Association Between Perceived Skin Cancer Risk Reduction and Sunscreen Use.

BACKGROUND: Understanding factors that influence people to use sunscreen would allow clinicians to counsel patients in a way that is influential. Perceived efficacy of sunscreen has been associated with sunscreen use, but it is unclear whether the degree of efficacy is important. OBJECTIVE: To determine whether larger perceived efficacy of sunscreen (larger skin cancer risk reduction) is associated with increased sunscreen use. MATERIALS AND METHODS: A cohort of 131 patients with a history of skin cancer visiting a Mohs micrographic surgery center were surveyed. RESULTS: Participants believed sunscreen would reduce their risk of basal cell carcinoma (BCC) by 61.1% (95% confidence interval [CI] = 56.4-65.9), squamous cell carcinoma (SCC) by 59.4% (95% CI = 54.6-64.2), and melanoma by 59.5% (95% CI = 54.8-64.3). Perceived magnitude of risk reduction of BCC, SCC, and melanoma was significant independent predictors of sunscreen use (BCC: odds ratio [OR] 3.5, 95% CI 1.1-11.2, p = .04. Squamous cell carcinoma: OR 2.8, 95% CI 1.0-7.6, p = .05. Melanoma: OR 5.0, 95% CI 1.8-14.2, p = .002). CONCLUSION: Larger perceived skin cancer (BCC, SCC, and melanoma) risk reduction was associated with increased sunscreen use.

Time to antibody detection and associated factors for presence of anti-drug antibodies in pediatric inflammatory bowel disease patients treated with anti-TNF therapy.

BACKGROUND: Loss of response in pediatric inflammatory bowel disease patients treated with biologic medications can be due to development of anti-drug antibodies. Natural history of anti-drug antibodies development has not been well described in pediatric inflammatory bowel disease. The primary aim of this study was to describe a single-center experience for the temporal onset of anti-drug antibodies detection. METHODS: We performed a retrospective, single-center chart review of pediatric inflammatory bowel disease patients at the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at Rainbow Babies and Children's Hospital from 2010 to 2015. Patients were treated with infliximab or adalimumab and had at least two evaluations for anti-drug antibodies with the homogenous mobility shift assay. Demographics, laboratory and medication data, and clinical disease activity were collected. RESULTS: A total of 75 subjects are included in the analysis. Eighty-one percent of subjects were treated with infliximab. Eleven subjects developed anti-drug antibodies; average time to anti-drug antibodies detection was 13.2 ± 7.3 months. Longer duration of inflammatory bowel disease, L1 location in Crohn's disease, and not having immunomodulatory therapy before biologic was associated with higher risk of antibody detection. Antibody detection occurred more frequently with infliximab vs. adalimumab. Time-to-antibody detection for infliximab and adalimumab was 14.83 and 23.48 months, respectively. CONCLUSION: Chances of anti-drug antibodies detection in the infliximab group were higher than the adalimumab group. Time-to-antibody detection was 8.65 months longer in patients who received adalimumab when compared to infliximab. These results may have implications for long-term therapy and help guide use of concomitant immunomodulators.

Plasma glycomics predict cardiovascular disease in patients with ART-controlled HIV infections.

Despite effective control of HIV infection with antiretroviral drugs, individuals with HIV have high incidences of secondary diseases. These sequelae, such as cardiovascular disease (CVD), are poorly understood and represent a major health burden. To date, predictive biomarkers of HIV-associated secondary disease have been elusive, making preventative clinical management essentially impossible. Here, we applied a newly developed and easy to deploy, multitarget, and high-throughput glycomic analysis to banked HIV+ human plasma samples to determine whether the glycome may include biomarkers that predict future HIV-associated cardiovascular events or CVD diagnoses. Using 324 patient samples, we identified a glycomic fingerprint that was predictive of future CVD events but independent of CD4 counts, diabetes, age, and birth sex, suggesting that the plasma glycome may serve as a biomarker for specific HIV-associated sequelae. Our findings constitute the discovery of novel glycan biomarkers that could classify patients with HIV with elevated risk for CVD and reveal the untapped prognostic potential of the plasma glycome in human disease.-Oswald, D. M., Sim, E. S., Baker, C., Farhan, O., Debanne, S. M., Morris, N. J., Rodriguez, B. G., Jones, M. B., Cobb, B. A. Plasma glycomics predict cardiovascular disease in patients with ART-controlled HIV infections.

