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Sickle cell disease (SCD) is a group of genetic disorders primarily affecting individuals of African descent. Adults with SCD experience both acute and chronic pain. Data on music preferences, resources, and music-based pain strategies of adults with SCD are needed to tailor future music therapy interventions to the unique needs of adults with SCD. The purpose of this study was to (1) gather descriptive data related to music use in adults with SCD and (2) explore associations between participants’ music use, pain interference, and perceived helpfulness of music for reducing pain. In total, 100 adults with SCD participated in this survey during outpatient clinic visits. Results indicate a population that: (1) faces significant challenges related to pain interference (M = 61.13, SE = 0.76); (2) perceives music as being helpful for managing challenges, including mood (57%), sleep (48%), stress (47%), and pain (37%); (3) purposefully engages in music listening to manage pain (74%); and (4) would be interested in participating in music therapy services in inpatient (88%) and outpatient (81%) settings. Participants selected songs in genres, such as Hip-Hop/Rap and R&B/Soul, that contrast with previously reported characteristics of music for pain management. There was a moderate positive correlation (rs = 0.516, p < .001) between the number of strategies used alongside music and the perceived helpfulness of music for reducing pain. Findings inform the clinical use of music therapy and support future music therapy research with this population to address quality of life.

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.

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.

This study assessed microbiome adherent to contact lenses and defined the bacterial communities associated with use of lens care solutions.Among 84 lenses screened for adherent ocular surface bacterial microbiome using 16S rRNA molecular amplification, 63 (75%) generated bacterial-specific amplicons processed using the Ion Torrent Personal Genome Machine workflow. Data were stratified by solution use (peroxide vs. polyhexamethylene biguanide [PHMB]-preserved multipurpose solution [MPS]). Diversity of lens-adherent microbiome was characterized using Shannon diversity index and richness index. Data were analyzed using principal components analysis and Kruskal-Wallis tests.We identified 19 phyla and 167 genera of bacteria adherent to the lenses. Proteobacteria was the most abundant phyla, followed by Firmicutes and Actinobacteria. The most abundant bacterial genera (1% abundance) were Ralstonia, Enterococcus, Streptococcus, Halomonas, Corynebacterium, Staphylococcus, Acinetobacter, Shewanella, Rhodococcus, and Cobetia. Sixteen of 20 lenses (80%) negative for bacterial DNA were worn by participants using peroxide solutions while only 4 (20%) were MPS-treated lenses (P=0.004). Genera diversity of lens-adherent microbiome showed a significant increase in MPS-treated lenses compared with peroxide (P=0.038). Abundance of Corynebacterium, Haemophilus, and Streptococcus were increased 4.3-, 12.3-, and 2.7-fold, respectively, in the MPS group compared with peroxide (P=0.014, 0.006, 0.047, respectively).Commensal, environmental, and pathogenic bacteria known to be present in the conjunctival microbiome can be detected on worn contact lenses. Although most contact lenses worn by asymptomatic wearers harbor bacterial DNA, compared with peroxide, lenses stored in a PHMB-preserved MPS have more quantifiable, abundant, and diverse bacterial communities adherent to them.

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.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.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).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.

PURPOSE This study hypothesized that a traditional high-water contact lens of moderate oxygen transmissibility (Dk/t) is noninferior to common silicone hydrogel (SH) lenses worn for daily wear with respect to measures of hypoxic stress. METHODS Thirty-six habitual contact lens wearers completed wear of three lens types worn in a randomized order: etafilcon A (ACUVUE 2, control), lotrafilcon B (Air Optix Aqua), and comfilcon A (Biofinity). Central corneal thickness (CT) and limbal hyperemia were measured >2 hr after waking and after 6 to 8 hr of wear on days 1 and 7. Endothelial bleb formation was measured on day 1 of each lens type. Noninferiority of etafilcon A, with respect to the other two lens types, was assumed if the following difference margins of equivalence were met

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.

