for <6 months became pregnant than women who had been trying to conceive for >6 months (odds ratio: 2.67). Previous pregnancy and younger age of partners were also significant prognostic factors, but use of other aids to conception was not. After adjustment for other factors, CEFM use remained a significant factor affecting the chance of conceiving within two cycles (odds ratio: 1.89). CEFM users found the device to be easy/very easy to use (90%) and convenient/very convenient (80%). CONCLUSION(S): Use of the CEFM increases the likelihood of getting pregnant during the first two cycles of use compared with its nonuse, in women who had been trying to conceive for up to 2 years.

Ethical health care policy: nursing's voice in allocation.

Nurse administrators must become more involved in the policy debates concerning universal access to care and allocation of health care resources. In order to promote nursing's agenda in the policy debates, nurses must be familiar with the numerous ethical issues that impact macroallocation decisions. This article explores the ethical viewpoint of the nursing profession as it relates to allocation decisions and examines how the ethical principles of the nursing profession, along with the ethical theories of egalitarianism and utilitarianism, can be used throughout the policy process to guide the development of a plan for universal access to care.