Incidence and Outcomes of Infections Caused by Multidrug-Resistant Enterobacteriaceae in Children, 2007-2015.

BACKGROUND: The escalating incidence of invasive disease caused by multidrug-resistant Gram-negative enteric Enterobacteriaceae (MDR-GNE) is a global concern. Scant published studies in which the epidemiology of these infections in children is described exist; previous studies focused mainly on adults, described circumscribed populations, or lacked clinical detail. The objective of this study was to examine and describe the incidence, risk factors, and outcomes associated with MDR-GNE infection in children. METHODS: In this cohort study, we used data from 48 children's hospitals maintained by the Pediatric Health Information System. We documented the proportion of MDR-GNE diagnoses among children's hospital patients aged 0 to <18 years who were diagnosed with an Enterobacteriaceae-associated infection between January 1, 2007, and March 31, 2015, and we analyzed the association between MDR-GNE infection and hospital length of stay and death before discharge. RESULTS: During the study period, 107610 discharges included a diagnosis code for Enterobacteriaceae infection, 724 (0.7%) of which included MDR-GNE infection. The incidence of MDR-GNE, and the proportion of infections with Enterobacteriaceae organisms that were MDR-GNE increased over the study period; from 0.2% in 2007 to 1.5% by 2015 (test for trend < .001). Almost one-quarter (23%) of the infections in children hospitalized for MDR-GNE were nosocomial. Increased odds of MDR-GNE infection were associated with older age and comorbid illnesses. Lengths of stay in patients with MDR-GNE infection were increased 20% (95% confidence interval, 9.9%-30.5%; P < .001) over those without MDR-GNE infection; the increased odds for death did not reach statistical significance (1.46 [95% confidence interval, 0.98-2.18]; P = .06). Results were robust to sensitivity analyses. CONCLUSIONS: The incidence of pediatric MDR-GNE infection increased during 2007-2015. MDR-GNE infection was associated with increased length of stay, and we found a trend toward increased risk of death. Infections with Gram-negative enteric bacilli are becoming increasingly difficult to treat; considering the global burden of these antimicrobial-resistant organisms, interventions to curtail or even reverse this trend are needed urgently.

A Randomized Comparative Study Evaluating Various Cough Stress Tests and 24-Hour Pad Test with Urodynamics in the Diagnosis of Stress Urinary Incontinence.

PURPOSE: The cough stress test is a common and accepted tool to evaluate stress urinary incontinence but there is no agreement on how the test should be performed. We assessed the diagnostic ability of different cough stress tests performed when varying patient position and bladder volume using urodynamic stress urinary incontinence as the gold standard. The 24-hour pad test was also evaluated. MATERIALS AND METHODS: We recruited women who presented to specialty outpatient clinics with the complaint of urinary incontinence and who were recommended to undergo urodynamic testing. A total of 140 patients were randomized to 4 cough stress test groups, including group 1-a comfortably full bladder, group 2-an empty bladder, group 3- a bladder infused with 200 cc saline and group 4-a bladder filled to half functional capacity. The sequence of standing and sitting was randomly assigned. The groups were compared by 1-way ANOVA or the generalized Fisher exact test. The κ statistic was used to evaluate agreement between the sitting and standing positions. The 95% CIs of sensitivity and specificity were calculated using the Wilson method. ROC analysis was done to evaluate the performance of the 24-hour pad test. RESULTS: The cough stress test performed with a bladder filled to half functional capacity was the best performing test with 83% sensitivity and 90% specificity. There was no statistically significant evidence that the sensitivity or specificity of 1 cough stress test differed from that of the others. The pad test had no significant predictive ability to diagnose urodynamic stress urinary incontinence (AUC 0.60, p = 0.08). CONCLUSIONS: Cough stress tests were accurate to diagnose urodynamic stress urinary incontinence. The 24-hour pad test was not predictive of urodynamic stress urinary incontinence and not helpful when used in conjunction with the cough stress test.

Health impact and cost-effectiveness of a domestically-produced rotavirus vaccine in India: A model based analysis.