Background Few studies have investigated metabolic complications in HIV-infected African children and their relation with inflammation. Methods We compared baseline and changes in insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)] and in markers of inflammation over 48 weeks, in a subset of antiretroviral therapy (ART)-naive Ugandan children from the Children with HIV in Africa-Pharmacokinetics and Adherence/Acceptability of Simple Antiretroviral Regimens trial randomized to zidovudine-, stavudine- or abacavir (ABC)-based regimen. Nonparametric methods were used to explore between-group and within-group differences, and multivariable analysis to assess associations of HOMA-IR. Results One-hundred eighteen children were enrolled, and median age (interquartile range) was 2.8 years (1.7-4.3). Baseline median HOMA-IR (interquartile range) was 0.49 (0.38-1.07) and similar between the arms. At week 48, median relative changes in HOMA-IR were 14% (-29% to 97%) in the zidovudine arm, -1% (-30% to 69%) in the stavudine arm and 6% (-34% to 124%) in the ABC arm (P ≤ 0.03 for all the arms compared with baseline, but P = 0.90 for between-group differences). Several inflammation markers significantly decreased in all study arms; soluble CD14 increased on ABC and did not change in the other 2 arms. In multivariate analysis, only changes in soluble CD163 were positively associated with HOMA-IR changes. Conclusions In ART-naive Ugandan children, HOMA-IR changed significantly after 48 weeks of ART and correlated with monocyte activation.

Purpose To assess corneal epithelial microstructure via confocal microscopy and determine if cellular changes are associated with lens care solutions during daily wear of silicone hydrogel contact lenses. Methods Corneal in vivo confocal microscopy with the Nidek ConfoScan4 was performed at baseline and after 5 months of lotrafilcon A daily contact lens wear. Enrolled participants were randomized to use either a polyhexamethylene biguanide (PHMB) preserved multipurpose care solution (MPS) or a peroxide based solution system. Lens and storage case bioburden were assessed with aerobic culture methods. Univariate and multivariable analyses were done to evaluate the association between solution use, or solution-related clinical covariates, and morphologic differences (hyper-reflectivity) in the superficial epithelial cells and epithelial basal cell density. Results Data on 139 participants were available for analysis of superficial epithelial cells while data on 92 participants were available for epithelial basal cell density. Five months after randomization to the solution groups, 33% of participants had visible hyper-reflective cells. More participants using MPS had ≥1 hyper-reflective cells compared to peroxide users at 5 months (44% vs. 22%; p=0.006). Similarly at 5 months, more participants with solution-induced corneal staining (SICS) had ≥1 hyper-reflective cells compared to non-SICS participants (57% vs. 29%; p=0.010). The adjusted odds ratios (ORs) for risk of presenting with hyper-reflective cells in MPS users or SICS participants was 2.7 (95% CI; 1.27–5.65) and 3.4 (95% CI; 1.29–8.97), respectively. Basal cell density decreased by over 350 cells/mm 2 over time (about 6%) in participants who had substantial bioburden on their lenses or in their storage case. Conclusion The confocal microscope can detect epithelial cellular changes in vivo during contact lens wear. Hyper-reflective superficial epithelial cells are associated with a PHMB preserved solution and decreases in basal epithelial cell density may be associated with bacterial bioburden.

Objectives Fall assessment tools are commonly used to evaluate the likelihood of fall. For patients found to be at high risk, patient-specific fall prevention interventions are implemented. The purposes of this study were to describe the population, evaluate and compare the efficacy of fall assessment tools, and suggest the best use for these tools in hospice. Methods Data were downloaded from the electronic medical record for all patients who were admitted to and died in hospice care in 2013. Variables included demographic, clinical and initial fall assessment scores that had been computed on admission to hospice care, using our standard fall assessment tool. To facilitate comparison among three tools, additional fall assessment calculations were made for each patient using the Morse Fall Scale and MACH-10, two tools commonly used in a variety of healthcare settings. Results Data were available for 3446 hospice patients. Female patients were less likely to fall than males; Fallers lived longer than Nonfallers; and patients with a primary dementia diagnosis fell 10 days sooner than those with a primary non-dementia diagnosis. A comparison of three fall assessment tools revealed that no tool had a good positive predictive value, but each demonstrated a good negative predictive value. Conclusions Fall assessment scores should not be used as the sole predictor of likelihood of fall, and are best used as a supplement to clinical judgement. Patients with a primary dementia diagnosis are likely to fall earlier in their hospice care than those with other primary diagnoses.

