Circulating mediators of inflammation and immune activation in AIDS-related non-Hodgkin lymphoma

Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods: This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed beadbased immunoassays. Results: A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions: These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease. © 2014 Nolen et al

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2–5.3) and IL-6 (OR; 95% CI: 2.6; 1.03–6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2–6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3–5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1–3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1–4.2)

Relationship between patients' and clinicians' assessments of health status before and after knee arthroplasty.

INTRODUCTION: The use of patient reported outcome measures (PROMs) for four elective operations is mandatory in the English NHS from April 2009. In view of some scepticism by some clinicians as to the validity of PROMs, our aim was to explore the relationship between patients' and clinicians' reports of health status before and after knee arthroplasty. METHODS: A secondary analysis of linked data from the Knee Arthroplasty Trial (patients' reports using the Oxford Knee Score) and the Tayside Arthroplasty Audit (clinicians' reports using the American Knee Society Score--Knee Score and Functional Score) was carried out. Correlations of scores were obtained for 284 patients before and 226 patients after surgery. RESULTS: There was a moderately strong correlation between patients' and clinicians' views 1 year after surgery: Oxford Knee Score (OKS) versus American Knee Society Scores (AKSS) Knee Score r = -0.64; OKS versus AKSS Functional Score r = -0.44. Before surgery, the correlation between the OKS and the AKSS Functional Score was also moderate (r = -0.55) but was weak with the Knee Score (r = -0.23). There was no systematic direction to the differences between patients' and clinicians' assessments; patients were just as likely to report better health than their clinician as to report worse health. DISCUSSION: Patients' postoperative assessments following knee arthroplasty, as regards their symptoms and disability, are practical to collect and can make a meaningful and useful contribution in routine use. In view of the advantages of collecting data on symptoms and disability directly from patients-lower cost, higher response rates, avoidance of systematic biases-confirmation of a moderately strong association with clinicians' views offers further reassurance for the routine use of PROMs, at least with knee arthroplasty

What is the relationship between patients' and clinicians' reports of the outcomes of elective surgery?

OBJECTIVES: To identify studies in which patients' and clinicians' reports of health status and complications of one of four elective operations - hip and knee replacement, varicose vein surgery and groin hernia repair - are reported, and to describe the associations that have been reported between clinicians' and patients' reports. METHODS: Systematic search of several bibliographic databases and review of citations of articles meeting inclusion criteria. A narrative summary of the findings was conducted. RESULTS: Most of the 62 studies of health status identified were for hip (23) or knee (33) disease. The literature on complications was even more limited with 12 studies of surgical site infection, one for urinary tract infection and none for lower respiratory tract infections. Procedure-specific complications were restricted to one for arthroplasties and three for hernia repair. Despite considerable variation in the findings of studies, some clear patterns emerge, albeit they are largely based on arthroplasty. Patients' and clinicians' views of health status generally correlate moderately (0.5-0.6) when both are reporting on the same dimension of health status. Inevitably this is confined to disability, though patients' and clinicians' reports of symptoms are also moderately correlated. In contrast, comparisons of different dimensions, such as patients' reports of disability and clinicians' reports of impairment, result in poor correlation (0.3). There is huge variation in the way postoperative complications are measured which limits the extent to which an overview can be undertaken. Despite that, moderate to strong correlations have been reported between patients' and clinicians' views of complications. CONCLUSIONS: Patients' views of their level of disability reflect clinicians' views and can be relied upon to assess this dimension of health status. In addition, patients are the 'gold standard' judges of symptoms and quality of life. Given these findings, clinicians, provider managers, commissioners and politicians can be confident that patients' reports provide an accurate indication of the outcome of elective surgery

Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation.