BACKGROUND: Currently, Indian officials are incorporating a domestically manufactured rotavirus vaccine (based on the 116E rotavirus strain) into the country's universal immunization program; this vaccine will cost significantly less than western rotavirus vaccines. Here, we examine the public health impact, cost, and cost-effectiveness of universal vaccination in India using the 116E vaccine. This work will allow comparison of universal 116E vaccination with other approaches to child mortality reduction, shed light on the future burden of rotavirus disease in India, and help stakeholders understand future resource needs. METHODS: Using information from published literature, we developed a dynamic simulation model of rotavirus transmission, natural history, and related utilization among Indian infants followed until age five. Infection risk depended on the degree of viral shedding in the population. Infection risk and severity were influenced by age, number of previous infections, and vaccination history. Probabilities of inpatient and outpatient health services utilization depended on symptom severity. With the model, we compared a strategy of nationwide 116E vaccination to one of no vaccination. Costs were considered from the perspective of all payers (including families) and from the societal perspective. RESULTS: We estimated that an established 116E vaccination program would reduce symptomatic rotavirus infection by 13.0%, while reducing population-wide rotavirus mortality by 34.6% (over 34,000 lives annually). Rotavirus outpatient visits would decline by 21.3%, and hospitalization would decline by 28.1%. The cost per disability-adjusted life year (DALY) averted was estimated at 3,429 Rupees (approximately $56). Predicted mortality reduction in children born during the first five years of vaccination implementation was nearly identical to that in children born in later years (34.4% versus 34.6%). CONCLUSIONS: 116E vaccination of Indian infants would likely substantially reduce rotavirus-related morbidity, mortality, and utilization at a cost considered highly cost-effective by standard criteria. Nearly the entire mortality reduction benefit of vaccination was attributable to direct protection of those vaccinated, as opposed to indirect "herd immunity" effects.

Oral Vitamin D Rapidly Attenuates Inflammation from Sunburn: An Interventional Study.

The diverse immunomodulatory effects of vitamin D are increasingly being recognized. However, the ability of oral vitamin D to modulate acute inflammation in vivo has not been established in humans. In a double-blinded, placebo-controlled interventional trial, 20 healthy adults were randomized to receive either placebo or a high dose of vitamin D3 (cholecalciferol) one hour after experimental sunburn induced by an erythemogenic dose of UVR. Compared with placebo, participants receiving vitamin D3 (200,000 international units) demonstrated reduced expression of proinflammatory mediators tumor necrosis factor-α (P = 0.04) and inducible nitric oxide synthase (P = 0.02) in skin biopsy specimens 48 hours after experimental sunburn. A blinded, unsupervised hierarchical clustering of participants based on global gene expression profiles revealed that participants with significantly higher serum vitamin D3 levels after treatment (P = 0.007) demonstrated increased skin expression of the anti-inflammatory mediator arginase-1 (P = 0.005), and a sustained reduction in skin redness (P = 0.02), correlating with significant expression of genes related to skin barrier repair. In contrast, participants with lower serum vitamin D3 levels had significant expression of proinflammatory genes. Together the data may have broad implications for the immunotherapeutic properties of vitamin D in skin homeostasis, and implicate arginase-1 upregulation as a previously unreported mechanism by which vitamin D exerts anti-inflammatory effects in humans.

Early Bactericidal Activity of AZD5847 in Patients with Pulmonary Tuberculosis.

AZD5847 is an oxazolidinone antibiotic with in vitro activity against Mycobacterium tuberculosis The objective of this study was to evaluate the antimycobacterial activity, safety, and pharmacokinetics of AZD5847 in patients with pulmonary tuberculosis. Groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to receive AZD5847 at one of four doses (500 mg once daily, 500 mg twice daily, 1,200 mg once daily, and 800 mg twice daily) or daily standard chemotherapy. The primary efficacy endpoint was the mean daily rate of change in the log10 number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log10 number of CFU per milliliter of sputum per day. The mean 14-day activity of the combination of isoniazid, rifampin, ethambutol, and pyrazinamide (-0.163 log10 CFU/ml sputum/day; 95% confidence interval [CI], -0.193, -0.133 log10 CFU/ml sputum/day) was consistent with that found in previous studies. AZD5847 at 500 mg twice daily significantly decreased the number of CFU on solid medium (-0.039; 95% CI, -0.069, -0.009; P = 0.0048). No bactericidal activity was detected at doses of AZD5847 of 500 mg once daily (mean early bactericidal activity [EBA], 0.02 [95% CI, -0.01, 0.05]), 1,200 mg once daily (mean EBA, 0.02 [95% CI, -0.01, 0.05]), and 800 mg twice daily (mean EBA, 0.02 [95% CI, -0.01, 0.05]). AZD5847 at doses of both 500 mg and 800 mg twice daily also showed an increase in the time to a positive culture in MGIT liquid culture medium. Two serious adverse events (grade 4 thrombocytopenia and grade 4 hyperbilirubinemia) occurred in patients receiving AZD5847 at higher doses. AZD5847 dosed twice daily kills tubercle bacilli in the sputum of patients with pulmonary tuberculosis and has modest early bactericidal activity. (This study has been registered at ClinicalTrials.gov under registration no. NCT01516203.).