The clinical extent of psoriasis pathology is regulated in part by defects in immune networks, including a defect in the suppressive actions of regulatory T cells. Recently, CD14(+) HLA-DR(-/low) monocytic myeloid-derived suppressor cells (Mo-MDSCs) have been shown to suppress T-cell activation as one of their suppressive mechanisms. However, little is known about the role of Mo-MDSCs and their functional relationship to T-cell suppression in relation to human chronic immune-mediated inflammatory diseases, including psoriasis. Despite psoriasis being a hyperinflammatory condition, Mo-MDSCs were elevated in psoriatic patient peripheral blood mononuclear cells compared to nonpsoriatic healthy controls (2.6% vs. 0.9%, P0.002). Freshly isolated psoriatic Mo-MDSCs directly suppressed CD8 T-cell proliferation less efficiently than healthy control Mo-MDSCs. In addition, psoriatic Mo-MDSCs expressed reduced surface expression of programmed cell death protein 1 compared to healthy controls. Additional in vitro assays also demonstrated that psoriatic and control Mo-MDSCs both induce regulatory T-cell conversion from naïve T effector cells, but, importantly, the regulatory T cells induced by psoriatic Mo-MDSCs displayed decreased suppressive functionality. These results suggest that aberrations in psoriatic Mo-MDSCs prevent proper suppression of effector T-cell expansion and hamper the immune system's ability to correctly self-regulate.

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.

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.

OBJECTIVE To determine the relationships between Kruppel-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.

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.

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.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.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.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.

Objective HIV-infected participants are at a higher risk for cardiovascular disease (CVD). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a significant predictor of CVD in the general population and is associated with mortality in HIV. Design and methods The 96-week Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV (SATURN-HIV) trial randomized 147 patients on stable antiretroviral therapy with low-density lipoprotein-cholesterol level lower than 130 mg/dl and without overt heart failure to 10 mg daily rosuvastatin or placebo. We measured NT-proBNP levels by enzyme-linked immunosorbent assay (ELISA). Baseline and changes in NT-proBNP were compared between groups. Spearman correlation was used to explore relationships between baseline NT-proBNP, inflammation, and CVD risk markers. Multivariable analyses were conducted to assess associations with NT-proBNP levels. Results Median age was 46 years, 80% were men, 69% were African American, and 46% were on protease inhibitors. At baseline, median (Q1, Q3) NT-proBNP was higher in the rosuvastatin group than placebo [41 (20, 66.5) versus 25 pg/ml (11, 56), P = 0.012)]. Baseline NT-proBNP correlated with bulb and common carotid artery intima-media thickness, coronary calcium score, interleukin 6, and cystatin C. After 96 weeks, median NT-proBNP decreased significantly in the rosuvastatin group versus placebo (-1.50 versus +4.50 pg/ml, P = 0.041). Within the rosuvastatin group, changes in NT-proBNP were negatively correlated with changes in insulin resistance and total limb fat. Conclusion Rosuvastatin reduces plasma NT-proBNP in HIV-infected participants on antiretroviral therapy. NT-proBNP correlated with several measures of CVD risk, independent of inflammation markers.

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

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.

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.

Objectives HIV-infected patients on antiretroviral therapy (ART) have an increased cardiovascular disease (CVD) risk as a result of heightened inflammation and immune activation, despite at times having normal lipids and few traditional risk factors. Biomarkers are needed to identify such patients before a clinical event. Lipoprotein-associated phospholipase A2 (Lp-PLA2) predicts CVD events in the general population. This study investigated the relationship between Lp-PLA2 and markers of CVD risk, systemic inflammation, immune activation, and coagulation in HIV infection. Methods One hundred subjects on stable ART with normal fasting low-density lipoprotein (LDL) cholesterol were enrolled in the study. Plasma Lp-PLA2 concentrations were measured by enzyme-linked immunosorbent assay (ELISA; > 200 ng/mL was considered high CVD risk). Subclinical atherosclerosis, endothelial function, inflammation, immune activation and fasting lipids were also evaluated. Results The median age of the patients was 47 years and 77% were male. Median (range) Lp-PLA2 was 209 (71–402) ng/mL. Fifty-seven per cent of patients had Lp-PLA2 concentrations > 200 ng/mL. Lp-PLA2 was positively correlated with soluble markers of inflammation or immune activation (tumour necrosis factor receptor-II, intercellular and vascular cellular adhesion molecules, and CD14; all R = 0.3; P