ObjectiveChronic inflammation and B-cell hyperactivation are seen in HIV infection, contributing to an increased risk for the accrual of genetic errors that may result in B-cell lymphoma. The primary objective of this study was to determine the effect of highly active antiretroviral therapy (HAART) on serum levels of molecules that are associated with immune activation and/or inflammation, including several that are associated with B-cell activation, specifically IL-6, sCD30, sCD27, IgG, IgA, CXCL13 (B lymphocyte chemoattractant, BLC), a B-lymphocyte chemokine involved in B-cell trafficking, as well as C-reactive protein, an acute-phase protein.DesignWe used a retrospective cohort study design, measuring serum levels of these markers at each of four 1-year intervals, 2 years before and 2 years after HAART initiation, in a subgroup of 290 HIV-infected men enrolled in the Multicenter AIDS Cohort Study (MACS).MethodsSerum levels of immune activation-associated molecules were measured by ELISA and multiplexed immunometric assays. Reference values were determined by the 5th to 95th percentiles from a sample of 109 HIV-uninfected MACS men.ResultsHAART use was associated with a reduction, but not normalization, of most biomarkers tested. Serum levels of IL-6 and C-reactive protein appeared to be unaffected by HAART.ConclusionsThese results suggest a partial normalization of serum cytokine levels post HAART. However, a chronic state of B-cell hyperactivation continues 2-3 years after HAART initiation. These findings may explain, in part, the excess incidence of lymphoma still occurring in HIV-infected persons in the post-HAART era

Temporal Stability of Serum Concentrations of Cytokines and Soluble Receptors Measured Across Two Years in Low-Risk HIV-Seronegative Men

BackgroundProspective cohort studies often quantify serum immune biomarkers at a single time point to determine risk of cancer and other chronic diseases that develop years later. Estimates of the within-person temporal stability of serum markers partly assess the utility of single biomarker measurements and may have important implications for the design of prospective studies of chronic disease risk.MethodsUsing archived sera collected from 200 HIV-seronegative men at three visits spaced over approximately 2 years, concentrations of 14 biomarkers (ApoA1, sCD14, sgp130, sIL-6R, sIL-2Rα, sTNFR2, BAFF/BLyS, CXCL13, IFN-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, and TNF-α) were measured in a single laboratory. Age- and ethnicity-adjusted intraclass correlation coefficients (ICC) were calculated for each biomarker, and mixed linear regression models were used to examine the influence of age, ethnicity, season, and study site on biomarker concentrations.ResultsAcross all three study visits, most biomarkers had ICC values indicating fair to excellent within-person stability. ApoA1 (ICC = 0.88) and TNF-α (ICC = 0.87) showed the greatest stability; the ICC for IL-8 (ICC = 0.33) was remarkably less stable. The ICCs were similar when calculated between pairs of consecutive visits. The covariables did not influence biomarker levels or their temporal stability. All biomarkers showed moderate to strong pairwise correlations across visits.ConclusionsSerum concentrations of most evaluated immune biomarkers displayed acceptable to excellent within-person temporal reliability over a 2-year period. Further investigation may be required to clarify the stability of IL-8.ImpactThese findings lend support to using these serologic immune biomarkers in prospective studies investigating associations with chronic diseases

An algorithm for identifying and classifying cerebral palsy in young children

OBJECTIVE: To develop an algorithm on the basis of data obtained with a reliable, standardized neurological examination and report the prevalence of cerebral palsy (CP) subtypes (diparesis, hemiparesis, and quadriparesis) in a cohort of 2-year-old children born before 28 weeks gestation. STUDY DESIGN: We compared children with CP subtypes on extent of handicap and frequency of microcephaly, cognitive impairment, and screening positive for autism. RESULTS: Of the 1056 children examined, 11.4% (120) were given an algorithm-based classification of CP. Of these children, 31% had diparesis, 17% had hemiparesis, and 52% had quadriparesis. Children with quadriparesis were 9 times more likely than children with diparesis (76% versus 8%) to be more highly impaired and 5 times more likely than children with diparesis to be microcephalic (43% versus 8%). They were more than twice as likely as children with diparesis to have a score \u3c70 on the mental scale of the BSID-II\u3e(75% versus 34%) and had the highest rate of the Modified Checklist for Autism in Toddlers positivity (76%) compared with children with diparesis (30%) and children without CP (18%). CONCLUSION: We developed an algorithm that classifies CP subtypes, which should permit comparison among studies. Extent of gross motor dysfunction and rates of co-morbidities are highest in children with quadriparesis and lowest in children with diparesis

Characteristics of Study Population.

<p>HAART – highly active antiretroviral therapy; HBV/HHV-8 status obtained at time of blood draw; CNS – central nervous system; BL – Burkitt's lymphoma; NOS – not otherwise specified.</p