Effect of rosuvastatin on plasma coenzyme Q10 in HIV-infected individuals on antiretroviral therapy.

BACKGROUND: Coenzyme Q10 (CoQ10) deficiency has been associated with statin-induced myopathy, and supplementation with CoQ10 may reduce inflammation markers. The effects of statins on CoQ10 and its anti-inflammatory properties have not been investigated in HIV-positive patients. OBJECTIVE: The objectives of this study were to examine the effect of rosuvastatin on CoQ10 and CoQ10/LDL ratio over 24-week SATURN-HIV trial, explore the associations between CoQ10 levels and markers of vascular disease, inflammation, and immune activation, and assess whether changes in CoQ10 affected the anti-inflammatory effects of statin therapy or were associated with myalgia symptoms. METHODS: This was a secondary analysis of the SATURN-HIV trial, a 96-week randomized clinical trial of 10 mg daily rosuvastatin vs. placebo in HIV-infected patients on antiretroviral therapy. We assessed the statin treatment effect on CoQ10 levels and CoQ10/LDL ratios and whether changes in these markers were related to myalgias. Relationships between CoQ10, subclinical vascular disease, and biomarkers of inflammation and immune activation were explored using Spearman correlations and multivariable regression models. RESULTS: Overall, 147 patients were included. Median age was 46 years; 78% were male and 68% African American. At baseline, CoQ10 levels and CoQ10/LDL ratio were modestly correlated with markers of HIV disease, immune activation, and carotid distensibility. After 24 weeks of statin therapy, CoQ10 levels decreased (p = 0.002 for between group difference) and CoQ10/LDL ratio increased (p = 0.036). In the statin treatment arm, we did not find evidence of a relationship between changes in CoQ10 or CoQ10/LDL ration and changes in markers of inflammation or immune activation. There was a borderline statistically significant association between changes in CoQ10 and myalgia symptoms [OR 4.0 per 0.1 mg/L decrease in CoQ10, p = 0.07]. CONCLUSION: Twenty-four weeks of 10 mg daily rosuvastatin decreases CoQ10 concentration and increases CoQ10/LDL ratio in HIV-infected patients on antiretroviral therapy.

Evaluation of ELISA testing for BP180 and BP230 as a diagnostic modality for bullous pemphigoid: a clinical experience.

Bullous pemphigoid (BP) is a common autoimmune blistering disorder of the elderly. Several diagnostic modalities are available, including clinical impression, histopathology, direct and indirect immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) detection of pathogenic antibodies. In this study, we aim to examine the utility of the newest test, ELISA, in comparison to the constellation of other tests. We describe our clinical experience in which 170 patients diagnosed with bullous pemphigoid had multiple tests performed. BP180 alone showed a sensitivity of 54 % and specificity of 94 %. The positive predictive value (PPV) is 95 % while the negative predictive value (NPV) is 52 %. BP230 alone yielded a sensitivity of 48 % and specificity of 94 %. The PPV is 94 % and the NPV is 49 %. Using both tests in combination yielded a sensitivity of 66 % and specificity of 89 %. The PPV of at least one of two tests returning positive is 92 % while the NPV of dual negative tests is 58 %. Use of ELISAs for suspected cases of BP are an inadequate standalone test, and are only helpful in making the diagnosis should they return positive. However, they would appear to miss about one-third of cases.

Effects of 96 Weeks of Rosuvastatin on Bone, Muscle, and Fat in HIV-Infected Adults on Effective Antiretroviral Therapy.