Inflammation and immune activation may contribute to the progression of cardiovascular disease (CVD) in the general population [1, 2]. Patients infected with the human immunodeficiency virus (HIV) appear to have a greater risk for CVD than uninfected controls [3–6], and within HIV-infected subjects, markers of inflammation, immune activation, and coagulation are associated with mortality, HIV disease progression, vascular disease, and diabetes [7–11]. The drivers of increased inflammation and cardiovascular risk in HIV disease remain unclear, but have been attributed to coinfections with agents such as cytomegalovirus [12], to persistence of HIV replication in sanctuary sites [13], by exposure to bioactive lipids [14–16], to homeostatic cytokines [17], and to microbial elements translocated through a damaged gut [18]. Activated monocytes may contribute to inflammation and cardiovascular disease [19]. Three monocyte subsets can be identified based on CD14 and CD16 expression [20–23]. Traditional (CD14+CD16−) monocytes engulf and present antigen. Patrolling (CD14DimCD16+) monocytes home to the vascular endothelium and recognize viral products; inflammatory (CD14+CD16+) monocytes produce high levels of inflammatory cytokines in response to bacterial products [22]. Proportions of monocytes from HIV-infected donors, and uninfected donors who have recently had an acute coronary event, are enriched for patrolling and inflammatory monocytes, and these cells have a procoagulant phenotype [24]. Soluble CD14 (sCD14), a marker of monocyte activation, is an independent predictor of mortality in HIV-infected subjects [9] and has been linked to faster vascular disease progression, as measured by carotid intima-media thickness [25]. Similarly, the macrophage activation marker soluble CD163 (sCD163) is associated with noncalcified plaques in the coronary arteries [26] and with arterial inflammation in HIV-infected subjects [27]. These markers provide a link between myeloid cell activation and cardiovascular risk in HIV disease. Identifying successful therapies that would reduce chronic immune activation in treated HIV disease is an ongoing research priority. Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects beyond those related to cholesterol lowering [28, 29]. Several statin studies have been performed in HIV-infected subjects, but most were aimed at the effects of statins on lipid levels and on HIV viremia [30–34]. Recently, administration of high-dose atorvastatin (80 mg) modestly reduced the proportion of HLA-DR–expressing CD8+ T cells in HIV-infected subjects who were not receiving antiretroviral therapy (ART) [35]. In our current study, the Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial, HIV-infected subjects who were undergoing successful ART and had normal low-density lipoprotein (LDL) cholesterol levels, but elevated levels of inflammation and immune activation, were randomized to receive rosuvastatin (10 mg daily) or placebo. We present the results of a prespecified secondary analysis aimed at assessing the effects of statin administration on markers of immune activation and inflammation, including plasma levels of monocyte/macrophage activation markers (sCD14 and sCD163), and proportions of activated T cells and monocytes.

HIV-infection is characterized by chronic immune activation that persists despite effective antiretroviral therapy (ART) and is associated with elevated cardiovascular risk. Whether specific perivascular fat depots are associated with inflammation in HIV is unknown.In a cross-sectional study, epicardial (EAT) and thoracic periaortic (TAT) adipose tissue volumes were measured by computed tomography in 100 HIV-infected adults, on stable ART, with LDL-cholesterol ≤130 mg/dL and evidence of heightened T-cell activation (CD8+CD38+HLA-DR+ ≥19%) or increased inflammation (high sensitivity C-reactive protein ≥2 mg/L).Overall, 77% were males and 70% African American. Mean (standard deviation) age and body mass index were 47 (10) years and 28 (6.4) kg/m(2), respectively. All subjects had HIV-1 RNA1000 copies/mL with mean (standard deviation) CD4+ T cell count of 665 (280) cells/μL; 50% were on a protease inhibitor. EAT and TAT were correlated with each other (r = 0.766, p0.0001). Both were associated with metabolic syndrome, atherogenic lipid profile, insulin resistance, total and central body fat, serum biomarkers of inflammation, and soluble CD163, but not with cellular immune activation markers. In multivariable models that adjusted for age, sex, and other measures of adiposity, both perivascular fat depots were independently associated with the presence of coronary calcium.Perivascular fat is associated with soluble CD163, biomarkers of inflammation, insulin resistance, and subclinical atherosclerosis in this population of virologically suppressed HIV-infected patients on ART. The association of perivascular fat with coronary artery calcification appears to be independent of other measures of adiposity.

We examined the relationship between plasma adipokine concentrations and ultrasound measures of vascular health in 100 HIV-infected adults on antiretroviral therapy. Leptin was positively correlated with flow-mediated dilation of the brachial artery and negatively with carotid intima–media thickness. These relationships were independent of traditional risk factors and trunk fat in women but not men. Neither adiponectin nor resistin was associated with either measure of vascular health.