Heightened inflammation and immune activation are associated with lower bone mineral density (BMD) and lean body mass (LBM) among HIV-infected persons. We hypothesized that a reduction in inflammation with rosuvastatin would be associated with improvements in BMD and LBM. HIV-infected participants on stable antiretroviral therapy without statin indication and with heightened immune activation (≥19% CD8(+)CD38(+)HLA-DR(+) T cells) or inflammation (hsCRP ≥2 mg/liter) were randomized to rosuvastatin 10 mg daily or placebo for 96 weeks. Among 72 participants randomized to rosuvastatin and 75 to placebo, there were no significant differences in the relative changes in BMD (p > 0.29) or in fat (p ≥ 0.19). A trend toward increased LBM (p = 0.059) was seen in the rosuvastatin arm without differences in creatinine kinase or self-reported physical activity (p ≥ 0.10). In a multivariable regression model, rosuvastatin was associated with a significant positive effect on LBM after adjusting for age, sex, race, smoking status, and detectable HIV-1 viral load. Higher baseline sCD163 correlated with increases in LBM from weeks 0 to 96 (p = 0.023); greater changes in total and leg lean mass were seen among statin users with higher compared to lower baseline IP-10 levels (LBM 1.8 vs. -0.3%; p = 0.028 and leg lean mass 2.9 vs. -1.7%; p = 0.012). Rosuvastatin is associated with an absence of toxicity on BMD and a potential benefit on LBM over 96 weeks of therapy. The preservation of LBM in the rosuvastatin arm over the 2 years of the study is of major clinical relevance in delaying loss of muscle mass with aging.

Chronic, not acute, skin-specific inflammation promotes thrombosis in psoriasis murine models.

BACKGROUND: Psoriasis patients exhibit an increased risk of atherothrombotic events, including myocardial infarction and stroke. Clinical evidence suggests that psoriasis patients with early onset and more severe disease have the highest risk for these co-morbidities, perhaps due to the extent of body surface involvement, subsequent levels of systemic inflammation, or chronicity of disease. We sought to determine whether acute or chronic skin-specific inflammation was sufficient to promote thrombosis. METHODS: We used two experimental mouse models of skin-specific inflammation generated in either an acute (topical Aldara application onto wild-type C57Bl/6 mice for 5 days) or chronic (a genetically engineered K5-IL-17C mouse model of psoriasiform skin inflammation) manner. Arterial thrombosis was induced using carotid artery photochemical injury (Rose Bengal-green light laser) and carotid artery diameters were measured post-clot formation. We also examined measures of clot formation including prothrombin (PT) and activated partial thromboplastin time (aPTT). Skin inflammation was examined histologically and we profiled plasma-derived lipids. The number of skin-draining lymph-node (SDLN) and splenic derived CD11b(+)Ly6C(high) pro-inflammatory monocytes and CD11b(+)Ly6G(+) neutrophils was quantified using multi-color flow cytometry. RESULTS: Mice treated with topical Aldara for 5 days had similar carotid artery thrombotic occlusion times to mice treated with vehicle cream (32.2 ± 3.0 vs. 31.4 ± 2.5 min, p = 0.97); in contrast, K5-IL-17C mice had accelerated occlusion times compared to littermate controls (15.7 ± 2.1 vs. 26.5 ± 3.5 min, p < 0.01) while carotid artery diameters were similar between all mice. Acanthosis, a surrogate measure of inflammation, was increased in both Aldara-treated and K5-IL-17C mice compared to their respective controls. Monocytosis, defined as elevated SDLN and/or splenic CD11b(+)Ly6C(high) cells, was significantly increased in both Aldara-treated (SDLN: 3.8-fold, p = 0.02; spleen: 2.0-fold, p < 0.01) and K5-IL-17C (SDLN: 3.4-fold, p = 0.02; spleen: 3.5-fold, p < 0.01) animals compared to controls while neutrophilia, defined as elevated SDLN and/or splenic CD11b(+)Ly6G(+) cells, was significantly increased in only the chronic K5-IL-17C model (SDLN: 11.6-fold, p = 0.02; spleen: 11.3-fold, p < 0.01). Plasma-derived lipid levels, PT and aPTT times showed no difference between the Aldara-treated mice or the K5-IL-17C mice and their respective controls. CONCLUSIONS: Chronic, but not acute, skin-specific inflammation was associated with faster arterial thrombotic occlusion. Increased numbers of splenic and SDLN monocytes were observed in both acute and chronic skin-specific inflammation, however, increased splenic and SDLN neutrophils were observed only in the chronic skin-specific inflammation model. Understanding the cellular response to skin-specific inflammation may provide insights into the cellular participants mediating the pathophysiology of major adverse cardiovascular events associated with psoriasis.

HIV vasculopathy: role of mononuclear cell-associated Krüppel-like factors 2 and 4.

OBJECTIVE: To determine the relationships between Krüppel-like factors (KLF) 2 and 4, immune-activation, and subclinical vascular disease in HIV-infected patients on antiretroviral therapy (ART). DESIGN: Double-blind, randomized, placebo-controlled trial. METHODS: We studied 74 HIV-infected adults on ART enrolled in a randomized clinical trial of statin therapy. KLF2 and KLF4 gene expression was measured by quantitative PCR from peripheral blood mononuclear cells (PBMCs) at baseline and after 24 weeks of 10 mg daily rosuvastatin or placebo. At the same time points, T-cell and monocyte activation were assessed by flow cytometry and vascular health was assessed by cardiac computed tomography and carotid ultrasound. RESULTS: KLF4 expression was negatively correlated with duration of ART (r = -0.351, P = 0.004) and positively correlated with measures of immune activation: proinflammatory monocytes [CD14CD16 (r = 0.343, P = 0.003)], patrolling monocytes [CD14CD16 (r = 0.276, P = 0.017)], and activated CD8 T-lymphocytes [CD8DRCD38 (r = 0.264, P = 0.023)]. KLF2 expression was negatively correlated with subclinical atherosclerosis: mean-mean common carotid artery intima-media thickness (r = -0.231, P = 0.048), mean-max carotid artery intima-media thickness (r = -0.271, P = 0.020), and coronary artery calcium score (r = -0.254, P = 0.029). There were no statistically significant changes in KLF2/4 expression in PBMCs after 24 weeks of rosuvastatin. CONCLUSION: Expression of KLF4 in PBMCs positively correlates with cellular markers of immune activation, whereas KLF2 expression negatively correlates with markers of subclinical atherosclerosis in this HIV-infected population on ART. Additional studies are needed to determine if targeted interventions might alter KLF2/4 expression to reduce inflammation and vascular risk in humans.

Rosuvastatin Worsens Insulin Resistance in HIV-Infected Adults on Antiretroviral Therapy.

BACKGROUND: Statins are associated with increased diabetes risk in large, human immunodeficiency virus (HIV)-uninfected cohorts; the impact of statins on insulin resistance or diabetes in HIV-infected persons has not been assessed within a randomized controlled study. METHODS: HIV-infected participants on stable antiretroviral therapy with a low-density lipoprotein cholesterol level of ≤130 mg/dL and heightened immune activation or inflammation were randomized to rosuvastatin 10 mg daily or placebo for 96 weeks. Fasting serum glucose, insulin, and hemoglobin A1C (HgbA1C) were measured; insulin resistance was estimated by calculating the homeostatic model assessment of insulin resistance (HOMA-IR); and a 2-hour oral glucose tolerance test was administered. RESULTS: Seventy-two participants were randomized to rosuvastatin therapy and 75 to placebo. Increases in fasting glucose were observed within both groups but were not different between study arms (P = .115); changes in glucose tolerance and HgbA1C did not differ between study arms (P = .920 and P = .650, respectively). Criteria for diabetes were met by 1 participant in the rosuvastatin and 3 in the placebo arm by week 96. Compared with placebo, rosuvastatin therapy was associated with significantly greater increases in insulin and HOMA-IR (P = .008 and P = .004, respectively). CONCLUSIONS: We detected a significant worsening in insulin resistance and an increase in the proportion of participants with impaired fasting glucose but not a clinical diagnosis of diabetes in the rosuvastatin arm. Our findings suggest that prescription of statin therapy should be accompanied by a careful consideration of the risks and benefits, particularly in patients with lower cardiovascular disease risk. CLINICAL TRIALS REGISTRATION: NCT01218802.

Chronic Psoriatic Skin Inflammation Leads to Increased Monocyte Adhesion and Aggregation.