Purpose To determine whether mucin ball (MB) formation is protective against corneal infiltrative events (CIEs) as previously reported. Methods Two hundred eighty-two eligible participants were enrolled at three sites in the USA. Participants began a 1-month continuous wear run-in period with high modulus lotrafilcon A lenses to assess their ability to form MBs (phase 1). Subsequently, they were stratified by this characteristic and randomized to balafilcon A or comfilcon A lenses for 7-day extended wear and followed for 1 year (phase 2). MB formation in each phase was defined as repeated presence of any MBs on a person level. Multivariable Cox proportional hazards regression was used to model the probability of a CIE as a function of MB formation in each phase and other covariates. Results Of the 282 participants who entered phase 1, 218 of them entered the phase 2 randomized trial during which 33 CIEs occurred. Overall, 74%, 61%, and 79% of participants repeatedly produced MBs in lotrafilcon A, balafilcon A, and comfilcon A lenses, respectively. Early repeated MB presence in phase 1 with lotrafilcon A lenses significantly increased the rate of CIEs in phase 2 (12-month follow-up) by 466% (HR 4.66, 95% confidence interval 1.10-19.79, P = .0372). Repeated, longer-term MB presence during wear of balafilcon A or comfilcon A in phase 2 did not significantly reduce the incidence of CIEs; however, it significantly decreased the rate of CIEs by 62% (hazard ratio (HR) 0.380, 95% confidence interval 0.145-0.998, P = .0494). Conclusions The overarching hypothesis that MB formation is protective against CIEs throughout extended wear was not supported. Although a protective effect of longer-term MB presence on rate of CIEs was detected, early-onset MB formation substantially increased the hazard for CIE in subsequent wear with different lens types.

OBJECTIVE To explore the relationships between lymphocyte and monocyte activation, inflammation, and subclinical vascular disease among HIV-1 infected patients on antiretroviral therapy.

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 log 10 number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log 10 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 log 10 CFU/ml sputum/day; 95% confidence interval [CI], −0.193, −0.133 log 10 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.)

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

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.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.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.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].Twenty-four weeks of 10 mg daily rosuvastatin decreases CoQ10 concentration and increases CoQ10/LDL ratio in HIV-infected patients on 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 (p0.29) 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.

Abacavir has been associated with myocardial infarction in several studies. This may be related to inflammation and endothelial cell activation. We compared changes in inflammation and endothelial activation markers between antiretroviral-naive adults initiating zidovudine, lamivudine, abacavir, and nonnucleoside reverse transcriptase inhibitor (NNRTI) or this regimen without abacavir. Changes in soluble tumor necrosis factor receptors-I, -II (sTNFR-I, -II), high sensitivity C-reactive protein, and soluble vascular cell adhesion molecule-1 (sVCAM-1) from baseline (pre-ART) to a second time point about 24 weeks after initiating antiretroviral therapy (ART) were compared between groups using multivariable linear regression. A total of 37 met eligibility criteria; 12 received abacavir. The median (interquartile range) age was 37 years (27-45). Most were men (32/37), African-American (15/37), or white (15/37). The median nadir CD4(+) and baseline HIV-1 RNA were 230 cells/mm(3) (180-301) and 82,642 copies/ml (34,400-204,703). In all, 15/30 smoked, 7/37 had hypertension, 1/37 had diabetes, and 1/37 had hyperlipidemia. None had coronary or renal disease. Changes in CD4(+) and HIV-1 RNA level and timing of stored samples with regard to ART initiation were not different between groups. In univariable analysis, log transformed percent change in sTNFR-I (p=0.05) and -II (p=0.04) showed significant between-group differences and trended toward significance for sVCAM-1 (p=0.08). These markers decreased less in the abacavir group. After adjustment for confounders, significantly less decrease for sTNFR-II and sVCAM-1 was seen for those receiving the abacavir-containing regimen. When taken with an NNRTI, abacavir induced a smaller decrease in inflammation biomarkers in this cohort, suggesting a possible proinflammatory effect of this nucleoside analogue.

Background and Purpose— Compared with normotensive individuals, there is a higher incidence of stroke in patients with hypertensive, as well as prehypertensive, blood pressure levels (ie, 120–139/80–89 mm Hg). Although several studies have shown that blood pressure reduction in hypertensive patients reduces the incidence of cardiovascular events, including stroke, it is still unknown whether treatment of prehypertensive blood pressure levels has a similar effect. We sought to determine whether reduction in blood pressure in the prehypertensive range reduces the incidence of stroke by performing a meta-analysis of randomized trials comparing an antihypertensive drug against placebo in cohorts with prehypertensive baseline blood pressure levels. Methods— Randomized controlled trials performed with the 95 different antihypertensive agents available in the market were identified using MEDLINE, returning a total of 2852 results. Exclusion criteria included: average blood pressure of ≥140/90 mm Hg at baseline, crossover studies, and lack of a control group receiving placebo. Results— A total of 16 trials involving 70 664 patients were included. Patients randomized to the active treatment arm had a statistically significant 22% reduction in the risk of stroke compared with placebo, with little heterogeneity among the trials (I 2 , 18.0%; RR, 0.78 [95% CI, 0.71–0.86]; P Conclusions— The risk of stroke is significantly reduced with antihypertensive therapy in cohorts with prehypertensive blood pressure levels. These findings can have important clinical implications.