Psoriasis patients exhibit an increased risk of death by cardiovascular disease (CVD) and have elevated levels of circulating intermediate (CD14(++)CD16(+)) monocytes. This elevation could represent evidence of monocyte dysfunction in psoriasis patients at risk for CVD, as increases in circulating CD14(++)CD16(+) monocytes are predictive of myocardial infarction and death. An elevation in the CD14(++)CD16(+) cell population has been previously reported in patients with psoriatic disease, which has been confirmed in the cohort of our human psoriasis patients. CD16 expression was induced in CD14(++)CD16(-) classical monocytes following plastic adhesion, which also elicited enhanced ß2 but not ß1 integrin surface expression, suggesting increased adhesive capacity. Indeed, we found that psoriasis patients have increased monocyte aggregation among circulating PBMCs, which is recapitulated in the KC-Tie2 murine model of psoriasis. Visualization of human monocyte aggregates using imaging cytometry revealed that classical (CD14(++)CD16(-)) monocytes are the predominant cell type participating in these aggregate pairs. Many of these pairs also included CD16(+) monocytes, which could account for apparent elevations of intermediate monocytes. Additionally, intermediate monocytes and monocyte aggregates were the predominant cell type to adhere to TNF-α- and IL-17A-stimulated dermal endothelium. Ingenuity Pathway Analysis demonstrated that monocyte aggregates have a distinct transcriptional profile from singlet monocytes and monocytes following plastic adhesion, suggesting that circulating monocyte responses to aggregation are not fully accounted for by homotypic adhesion, and that further factors influence their functionality.

Randomized, prospective, single-masked clinical trial of endothelial keratoplasty performance with 2 donor cornea 4°C storage solutions and associated chambers.

PURPOSE: The aim of this study was to compare endothelial cell loss and graft success 6 months after endothelial keratoplasty (EK) with paired donor corneas stored in Optisol GS and Life4°C solutions and their associated storage chambers. METHODS: Donor pairs were stored, one in Optisol GS and the other in Life4°C, and prepared for Descemet stripping automated EK or Descemet membrane EK. Matched pairs of recipients with Fuchs dystrophy were randomized to 1 member of each donor pair. Clarity of recipient stroma, intraocular pressure, and complications were followed for 6 months. Central endothelial images of the donor cornea at screening and 3 and 6 months after EK were analyzed by a masked central reading center. Dual grading of endothelial cell density was performed using the center method. Differences in endothelial cell density and cell loss were examined by paired analysis. RESULTS: Thirty-two pairs were enrolled, and 27 were analyzed (5 had improper matching or loss to follow-up). Donor age was 59 ± 14 years, median death-to-surgery time was 4 days (range, 2-9 days), 6 recipient pairs had Descemet membrane EK, and 21 had Descemet stripping automated EK. Recipient age was comparable in the Optisol GS and Life4°C groups (70 vs. 68 years, respectively, P = 0.46). Six-month central endothelial cell loss did not differ significantly between the Life4°C and Optisol GS groups (18 ± 18% vs. 20 ± 20%, respectively, P = 0.55). All recipient corneas were clear at 6 months in both groups. CONCLUSIONS: Endothelial cell loss and graft success were comparable at 6 months for paired donor corneas stored in Optisol GS and Life4°C.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01657500.

Effects of randomized rosuvastatin compared with placebo on bone and body composition among HIV-infected adults.

BACKGROUND: Statins have a beneficial effect on bone mineral density (BMD) and lean mass in some studies of HIV-uninfected adults; however, this has never been investigated in the setting of HIV infection. DESIGN: HIV-infected individuals on stable antiretroviral therapy with a low-density lipoprotein cholesterol level of 130 mg/dl or less and evidence of heightened immune activation or inflammation were randomized to rosuvastatin 10 mg daily or placebo for 96 weeks. METHODS: This was a prespecified interim analysis at 48 weeks. Between-group and within-group differences were compared; multivariable regression models were constructed. RESULTS: Seventy-two individuals were randomized to statin therapy and 75 to placebo. Modest 48-week relative increases in trochanter BMD [0.9%; 95% confidence interval (95% CI) -0.9 to 0.6] and total hip BMD (0.6%; 95% CI 0.0-1.1) in the statin arm were significantly greater than placebo (P < 0.05). The relationship between statin use and total hip BMD change was robust to adjustment of age, sex, race and smoking status (P = 0.02) and strengthened by inclusion of baseline (P = 0.01) and week 48 change in soluble tumour necrosis factor-α receptor (sTNFR)-1 (P = 0.009). Relative increases in total body, trunk and limb fat were similar between statin and placebo arms (P ≥ 0.58). Although a significant gain in leg lean mass was seen in the statin arm, this was not significantly different compared with placebo (P = 0.36). CONCLUSION: The improvements seen in total hip BMD after 48 weeks of rosuvastatin therapy support further potential benefits of statin therapy in HIV, beyond a reduction of cardiovascular risk.