The renin-angiotensin system is an important mediator of tumor progression and metastasis. A recent meta-analysis of randomized controlled trials reported an increased risk of cancer with angiotensin receptor blockers. It is unknown whether angiotensin-converting enzyme (ACE) inhibitors may have a similar effect. Our primary objective was to determine the effect of ACE inhibitors on cancer occurrence and cancer death. Our secondary objective was to determine the effect of ACE inhibitors on occurrence of gastrointestinal (GI) cancers given previous concerns of increased risk. Systematic searches of SCOPUS (covering MEDLINE, EMBASE, and other databases) and the Food and Drug Administration official web site were conducted for all randomized controlled trials of ACE inhibitors. Trials with ≥1 year of follow-up and enrolling a minimum of 100 patients were included. Fourteen trials reported cancer data in 61,774 patients. This included 10 trials of 59,004 patients providing information on cancer occurrence, 7 trials of 37,515 patients for cancer death, and 5 trials including 23,291 patients for GI cancer. ACE inhibitor therapy did not have an effect on occurrence of cancer (I(2) 0%, risk ratio [RR] 1.01, 95% confidence interval [CI] 0.95 to 1.07, p = 0.78), cancer death (I(2) 0%, RR 1.00, 95% CI 0.88 to 1.13, p = 0.95), or GI cancer (RR 1.09, 95% CI 0.88 to 1.35, p = 0.43). In conclusion, ACE inhibitors did not significantly increase or decrease occurrence of cancer or cancer death. There was also no significant difference in risk of GI cancer.

Summary Background Angiotensin-receptor blockers (ARBs) are a widely used drug class approved for treatment of hypertension, heart failure, diabetic nephropathy, and, recently, for cardiovascular risk reduction. Experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis, and tumour progression. We assessed whether ARBs affect cancer occurrence with a meta-analysis of randomised controlled trials of these drugs. Methods We searched Medline, Scopus (including Embase), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the US Food and Drug Administration website for studies published before November, 2009, that included any of the seven currently available ARBs. Randomised controlled trials with an ARB given in at least one group, with a follow-up of at least 1 year, and that enrolled at least 100 patients were included. New-cancer data were available for 61 590 patients from five trials. Data on common types of solid organ cancers were available for 68 402 patients from five trials, and data on cancer deaths were available for 93 515 patients from eight trials. Findings Telmisartan was the study drug in 30 014 (85·7%) patients who received ARBs as part of the trials with new cancer data. Patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7·2% vs 6·0%, risk ratio [RR] 1·08, 95% CI 1·01–1·15; p=0·016). When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1·11 (95% CI 1·04–1·18, p=0·001). Among specific solid organ cancers examined, only new lung-cancer occurrence was significantly higher in patients randomly assigned to receive ARBs than in those assigned to receive control (0·9% vs 0·7%, RR 1·25, 1·05–1·49; p=0·01). No statistically significant difference in cancer deaths was observed (1·8% vs 1·6%, RR 1·07, 0·97–1·18; p=0·183). Interpretation This meta-analysis of randomised controlled trials suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug. These findings warrant further investigation. Funding None.

Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients.To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months.This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment.Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10).Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.

Background. Large-scale, government-based antiretroviral therapy (ART) programs in rural areas of resource-poor countries remain largely unevaluated. Methods. We conducted a retrospective review of all patients receiving ART (n = 399) to assess survival and retention in care and a prospective evaluation of patients on ART for at least 6 months (n = 175). We used 3-day self-report to measure adherence. Results. The probability (95% confidence interval [CI]) of surviving and remaining in care was 0.76 (0.72, 0.81) at 1 year. Men and patients with advanced disease were more likely to die or be lost to follow-up. At baseline, 149 (85%) reported 100% adherence. Nonadherence was associated with lack of suppression of viral replication (odds ratio [OR] = 4.5; 95% CI: 1.8, 11.5). Missing a scheduled clinic visit and lack of disclosure of HIV status were associated with nonadherence. Conclusion. Viral suppression was high, but counseling to include HIV disclosure to family and keeping scheduled clinic appointments may improve long-term adherence and treatment outcomes.

Linezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis.To evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis.Randomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid (300 mg daily) and linezolid (600 mg twice daily or 600 mg once daily) for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and the last 5 days of study drug administration (extended early bactericidal activity).The mean early bactericidal activity of isoniazid (0.67 log10 cfu/ml/d) was greater than that of linezolid twice and once daily (0.26 and 0.18 log10 cfu/ml/d, respectively). The extended early bactericidal activity of linezolid between Days 2 and 7 was minimal.Linezolid has modest early bactericidal activity against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended early bactericidal activity. Clinical trial registered with www.clinicaltrials.gov (NCT00396084).

Background: Chronic kidney disease and its concomitant sequelae represent a major public health problem. Recent data suggest periodontal infection contributes to chronic kidney disease.Methods: This United States population–based study of 4,053 adults ≥40 years of age investigated the association between chronic kidney disease and clinical measures and serologic markers of periodontal infection. Chronic kidney disease was defined as moderate-to-severe reduction of kidney function with glomerular filtration rate of 15 to 59 ml/minute/1.73 m2 based on stages 3 and 4 of the Kidney Disease Outcome Quality Initiative. Chronic oral inflammatory burden was measured as 1) clinical periodontal infection categorized as no periodontal disease, periodontal disease (at least one tooth with ≥4 mm loss of attachment and bleeding on probing as an indicator of inflammation), or edentulism and 2) serum immunoglobulin G antibody response to Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomita...

This study assessed predictive values of self-reported periodontal need to identify periodontal conditions using clinical examinations as the gold standard.We identified 12,370 adultsor = 18 years of age in the third National Health and Nutrition Examination Survey. Self-reported periodontal need was based on participants responding that gum treatment and/or cleaning was needed when asked: "What type of dental care do you need now?" Two periodontal conditions were at least two sites with pockets (pocketsor = 3 mm or pocketsor = 4 mm) and at least two sites with calculus. Main outcomes were: 1) positive predictive value (PPV(Clean)): proportion of those who self-reported the need for cleaning who had calculus; and PPV(Gum): proportion who self-reported the need for gum treatment who had pockets; 2) negative predictive value (NPV(Clean)): proportion of those who self-reported no need for cleaning who did not have calculus; and NPV(Gum): proportion who self-reported no need for gum treatment who did not have pockets; 3) association between predictive values and sociodemographic and behavioral characteristics; and 4) proportion of individuals with specific sociodemographic and behavioral characteristics whose self-reported periodontal need predicted periodontal conditions.The prevalence of periodontal conditions influenced predictive values. Calculus prevalence = 85%: corresponding PPV(Clean) = 88% and NPV(Clean) = 16%. Prevalence of pocketsor = 3 mm = 47%: corresponding PPV(Gum) = 62% and NPV(Gum) = 54%. Prevalence of pocketsor = 4 mm = 11%: corresponding PPV(Gum) = 25% and NPV(Gum) = 90%. Ninety percent of 30- to 44-year-old minority female smokers who did not visit the dentist in the past year and reported the need for gum treatment had pocketsor = 3 mm (PPV(Gum) = 90%).Self-reported periodontal need (cleaning/gum treatment) predicted the presence of the prevalent conditions (calculus/pocketsor = 3 mm). Not reporting a need for periodontal treatment predicted the absence of the less common condition (pocketsor = 4 mm) but not the more prevalent condition (calculus).

The purpose of this study is to examine the relationship of height, Apolipoprotein E genotype (APOE) and Alzheimer's disease (AD). Using a case-control design, subjects were recruited from the research registry of the University Memory and Aging Center of Case Western Reserve University and University Hospitals of Cleveland. On entry to the study, height was measured on 239 probable or possible AD patients and 341 healthy controls living in northeast Ohio. Risk of AD was modeled as a function of quartile of height, APOE genotype, years of education and year of birth. Analyses were stratified by gender. For men, cases were more likely to be shorter when compared to controls (p=0.001). There was only a small difference in mean height between AD cases and controls among women (p=0.05). For men, height in the highest quartile [>179.7 cm (70.75 in)] had a 59% lower risk of developing AD that in the lowest quartile [< 169.5 cm (66.75 in)], controlling for year of birth, and education (p=0.03). For women without an APOE epsilon4 allele, increasing height was associated with lower risk for AD (OR=0.88; p=0.01) but no significant association was found for women with at least one epsilon4 allele (OR=1.03; p=0.56).