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.

Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults.

RATIONALE: Global tuberculosis (TB) control may require mass vaccination with a new TB vaccine, such as a recombinant bacille Calmette Guerin (BCG) or attenuated Mycobacterium tuberculosis (MTB). The safety profile of live mycobacterial vaccines in latently infected adults with prior infant BCG vaccination is unknown. OBJECTIVES: Evaluate safety and reactogenicity of BCG revaccination, with or without isoniazid (INH) pretreatment, in adults with latent MTB infection (LTBI). METHODS: Eighty-two healthy, HIV uninfected, South African adults, with a BCG scar and tuberculin skin test (TST) diameter ≥ 15 mm, were randomized to receive 6 months of INH, starting either before, or 6 months after, intradermal revaccination with BCG Vaccine SSI (Statens Serum Institut, Copenhagen). Safety and reactogenicity data are reported through 3 months post BCG revaccination. RESULTS: Baseline characteristics were similar between treatment arms. Mean baseline TST diameter was 20 ± 4 mm. Seventy-two subjects received BCG revaccination. Injection site erythema (68%) and induration (86%) peaked 1 week after revaccination. Ulceration (76%) peaked at 2 weeks, and resolved by 3 months in all but 3 subjects. Diameter of ulceration was >10mm in only 8%, but a residual scar was common (85%). No regional lymphadenitis or serious morbidity related to BCG was seen. Reactogenicity was not affected by INH pretreatment. CONCLUSION: BCG revaccination of MTB infected adults is safe, well tolerated, and reactogenicity is similar to that of primary BCG vaccination. Clinical trials of live recombinant BCG or attenuated MTB vaccines may be considered in latently infected adults, with or without INH pretreatment (ClinicalTrials.gov identifier: NCT01119521).

Risk factors for microbial bioburden during daily wear of silicone hydrogel contact lenses.

PURPOSE: To assess risk factors associated with substantial microbial bioburden of lids, conjunctivae, contact lenses, and storage cases during daily wear of silicone hydrogel contact lenses. METHODS: Two hundred eighteen patients were fit to lotrafilcon A lenses, randomized to use either a multipurpose solution or a hydrogen peroxide care system, and followed up for 1 year. Lenses, lens transport saline, lids, conjunctivae, and storage cases were cultured and considered to have substantial microbial bioburden when they harbored high levels of commensal or pathogenic organisms. Univariate and multivariate logistic regression analyses were conducted to examine which demographic covariates were associated with significant bioburden at each location while controlling for solution use. RESULTS: In multivariate analyses, smoking trended toward an association with lens bioburden (odds ratio [OR]=2.15, 95% confidence interval [CI]: 0.95-4.88). Clerical occupations were found to be associated with more frequent overall storage case contamination (OR=3.51, 95% CI: 1.15-10.70) and, specifically, higher gram-positive storage case contamination (OR=5.57, 95% CI: 1.82-17.06). The peroxide system was associated with more frequent storage case contamination (OR=7.6, 95% CI: 3.79-15.19). Coagulase-negative staphylococci (CNS) were the most frequently cultured organisms within storage cases, and in multivariate analyses, CNS were more frequently found in storage cases of peroxide users (OR=6.12, 95% CI: 2.91-13.09). CONCLUSIONS: Clerical occupations were associated with increased microbial bioburden of storage cases during daily wear of silicone hydrogel lenses. Smoking may increase the risk of lens contamination. Storage cases are most frequently contaminated with normal skin flora, and peroxide cases were associated with more frequent contamination. However, the solution type was not associated with lid or lens contamination nor with corneal infiltrative events in this study.