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+Ly6Chigh 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

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.

The purpose of this clinical trial was to evaluate the effect of estrogen supplementation on bone mineral density in adolescent girls who received depot medroxyprogesterone acetate for contraception.One hundred twenty-three adolescents who began receiving depot medroxyprogesterone acetate injections every 12 weeks were assigned randomly to receive monthly injections of estradiol cypionate or placebo. The main outcome was bone mineral density that was measured by dual energy x-ray absorptiometry for 12 (n = 69) to 24 (n = 36) months. Participants, technicians, and physicians were blinded to estrogen treatment.Over the 24-month period, the percentage of change from baseline bone mineral density at the lumbar spine was 2.8% in the estradiol cypionate group versus -1.8% in the placebo group ( P.001). At the femoral neck, the percentage of change from baseline bone mineral density was 4.7% in the estradiol cypionate group versus -5.1% in the placebo group ( P.001).Our results suggest that estrogen supplementation is protective of bone in adolescent girls who receive depot medroxyprogesterone acetate injections.

Purpose To conduct a longitudinal comparison of bone mineral density (BMD) in 370 adolescent girls, aged 12–18, who self-selected depot medroxyprogesterone acetate (DMPA) or an oral contraceptive (OC) containing 20μg ethinyl estradiol/100μg levonorgestrel with that in girls who received no hormonal treatment (control group). Methods Lumbar spine and femoral neck BMD measurements were obtained by dual energy x-ray absorptiometry at baseline and 12 months. Data were analyzed with repeated measures analysis of covariance methods. Results Over 12 months, lumbar spine BMD decreased in the DMPA group (n = 29), with a mean percent change of −1.4% (95% confidence interval [CI] −2.73, −0.10), and increased by a mean of 3.8% (95% CI 3.11, 4.57) in the control group [n = 107 ( p p = .03). Over 12 months, the mean percent change in femoral neck BMD was −2.2% (95% CI −3.95, −0.39) in the DMPA group, but increased 2.3% (95% CI 1.29, 3.27) in the control group ( p p = .03). Conclusions Our study contributes to an increasing body of knowledge indicating a negative impact of DMPA on bone health in young women. Additional findings suggest a potential adverse effect of an OC containing 20 μg ethinyl estradiol/100 μg levonorgestrel on bone health in adolescents.

Background. To estimate the effect size of tuberculosis preventive therapy (PT) on the public health problem of tuberculosis in contemporary sub-Saharan Africa. Methods. A compartmental flow model that considers high levels of tuberculosis and human immunodeficiency virus (HIV) infection in contemporary sub-Saharan Africa was used to assess the impact of PT on the prevalence of tuberculosis and tuberculosis-associated mortality. Results. Model implementation shows that giving PT to 25% of HIV-positive individuals with latent tuberculosis infection (LTBI) leads to a 3.9% reduction in the prevalence of tuberculosis in 10 years and a 5.1% reduction in 20 years. This intervention also prevents a cumulative total of 3.0% of tuberculosis-associated deaths in a decade and 5.5% in two decades. Doubling PT coverage to 50% approximately doubles the effect size, suggesting a linear relationship within the 20-year period. The effect size is slightly sensitive to changes in level of HIV transmission, level of tuberculosis transmission, and level of case detection and treatment cure rates in the population. Conclusions. Contrary to suggestions by previous authors that PT can significantly reduce the public health problem of tuberculosis in sub-Saharan Africa, this model-based analysis suggests that the impact of PT on tuberculosis in the population is likely to be small.

Testing new drugs is critical to improving the treatment of tuberculosis. Quantitative cultures of Mycobacterium tuberculosis on solid media have been used in Phase 1 and 2 trials, but are time and resource intensive. Time to detection (TTD) of growth of M. tuberculosis in automated liquid culture systems is an alternative. TTD has been shown to correlate with CFU in quantitative cultures, and is faster and simpler to perform. We compared TTD in the BACTEC 460 liquid culture system with CFU in a clinical trial that included 110 subjects. Comparing all sputum cultures collected between baseline and 2 months we found a strong negative correlation between log(10) CFU and TTD (rho = -0.91). In addition, when TTD at baseline was compared with 1 and 2 month sputum culture positivity, subjects whose cultures were negative after 1 and 2 months had a significantly longer median baseline TTD compared with subjects whose cultures were positive at 1 and 2 months (5 vs. 3 days and 3 vs. 2 days, respectively). TTD compares closely with CFU and represents a faster, simpler alternative to quantitative cultures.